TECHNICAL REVIEW

The Effects of NMDA Receptor Antagonists and Nitric Oxide Synthase Inhibitors on Opioid Tolerance and Withdrawal Medication Development Issues for Opiate Addiction Barbara H. Herman, Ph.D., Frank Vocci, Ph.D., and Peter Bridge, M.D.

This article is an exploration of the National Institute on dependent rodents also can be inhibited by noncompetitive Drug Abuse (NIDA) Technical Review on the role of NMDA receptor antagonists (MKB0l, DM, ketamine), glutamatergic systems in the development of opiate competitive NMDA receptor antagonists (LY274614), addiction. The effects of "glutamate antagonist" glycine antagonists (felbamate), and NOS inhibitors medications on opioid tolerance and withdrawal are (L-NNA, L-NMMA, L-NAME, L-NIO, 7-NI, MB). examined. In rodents, mu opioid tolerance can be There are some serious toxicological effects associated inhibited by noncompetitive N-methyl D-aspartate with the administration of some of the noncompetitive (NMDA) receptor antagonists [MKB0l, NMDA receptor antagonists in rodent but not in squirrel dextromethorphan (DM), ketamine, phencyclidine monkey brain, and some medications induce PCP-like (PCP)], competitive NMDA receptor antagonists behavioral effects. The medications with the most (LY274614, NPC17742, LY235959), partial glycine immediate clinical appeal are those that could be agonists (ACPC), glycine antagonists (ACEA-1328), and coadministered with methadone to decrease mu opioid nitric oxide synthase (NOS) inhibitors [L-NNA, tolerance and dependence; they include DM, MB, 7-NI, L-NMMA, methylene blue (MB)]. Similarly, some of the ACPC, and ACEA-1328. {Neuropsychopharmacology symptoms of opioid withdrawal observed in opioid- 13:269-293, 1995]

KEY WORDS: NMDA receptor; Nitrzc oxide; Tolerance; On October 17 and 18, 1994, the National Institute on Withdrawal; Opiate addiction; Morphine Drug Abuse (NIDA) held a technical review entitled, "The Role of Glutamatergic Systems in the Develop­ ment of Opiate Addiction" (B. H. Herman and D. Ma­ From the Medications Development Division, National Institute jewska, chairs). The technical review focused on the on Drug Abuse, National Institutes of Health, Rockville, MD. effects of drugs that block the NMD A receptor complex Address correspondence to Barbara H. Herman, Ph.D., Director, (NMDA-RC) in the process of opioid tolerance and Clinical Opioid Medications Program, Clinical Trials Branch, Medi­ cations Development Division, National Institute on Drug Abuse, withdrawal. There were twelve scientific presentations 5600 Fishers lane, Room 11A55, Rockville, MD 20857. providing an overview of virtually every aspect of this Received question from the molecular biology of glutamate recep­ The opinions expressed herein are the views of the authors and may not necessarily reflect the official policy or position of the Na­ tors to preclinical and clinical investigations examining tional Institute on Drug Abuse or any other part of the U.S. Depart­ the effects of this class of drugs on these aspects of opi­ ment of Health and Human Services. The U.S. government does not ate addiction. The present review summarizes the ma­ endorse or favor any specific commercial product or company. Trade, proprietary, or company names appearing in this publication are used jor findings of some of these presenting scientists and only because they are considered essential in the context of the studies the research of many other investigators. (For further reported. details, refer to some of the individual original research

NEUROPSYCHOPHARMACOLOL \ 'Y

publications and laboratory perspectives provided by drug abusers in the United States, thereby providing these scientists in individual articles in this volume. For a new and powerful impetus for the search for novel recent reviews of the diversity of agents that modify medications for the treatment of opiate addiction (Re­ opioid tolerance and withdrawal see Bhargava 1994; port of the National Commission on AIDS: The Twin Jaffe 1994; Jaffe and Martin 1994; Szekely 1994; for a Epidemics of Substance Abuse and HIV, July 1991). Sec­ brief review of glutamate and opiate addiction, see Her­ ond, in the United States, the cost to society for heroin man et al. 1993). addicts who go untreated is over 10-fold greater than There is evidence from numerous laboratories that individuals who are treated with methadone on an out­ a variety of noncompetitive N-methyl D-aspartate patient basis (NIDA). The overall cost of drug abuse (NMDA) receptor antagonists, competitive NMDA in the United States in 1991 was estimated to be about receptor antagonists, glycine antagonists, and nitric ox­ $100 billion if one includes factors such as the associated ide synthase (NOS) inhibitors can inhibit mu opioid costs of care of addicted infants and the influence of (morphine) tolerance in the rodent (Marek et al. 1991a, drug abuse on the AIDS epidemic (Rice et al. 1991). 1991b; Trujillo and Akil 1991a, 1994; Ben-Eliyahu et al. Therefore, from an ethical, medical, and economic point 1992; Kolesnikov et al. 1992, 1993a, 1993b; Tiseo and of view, it is to the advantage of society to search for Inturrisi 1993; Bhargava and Matwyshyn 1993; Gutstein new medications for the treatment of opiate addiction. and Trujillo 1993; Lufty et al. 1993, 1995; Tiseo et al. Why would it be necessary to develop medications 1994; Babey et al. 1994; Elliott et al. 1994a, 1994b, and beyond methadone for the treatment of opiate addic­ this volume; Bhargava 1995a; Matwyshyn and Bhar­ tion? In fact, besides methadone, a variety of other orally gava 1995; Pasternak et al. this volume; Trujillo this vol­ administered opiate agonists have been shown to be ume). In addition, the potency and clinical potential of effective opiate maintenance medications. These in­ these agents on morphine tolerance are strengthened clude the recently Food and Drug Administration (FDA)­ by the findings of several studies indicating that both approved medication L-alpha-acetylmethadol [LAAM, noncompetitive and competitive NMDA receptor an­ (Ling et al. 1976)] and the recently studied (but not yet tagonists are capable of "reversing" morphine tolerance FDA-approved) medication buprenorphine (Johnson (Tiseo and Inturrisi 1993; Elliott et al. 1994a; see also et al. 1992). The COMP recognizes the value of these Trujillo and Akil 1994). There is also evidence from a opioid against medications for maintenance prior to smaller number of laboratories that some of the symp­ detoxification, but it is doubtful whether another opi­ toms of narcotic antagonist-precipitated opioid with­ oid or yet-untested nonopioid medication will prove drawal observed in rodents exposed in a chronic fash­ superior for this indication. Therefore, the development ion to a mu opioid agonist such as morphine can also of additional opioid medications for the "maintenance" be inhibited by noncompetitive NMDA receptor antag­ of opiate-dependent individuals is no longer a priority onists, competitive NMDA receptor antagonists, gly­ for the COMP. On the other hand, methadone has not cine antagonists, and NOS inhibitors (Koyuncuoglu et proven to be a good medication for preventing the re­ al. 1990; Rasmussen et al. 1991; Tanganelli et al. 1991; lapse to IV-administered opiates in individuals who Trujillo and Akil 1991a; Brent and Chahl 1993; Cappen­ have been medically withdrawn from this medication. dijk et al. 1993; Kimes et al. 1993; Kolesnikov et al. 1993b; Ball and Ross (1991) showed that about 82% of opi­ Vaupel et al. 1995 and in this volume; Kosten et al. this ate-dependent individuals previously maintained on volume; Rasmussen this volume), although other in­ methadone relapse to IV opiates about 1 year follow­ vestigators have failed to obtain significant effects of ing cessation of methadone therapy. Accordingly, the some of these agents on opioid withdrawal (Matwyshyn development of medications that will prevent the re­ et al. 1993; Thorat et al. 1994; Matwyshyn and Bhar­ lapse to IV-administered opiates once medically super­ gava 1995). vised withdrawal from an opiate against has been The mission of the Clinical Opioid Medications Pro­ achieved is the number one priority of the COMP. The gram (COMP) of NIDA is to develop medications for number two priority of the COMP is to develop medi­ the treatment of opiate addiction. The COMP is a pro­ cations that will ameliorate the abstinence agony as­ gram within the Clinical Trials Branch of the Medica­ sociated with opiate withdrawal. In particular, we are tions Development Division (MOD) of NIDA. There is seeking medications with a low side effects profile, at least a twofold rationale for the development of medi­ agents that affect both acute and protracted symptoms cations for the treatment of opiate addiction. First, from of opiate withdrawal and agents that ameliorate both an ethical and medical perspective, there are striking the physical and psychological symptoms of opioid data indicating that orally administered methadone withdrawal. In the United States, the only FDA­ maintenance therapy decreases the mortality of intra­ approved medications for this indication is methadone, venous (IV) heroin abusers about six- to eightfold in although alpha-2-adrenergic agonists are often used "off comparison with untreated abusers (Gronbladh et al. label" for this purpose. The number 3 priority of the 1990). As of 1990, at least 30% of AIDS cases were IV COMP is to develop medications that can be coad- NEUROPSYCHOPHARMACOLOGY 199'i-VOL. 13, NO. 4 Glutamatergic Systems in Opioid Tolerance and Withdrawal 271

ministered with methadone gradually to decrease the The NMDA receptor requires activation via two dependence of the addicted individual to mu opiate agonist sites, one of which blinds glutamate and the agonists and to help the individual achieve the transi­ other one of which binds glycine. Glycine is an obligate tion from opiate agonist to opiate antagonist phar­ coagonist [i.e., activation of the NMDA receptor re­ macotherapy. Of priority for the indications of relapse quires the simultaneous presence of glutamate and gly­ prevention, opiate withdrawal reduction, and decreased cine (Johnson and Ascher 1987; Palfreyman 1994)]. dependency by coadministered nonopiate compounds There are four major types of NMDA receptor an­ is the development of nonopioid medications with lit­ tagonists. Examples of each follow: tle or no abuse liability. The drug classes discussed in 1. Noncompetitive NMDA receptor antagonists. phencycli­ this review (noncompetitive and competitive NMDA dine (PCP), ketamine, MK801 (dizocilpine), dex­ receptor antagonists, glycine antagonists, partial gly­ trorphan, dextromethorphan, ADCI, FPL12495, cine agonists, and NOS inhibitors) all have a significant CNS1102. potential for the treatment of these novel medication indications for opiate addiction. Indeed even beyond 2. Competitive NMDA receptor antagonists. D-2amino-5- opiate addiction, the efficacy of NMDA receptor antag­ phosphovalerate (AP5), 2-amino-7-phosponohep­ onists in inhibiting cocaine self-administration in rats tanoate (AP7), LY274614, LY233536, LY233053, (Pulvirenti et al. 1992) and inhibiting the locomotor CGP40016, CGP43487, cis-4-(phosphonomethyl) potentiating effects of cocaine (Pulvirenti et al. 1991) piperidine-2-carboxylate (CGS19755) 3-(2 carboxy­ suggest that these agents show promise for the treat­ piperazine-4yl)-propylphosphonate (D(-)CPP], D(-)­ ment of cocaine dependency as well. CPPene. 3. Glycine site antagonists (see Baron et al. 1994). ky­ nurenic acid, MDL28469, 5,7-DCKA, MDL 100748, PHARMACOLOGICAL CLASSIFICATION OF MDL 29951, MDL 102288, MDL 100573, quinoxaline­ NMDA RECEPTOR ANTAGONISTS dione (e.g., ACEA-1328), DNXQ, 8-methyl-DDHB, Glutamate receptors are thought to be among the ma­ L-689560 (tetrahydroquinolones), MDL 105572 (3- jor excitatory neurotransmitter systems in mammalian Aryl-4-hydroxy-2-quinolones), 7-CKA, felbamate brain. They are characterized by their molecular biology, (Felbatol), ACPC (partial glycine agonist, see below). pharmacology, and electrophysiology. The best-known 4. Polyamine site antagonists (Scatton et al. 1994). Ifen- of these receptor types are ionotropic or ligand-gated prodil, eliprodil. ion channels that are subtyped into three categories: These pharmacological agents provide a rich array of alpha-amino-3-hydroxy-5-methyl-4 isoxazole propi­ drugs that can be used to address questions onate (AMPA), kainate (KA) receptors, and N-methyl concern­ ing the role of specific sites on the NMDA receptor D-aspartate (NMDA) receptors. More recently, metabo­ and functions modulated by these receptors. tropic glutamate receptors have been identified (Sugi­ yama et al. 1987). (For a review of the molecular biol­ ogy of the cloned glutamate receptors, see Hollmann EFFECTS OF NONCOMPETITIVE NMDA et al. 1989; Boulter et al. 1990; Moriyoshi et al. 1991; RECEPTOR ANTAGONISTS Sommer and See burg 1992; Hollmann and Heinemann 1994). ON OPIOID TOLERANCE Figure 1 provides a diagrammatic presentation of As shown in Table 1, to date there have been at least the NMDA ion-channel receptor complex and its 17 investigations exploring the effects of the noncom­ modulatory sites. (See Palfreyman 1994 for a complete petitive NMDA receptor antagonist MK801 (dizocil­ review of glutamate receptors and their regulators. Also pine), in either morphine tolerance and/or morphine see a review by Meldrum 1994 providing a summary withdrawal in three murine species (guinea pigs, rats, of the pharmacology of the glutamate receptor subtypes mice). Each of the 10 studies examining the effects of and associated antagonists, which is in part summa­ MK801 on morphine tolerance have found that this drug rized in brief below.) As described by Palfreyman (1994), inhibits the development of morphine tolerance, includ­ activation of the NMDA receptor by glutamate (or ing eight studies in rats (Trujillo and Akil 1991a, 1994; NMDA) opens a cation-selective ion channel, and cur­ Marek et al. 1991a, 1991b; Ben-Eliyahu et al. 1992; Bhar­ rent only flows if the membrane is first depolarized and gava and Matwyshyn 1993; Gutstein and Trujillo 1993; the Mg2 + + block removed. The cation channel is read­ Tiseo and Inturrisi 1993) and two studies in mice (Lufty ily permeable to calcium, sodium, and potassium, and et al. 1993a; Elliott et al. 1994b). Each of these studies the influx of any one of these activates the NMDA recep­ in rats have dissociated these effects of tolerance from tor. This activation may initiate prolonged changes in analgesia itself, since the same MK801 dose does not brain function associated with opiate addiction (toler­ appear to affect pain responsiveness itself (i.e., anal­ ance, dependence, craving; see below). gesic or hyperalgesic characteristics when administered 272 B.H. Herman et al NEUROPSYCHOPHARMACOLOGY 1995-VOL. 13, NO. 4

NMDA/Glutamate binding site

Figure 1. NMDA ion­ channel receptor complex and its modulatory sites in the resting state (top) and in the open state (bottom). PCP = phencyclidine. Source: Polyam1ne binding site Phosphorylation site Palfreyman MG, Glutamate receptors and their regula­ tors - an overview. In Pal­ freyman MG, Reynolds IJ, Skolnick P (eds), Direct and allosteric control of glutamate receptors. Boca Raton, FL, CRC Press, 1994, Fig. 1.2. With permission of the au­ thor and the publisher. Activated (Channel opened)

Polyam1ne alone) or to influence the acute analgesic effects of mor­ Webster mice (Lufty et al. 1993) or CD-1 mice (Elliott phine given as a single analgesic dose (Trujillo and Akil et al. 1994b). As indicated in Table 1, more studies are 1991a, 1994; Marek et al. 1991a, 1991b; Ben-Eliyahu et needed to determine whether MK801 is capable of re­ al. 1992; Bhargava and Matwyshyn 1993; Gutstein and versing mu opioid tolerance. Trujillo 1993; Tiseo and Inturrisi 1993). Similarly, MK801 Trujillo and Akil (1991a) and Marek et al. (1991a, when administered alone also does not appear to have and 1991b) were among the first to demonstrate the ca­ nociceptive or antinociceptive effects in either Swiss pacity of MK801 to inhibit morphine tolerance in the NEUROPSYCHOPHARMACOLOGY 199'i-VOL 13, NO. 4 Glutamatergic Systems in Opioid Tolerance and Withdrawal 273

rat (Trujillo et al. this volume). In the Trujillo and Aki! cess (not the expression) of mu opioid tolerance itself (1991a) study this inhibition in tolerance was shown (for noncompetitive drugs, see Trujillo and Akil 1991a; both during the period when MK801 was coadminis­ Ben-Eliyahu et al. 1992; for competitive drugs, see Tiseo tered with morphine and during a 24-hour period sub­ and Inturrisi 1993). In support of this notion, Marek et sequent to MK801 administration. Tolerance was in­ al. (1991b) showed that MK801 could inhibit the devel­ duced by the BID administration of morphine (10 mg/kg opment of morphine tolerance when administered SC) for a period of 9 days, and analgesia was assessed repeatedly as long as 2 hours after each daily injection with the radiant heat tail flick (TF) procedure. There of morphine in rats. (5) A single injection of these four were five major findings of this study. (1) MK801 was noncompetitive NMDA receptor antagonists failed to shown gradually to inhibit the development of mor­ reverse already established morphine tolerance. These phine tolerance, with a significant inhibition of toler­ results differ markedly from the reversal in morphine ance first emerging on days 5 through 9. (2) This effect tolerance obtained by Tiseo and Inturrisi (1993) using of MK801 in inhibiting morphine tolerance was dose the potent competitive NMDA receptor antagonist dependent and doses of 0.03 mg/kg MK801 were in­ LY274614 in rats and by Elliott et al. (1994a) using the effective while doses of 0.1 or 0.3 mg/kg MK801 pro­ noncompetitive NMDA receptor antagonist DM in duced a significant inhibition of tolerance. (3) MK801 mice. The reason for this difference across investiga­ alone was found to have no analgesic effects when ad­ tors may reflect the fact that Trujillo and Akil (1994) ad­ ministered chronically in combination with saline or ministered their NMDA receptor antagonists only once acutely immediately prior to morphine in doses from following the production of morphine tolerance, 0.1 to 0.3 mg/kg, suggesting that the effects of MK801 whereas both Tiseo and Inturrisi (1993) and Elliott et cannot be explained by simple agonist or antagonist al. (1994b) administered their NMDA receptor antago­ effects. (4) MK801 produced an inhibition in morphine nists daily for a number of days before reversal was tolerance that lasted at least 24 hours following the last achieved. This follow-up study by Trujillo and Akil chronic drug dose administration. This study demon­ (1994) provides evidence of the ubiquity of the inhibi­ strated the potency of a noncompetitive NMDA recep­ tion of morphine tolerance produced by a number of tor antagonist in inhibiting morphine tolerance in rats, different noncompetitive NMDA receptor antagonists. and similar results were reported almost simultaneouslv There also appears to be some symptom specift.city by Marek et al. (1991a, 1991b). in this effect of MK801 in morphine tolerance: Not all A follow-up series of experiments were subse­ morphine tolerance effects appear to be inhibited by quently performed by Trujillo and Akil (1994) examin­ MK801. For example, Bhargava and Matwyshyn (1993) ing the effects of four noncompetitive NMDA receptor reported that MK801 (0.03 to 0.3 mg/kg, IP) inhibited antagonists [MK801, phencyclidine (PCP), ketamine, the tolerance to the analgesic but not to the hyperther­ and dextrorphan] on the inhibition of morphine toler­ mic effects of morphine in rats. Finally, there is also ance in rats. There were five major findings. (1) All four some evidence that these effects may be modulated at noncompetitive NMDA receptor antagonists signifi­ the spinal levels. MK801 has been shown to inhibit the cantly inhibited morphine tolerance (produced bv tolerance to the analgesic effects of morphine on the repeated injections or pellets of morphine). (2) PCP (1. 0 radiant heat TF response in spinalized rats deprived of mg/kg IP) proved to be about 10-fold less potent than neural connections from the spine to higher brain MK801 (0.1 mg/kg IP) in inducing these effects, corre­ centers (Gutstein and Trujillo 1993). Additional studies sponding to the relative potency of these noncompeti­ are needed in both rats and mice to determine whether tive NMDA receptor antagonists in in vitro investiga­ MK801 and other noncompetitive NMDA receptor an­ tions and to the relative affinities of these agents at the tagonists are capable of reversing morphine tolerance NMDA binding site. (3) An inhibition of morphine toler­ when already established. There appears to be only one ance was produced by systemic osmotic minipump in­ out of the 17 studies using MK801 where the question fusion of MK801 (0.1 mg/kg/day), PCP (1.0 mg/kg/day). of reversal of morphine tolerance has been investigated dextrorphan (5.0 mg/kg/day), and ketamine (10 (Trujillo and Aki! 1994). Given the highly significant mg/kg/day) coadministered with morphine. These data effects of MK801 on the inhibition of morphine with­ indicate that the effects of NMDA receptor antagonists draw al symptoms in guinea pigs (see later), it would on morphine tolerance appear to reflect a fundamental seem valuable for other investigators to study the effects change in nonassociative tolerance (i.e., they appear of MK801 (at low doses) on morphine tolerance in to be unrelated to conditioned cues associated with mor­ guinea pigs. Such studies may afford a peek into the phine administration). (4) The inhibition of morphine phylogeny of the MK801/morphine tolerance response. tolerance persisted for as long as 17 days in the absence The usefulness of going beyond guinea pigs in higher­ of the continued administration of each of these four order species with MK801 testing is questionable given NMDA receptor antagonists. This indicates that these the high side effect profile of MK801 even in rats (see drugs induce a relatively permanent change in the pro- neurotoxicity section). These side effects include the en- 274 B.H. Herman et al. NEUROPSYCHOPHARMACOLOGY 1995-VOL. 13, NO. 4

Table 1. Effects of the Noncompetitive NMDA Receptor Antagonist MK801 on Mu (Morphine) Opioid Tolerance and Withdrawal

Inhibition of Reversal of Inhibition of Investigators Species Mu Tolerance Mu Tolerance Mu Withdrawal Tanganelli et al. (1991) Guinea pigs NT NT Yes Brent & Chahl (1993) Guinea pigs NT NT Yes Trujillo & Aki! (1991a) Rats Yes NT Yes Rasmussen et al. (1991) Rats NT NT Yes Marek et al. (1991a) Rats Yes NT NT Marek et al. (1991b) Rats Yes NT NT Ben-Eliyahu et al. (1992) Rats Yes NT NT Tiseo & lnturrisi (1993) Rats Yes NT NT Bhargava & Matwyshvn ( 1993) Rats Yes NT NT Trujillo & Aki! (1994) Rats Yes No NT Gutstein & Trujillo (1993) Rats Yes NT NT Marquis et al. (1991) Mice NT NT Yes/No Tanganelli et al. (1991) Mice NT NT Yes Matwyshyn et al. (1993) Mice NT NT No Lufty et al. (1993) Mice Yes NT NT Elliott et al. (1994b) \1ice Yes NT NT Thorat et al. (1994) \1ice NT NT No ------~-· NT not te,ted; i\io no ,1gnihcant ettect; ) es sigrnhcant effect; Ye,, No mixed effects.

hancement of morphine lethality produced by MK801 on either kappa1 (U50488H) tolerance or kappa3 agonist (Trujillo and Akil 1991a, 1991b; Bhargava and Mat­ [naloxone benzoylhydrazone (NalBzoH)] tolerance in wyshyn 1993), the phencyclidine (PCP)-like side effects CO-1 mice. Further research is needed to clarify the of MK801 (Willetts et al. 1990; Rasmussen et al. 1991), effects of MK801 on both kappa1 and kappa3 tolerance and the formation of vacuoles in the cingulate and to determine if this drug or other noncompetitive retrosplenial cortex produced by MK801 in rat brain (Ol­ NMOA receptor antagonists influence delta tolerance ney et al. 1989, 1991; Auer and Coulter 1994), although and to determine whether the tolerance induced by delta not in squirrel monkey brain (Auer 1994). or kappa receptor agonists can be "reversed" (not just The opioid receptor specificity for these effects of inhibited) by noncompetitive NMOA receptor antago­ MK801 on mu tolerance versus tolerance associated with nists such as MK801. other opioid receptor systems is not clear at this time Table 3 summarizes the effects of other noncom­ (see Table 2). Whereas Bhargava and coinvestigators petitive NMOA receptor antagonists on morphine toler­ have reported that MK801 inhibits kappa1 agonist ance and opiate withdrawal. As shown, there have been (U50488H) analgesia (but not hyperthermia) tolerance at least five studies investigating the effects of OM, dex­ in both rats (Bhargava 1994, 1995b; Bhargava et al trorphan, PCP, ketamine, and kynurenic acid on mor­ 1995b) and mice (Bhargava and Thorat 1994), Elliott et phine tolerance in two murine species (rats and mice). al. (1994b) failed to fmd a significant effect of MK801 The clinical utility of the OM data are particularly

Table 2. Effects of the t\uncompebtive NMDA Receptor Antagonist MK801 on Kappa1 (U50488H) and Kappa3 (Na!BzoH) Opioid Tolerance and Withdrawal Species Inhibition of Inhibition of Inhibition of Investigators Tested Kappa1 Tolerance Kappa3 Tolerance Kappa Withdrawal Bhargava (1994) Rats Yes NT NT Bhargava et al. (1995b) Rats Yes NT NT Bhargava (1995b) Rats Yes NT NT Elliott et al. (1994b) Mice No No NT Bhargava & Thorat (1994) Mice Yes NT NT

NT = not tested; '.'io no stgnihcant effect; Yes = signihcant effect NEUROPSYCHOPHARMACOLOGY ]995-VOL. 13, NO. 4 Glutamatergic Systems in Opioid Tolerance and Withdrawal 275

Table 3. Effects of Other (Dextrorphan, Dextromethorphan, Phencyclidine, Ketamine, Kynurenic Acid) Noncompetitive NMDA Receptor Antagonists on Mu (Morphine) Opioid Tolerance and Withdrawal Inhibition Reversal Inhibition Drug Name Investigators Species Mu Tolerance Mu Tolerance Mu Withdrawal Dextromethorphan Koyancuoglu & Saydam Humans NT NT Yes + diazepam + (1990) chlorpromazine Dextromethorphan Rosen et al. ( 1995) Humans :'-JT NT No Koyuncuoglu et al. ( 1990) Rats :\'T NT Yes Elliott et al. ( 1994a) Mice Yes Yes NT Dextrorphan Trujillo & Aki! (1994) Rats Yes No NT Phencyclidine Trujillo & Aki! (1994) Rats Yes No NT Ketamine Brent & Chahl (1993) Guinea pigs NT NT Yes Koyuncuoglu et al. ( 1990) Rats NT NT Yes Trujillo & Aki! (1994) Rats Yes No NT Kynurenic acid Marek et al. (1991b) Rats Yes NT NT

NT = not tested; No = m, s1gnihc,rnt effect. ) es = significant eftect

noteworthy and are discussed in greater detail in a later competitive or competitive NMOA receptor antagonists section. Elliott and coworkers (1994a, and this volume) fail to bind to any known opioid receptor includes the demonstrated that OM is capable of both inhibiting and following. First, Lufty et al. (1993) have shown that reversing morphine tolerance in mice. Antecedent ad­ MK801 is very poor at displacing [3H] naloxone and ministration of OM (30 mg/kg SC) compared to saline that it does this only in the µM range of a 1,000-fold prevented the fivefold increase in the EO50 value to the lower potency than either morphine or naloxone. Sec­ analgesic effects (TF) of morphine in CO-1 mice exposed ond, these investigators also found that naloxone, to escalating doses of morphine in a tolerance paradigm. naltrexone, and morphine are also poor at displacing Moreover, OM reversed the tolerance to the analgesic [3H]MK801 binding sites at the NMOA receptor ino­ effect of 3 days of exposure to implanted morphine phore complex (i.e., µM range). Third, as described in pellets, and the EOso for the analgesic effects of mor­ the sections that follow, Tiseo et al. (1994) have reported phine on TF were nearly equivalent to their saline con­ that chronic administration (at doses that inhibit mor­ trol comparison group. Similarly, as indicated, Trujillo phine tolerance) of the competitive NMOA receptor an­ and Akil (1994) also reported that dextrorphan inhibited tagonist LY274614 failed to result in changes in the tolerance to the analgesic effects of morphine in rats. affinity or binding of mu, delta, kappa1, or kappa3 opioid [OM is metabolized to dextrorphan in the rat (Zysset receptors in rat brain homogenate. In addition, et al. 1988) but has a lower affinity for inhibiting LY274614, did not interfere either with the binding of [ 3H]MK801 binding versus dextrorphan (Jaffe et al. selective opioid receptor subtypes at mu1, mu2, delta, 1989)). In agreement with these findings, other non­ kappa1, or kappa3, even at concentrations that are competitive NMOA receptor antagonists (PCP, keta­ greater than 10 µM (Tiseo et al. 1994). Incontrastto these mine, and kynurenic acid) have also been found to in­ findings, the results of a recent preliminary report by hibit morphine tolerance in rats (Marek et al. 1991b; Bhargava et al. (1995b) suggest that the effects ofMK801 Trujillo and Akil 1994). As indicated in Table 3, more in inhibiting morphine tolerance may be modulated by studies are needed to determine if these other noncom­ alterations in kappa opioid receptors in rat brain. petitive NMOA receptor antagonists are capable of also Specifically, Bhargava et al. (1995b) reported that MK801 reversing mu opioid tolerance. inhibited the in vitro binding of [3H]EKC (a kappa The biochemical mechanism underlying the inhibi­ agonist) to both brain (9.80 µM) and spinal cord mem­ tory effect of competitive and noncompetitive NMDA branes (1.37 µM) in rats. In addition, Bhargava et al. receptor antagonists on morphine tolerance is unknown (1995b) reported that chronic administration of MK801 and will require much further research. Although the resulted in an upregulation of kappa opioid receptors results of at least two studies suggest that these effects in brain. Further research is needed to clarify whether are not modulated through opioid receptors (Lufty et both noncompetitive or competitive NMOA receptor al. 1993; Tiseo et al. 1994), a preliminary report by Bhar­ antagonists have their effects on morphine or kappa gava et al. (1995b) suggests the possibility that in the opioid tolerance through kappa opioid receptors. There case of MK801 these effects may be modulated through is also evidence that these effects appear to relate kappa opioid receptors. The evidence that either non- to changes in glutamate, glycine, or some aspect of 276 B.H. Herman et al. NEUROPSYCHOPHARMACOLOGY 1995-VOL. 13, NO. 4

the NMDA receptor. For example, the binding of in mice because there has been one investigation of [ 3H]MK801 is decreased in some brain regions in significant effects (Tanganelli et al. 1991), one prelimi­ morphine-tolerant and -abstinent rats but only in the nary report of mixed results (Marquis et al. 1991) and presence of glutamate and glycine (Gudehithlu et al. two investigations that failed to obtain significant effects 1993; Bhargava 1994, 1995a) and only slightly in the cor­ (Matwyshyn et al. 1993; Thorat et al. 1994). Additional tex when these ligands are absent (Gudehithlu et al. investigations will be needed to clarify the discrepancy 1994). Based on these data, Bhargava (1994) has sug­ in results of MK801 and opiate withdrawal in mice. gested that endogenous glutamate and glycine may be However, the MK801 effects do not appear to be as ro­ altered following the activation of NMDA receptors in bust or as easily replicated as the effects of NMDA recep­ animals chronically treated with morphine. tor antagonists on the inhibition of morphine tolerance Recent research from Mao et al. (1994) has indicated in this species. that the thermal hyperalgesia that develops in associa­ As noted in Table 1, there have been at least two tion with morphine tolerance in rats involves the coac­ positive reports of MK801 inhibiting opiate withdrawal tivation of central NMDA and non-NMDA receptors. symptoms in guinea pigs (Tanganelli et al. 1991; Brent For example, coadministration of intrathecal morphine and Chahl 1993), and these effects are of particular in­ with MK801 prevented the development of this hyper­ terest considering that guinea pigs have a more evolved algesia. The authors suggest that these results may have brain than either rats or mice. Tanganelli et al. (1991) implications for the treatment of painful conditions such examined the effects of MK801 (1 mg/kg IP) on as neuropathic pain, postoperative pain, and cancer naloxone-precipitated (3 mg/kg IP) opiate withdrawal pain. Similarly, an earlier study by Mao et al. (1992) in­ in guinea pigs. Results indicated that MK801 decreased dicated that intrathecal MK801 and local nerve anesthe­ narcotic antagonist-precipitated hyperactivity (jump­ sia synergistically reduce the hyperalgesia shown in rats ing, exploration, wet dog shakes) and the threefold in­ with experimental peripheral mononeuropathy. [Fur­ crease in cortical acetylcholine (A Ch) produced by nal­ ther details on these studies and an update on the oxone. Brent and Chahl (1993) conducted a series of influence of OM on neuropathic pain was provided by studies on the effects of the inactive enantiomer of Mayer (1995) for this technical review]. (-)MK801 (1.0 mg/kg SC), the active enantiomer of It is yet unexplained why even though acute ad­ ( +)MK801 (0.025, 0.1, and 1.0 mg/kg SC), and ketamine ministration of MK801 does not appear to potentiate (20 mg/kg SC) (Table 3) on naloxone-precipitated (15 the analgesic effects of morphine in rodents (Trujillo mg/kg, SC) opiate [single dose of morphine (15 mg/kg and Akil 1991a, 1994), it does potentiate the capacity SC)] withdrawal in guinea pigs. Dependent measures of morphine to induce both catalespy and lethality (e.g .. included effects on spontaneous locomotor activity and Trujillo and Akil 1991b). It is not known whether other on the frequency of qualitative measures of opiate with­ noncompetitive or competitive NMDA receptor antag­ drawal. In animals treated with morphine alone, nal­ onists influence these other important side effects of oxone induced about a 20-fold increase in spontaneous morphine. The clinical relevance of this is that if a locomotor activity. As expected, (-)MK801 had no NMDA receptor antagonist inhibits the development significant effects. Although the two highest doses of of morphine tolerance, it might also alter the side effects MK801 completely abolished both the naloxone­ of mu opiates, including their motor and respiratory induced hyperactivity and virtually all of the motor effects. This question needs to be carefully evaluated withdrawal behaviors, these effects were difficult to in­ in nrPrlinir;il <:t11.-liP<: terpret because these doses also induced a large degree of motor impairment and ataxia. However, the lowest dose of MK801 (0.025 mg/kg) induced no motor abnor­ EFFECTS OF NONCOMPETITIVE NMDA malities, but it induced dramatic decreases in naloxone­ RECEPTOR ANTAGONISTS ON induced hyperactivity as well as decreases in many OPIOID WITHDRAWAL of the motor withdrawal behaviors. The effects of keta­ Table 1 indicates that there has been at least a total of mine (20 mg/kg SC were difficult to interpret because eight investigations examining the effects of MK801 on although this dose decreased withdrawal behavior it the naloxone-induced withdrawal symptoms associated also induced a marked degree of ataxia. These results with chronic morphine administration in three murine underscore the importance of including careful dose­ species. The evidence to date suggests that MK801 is response profiles of MK801 in opioid withdrawal capable of significantly inhibiting morphine withdrawal studies and indicate that a dissociation can be achieved symptoms in guinea pigs (Tanganelli et al. 1991; Brent in the capacity of this noncompetitive NMDA receptor and Chahl 1993) and in rats (Rasmussen et al. 1991. antagonist to inhibit opioid withdrawal versus induc­ Trujillo and Akil 1991a; Rasmussen this volume; Trujillo ing motoric PCP-like side effects. this volume). More controversial are the effects of A component of the experiment by Trujillo and Akil MK801 in inhibiting morphine withdrawal symptoms (1991a) involved the assessment of MK801 on naloxone- NEUROPSYCHOPHARMACOLOGY 1995-VOL. 13, NO. 4 Glutamatergic Systems in Opioid Tolerance and Withdrawal 277

precipitated opiate withdrawal in rats. After administer­ tion of morphine (10 mg/kg SC), acutely administered ing morphine chronically for 9 days and conducting the MK801 (0.17 mg/kg IP) also significantly reduced TF test on day 10, these investigators precipitated opi­ naloxone-precipitated (1.0 mg/kg IP) jumping. In con­ ate withdrawal with naloxone (2 mg/kg SC). Effects trast, in line with the findings of Thor at et al. (1994) and were assessed on the frequency of escape jumps. Large of Matwyshyn et al. (1993), Marquis et al. (1991) failed numbers of escape jumps were produced by naloxone to obtain a significant effect of chronic coadministra­ in the group that had received just chronic morphine tion of MK801 with morphine on naloxone-precipitated and saline, whereas the pretreatment of MK801 through­ jumping, suggesting that the effects of MK801 on mor­ out the morphine administration was associated with phine dependency may also depend on the intensity a nonsignificant increase in escape jumps (compared of the opiate withdrawal reaction produced. with control). The effects observed did not appear to Other than MK801, a variety of other noncompeti­ reflect the influence of MK801 on the "expression" of tive NMDA receptor antagonists have been evaluated opiate withdrawal symptoms because MK801 was dis­ for their capacity to inhibit morphine withdrawal. This continued for 24 hours before the test on day 10 was includes at least three studies using OM, including two run. Therefore, these results indicate that MK801 in­ in humans (Koyuncuoglu and Saydam 1990; Rosen et hibited the development of opiate withdrawal symp­ al. 1995, presented at this review, manuscript in prep­ toms in rats, including the "hyperactivity" of opiate aration), and one in rats (Koyuncuoglu et al. 1990) and withdrawal. two studies with ketamine, including one in guinea pigs During the same year Rasmussen et al. (1991) also (Brent and Chahl 1993, discussed above) and one in rats reported that MK801 inhibited narcotic antagonist­ (Koyuncuoglu et al. 1990; see Table 3). OM holds par­ induced morphine withdrawal in rats (Rasmussen et ticular interest because it is clinically available, has al. this volume). Dependence was produced by implant­ shown little history of dependence liability, is bioavail­ ing two morphine pellets for 2 days, and 2 to 3 hours able when given orally, and has proved safe to the point following this procedure withdrawal was precipitated that it is marketed on a nonprescription basis. (For fur­ with naltrexone. MK801 (0.1 and 1.0 mg/kg) was given ther exploration of OM and opiate addiction, see Elliott prior to the naltrexone. Results indicated that these et al. this volume). In addition to its over-the-counter doses of MK801 significantly suppressed a number of use as an antitussive, OM has been evaluated in pilot withdrawal behaviors, including teeth chattering, erec­ studies in humans for Parkinson's disease (Bonuccelli tions, ptosis, chewing action, wet dog shakes, lacrima­ et al. 1992; Saenz et al. 1993), intractable seizures (Fisher tion, weight loss, and diarrhea, but no significant effects et al. 1990; Schmitt et al. 1993), and in patients at risk were obtained on jumping, writhes, or salivation, and tor cerebral ischemia (Albers et al. 1991). OM is believed other withdrawal symptoms were intensified. How­ to modulate its effects on opiate withdrawal by an­ ever, these MK801 effects were difficult to interpret (es­ tagonizing the NMOA receptor, although it appears that pecially at the highest dose) because MK801 pretreat­ OM may act as both a noncompetitive and competitive ment produced a dose-related appearance of PCP-like NMDA receptor antagonist (Jaffe et al. 1989; Netzer et motor dysfunctions, including falling, hyperkinetic al. 1993). locomotion, and weaving. [The reason for the dis­ Koyuncuoglu et al. (1990) examined the effects of crepancy in the specific type of withdrawal symptoms DM (1 or 2 mg/kg) and ketamine (0.5 or 1.0 mg/kg) on decreased by MK801 in the Trujillo and Aki! (1991a) naloxone-precipitated (2.0 mg/kg IP) opiate withdrawal study (i.e., the finding that narcotic antagonist precipi­ in rats. Dependence was produced by subcutaneous tated jumping) versus the Rasmussen et al. (1991) study implantation of three pellets of 75 mg of morphine (225 is unknown but may relate to the lack of effects for this mg total). After 3 days of morphine exposure, the rats measure reported in mice, as stated below I. were divided into appropriate control and drug treat­ There may be genetic differences in the effects of ment groups. OM or ketamine were given just before MK801 in mice, as a report by Thor at et al. (1994) failed naloxone administration. The 1.0-mg/kg OM dose in­ to find significant effects of MK801 on narcotic antag­ duced a partial, although significant, suppression in onist-precipitated withdrawal in morphine dependent some opiate withdrawal responses (e.g., flying, teeth mice [see also preliminary report of no effect by Mat­ chattering), and the 2.0-mg/kg OM dose induced a near­ wyshyn et al. (1993)). Indeed, a preliminary report by complete suppression in all of the naloxone-precipiated Marquis et al. (1991) indicated that acute administra­ withdrawal symptoms, including flying, jumping, teeth tion of MK801 (0.1 mg/kg) significantly reduced the chattering, wet dog shakes, defecation, diarrhea, and number of naloxone-precipitated jumps in morphine­ ptosis. For ketamine, no significant effects were ob­ dependent mice (morphine pellets) when a lower dose tained for the low dose, but a significant suppression (0.05 mg/kg IP) but not when a higher dose (0.1 mg/kg in some of the withdrawal symptoms was produced by IP) of naloxone was used. Similarly, Marquis et al. (1991) the 1.0-mg/kg dose. Thus, these data suggest that a sin­ found that in mice rendered tolerant by repeated injec- gle administration of a low dose of OM minutes before 278 B.H. Herman et al. NEUROPSYCHOPHARMACOLOGY 1995-VOL. 13, NO. 4

naloxone administration can inhibit morphine with­ receptor (Ornstein et al. 1990; Rasmussen et al. 1991; drawal symptoms in rats. There is an obvious need to Schoepp et al. 1991). By comparison, noncompetitive attempt replication of this study in rats and in other mu­ NMDA receptor antagonists are thought to act by block­ rine species and in nonhuman and human primates if ing the ion channel for this receptor complex (Wong these other animal studies prove positive. and Kemp 1991). Although both noncompetitive and Based in part on animal modeling data, at least two competitive NMDA receptor antagonists block the groups of investigators have assessed the potential util­ NMDA receptor complex it is thought that the specific ity of OM for the treatment of opioid withdrawal in hu­ site where this takes place is different for noncompeti­ mans. Koyuncuoglu and Saydam (1990) treated 48 tive versus competitive antagonists. heroin addicts (44 males, 4 females) in a double-blind This difference in action between noncompetitive design. All participants received diazepam (DZ 10 mg, as compared with competitive NMDA receptor antag­ every 6 hours). One DZ-treated group also received OM onists may have important implications for the relative (15 mg, hourly, OM + DZ), and the other DZ-treated capacity of these agents to induce PCP-like side effects, group received chlorpromazine (4 mg, hourly; CPZ + and generalizations concerning this type of side effect DZ). There were no group differences with regard to have limited the clinical development of this class of gender, age, length or route of heroin dependency, or drugs. Unlike noncompetitive antagonists such as reported amounts of heroin used. Retention in the two MK801, the competitive NMDA antagonists do not ap­ groups varied. The CPZ + DZ group had 15 dropouts pear to substitute for PCP in drug discrimination proce­ on day 1 compared to 1 dropout for the OM + DZ group dures and generally do not produce PCP-like behaviors on the same day. Overall, there were 21/21 early termi­ at convulsant doses (Willetts et al. 1990). One of the nations in the CPZ + DZ group, and 10/27 early termi­ most potent competitive NMDA receptor antagonists nations in the OM + DZ group. It is difficult to inter­ is LY274614 (Schoepp et al. 1991). In support of the pret the results of this study because of the use of fmdings of Willetts et al. (1990), Rasmussen et al. (1991) adjunct medications, the considerable dropout rate have shown that in contrast with MK801, LY274614 within one arm of this study, and the baseline differ­ does not produce the motor dysfunctions (head weav­ ences between the two groups for signs of withdrawal ing, increased locomotion, falling) associated with PCP (the CPZ + DZ group was significantly more symptom­ in rats. In contrast with the motor hyperactivity asso­ atic than the OM + DZ group on 5 of the 15 symptoms ciated with PCP-like drugs and noncompetitive NMDA of withdrawal that were evaluated). receptor antagonists, competitive NMDA receptor an­ In another study reported by Rosen and colleagues tagonists such as LY274614 induce mild to moderate (1995) a double-blind, placebo-controlled design using sedation (Rasmussen et al. 1991). This argues for the a dose-escalating procedure failed to find a significant possibility of a more important role for competitive effect for DM in preventing or attenuating naloxone­ versus noncompetitive NMDA receptor antagonists in precipitated withdrawal. Doses used were comparable clinical applications for opiate addiction (although see with those in the Koyuncuoglu and Saydam (1990) results of preclinical and preliminary human studies study. Even though naloxone-precipitated withdrawal earlier in this article, including the effects of low-affinity may not be equivalent to gradual withdrawal of an opi­ noncompetitive NMDA receptor antagonists such as oid agonist, three subjects in the Rosen sample under­ DM). For humans the dose of a competitive NMDA went medically supervised withdrawal from metha­ receptor antagonist required to affect opiate addiction done while receiving 60 mg of OM every 4 hours. Two phenomena may be lower than the dose found to in­ of these three participants experienced withdrawal duce PCP-like side effects, whereas for certain noncom­ symptoms although there was no comparison group. petitive NMDA receptor antagonists the therapeutic Clearly, additional studies will be needed to determine window may be very narrow. This important hypoth­ the efficacy of OM alone or coadministered with mor­ esis remains to be tested. phine in the alleviation of opioid withdrawal symptoms A summary of the effects of competitive NMDA in humans. receptor antagonists in inhibiting and/or reversing mu and kappa opioid tolerance and withdrawal is shown in Table 4. Note that the most replicated finding to date COMPETITIVE NMDA RECEPTOR ANTAGONISTS is that competitive NMDA receptor antagonists are AND OPIOID TOLERANCE capable of inhibiting mu opioid tolerance in murine spe­ cies [5/5 reports of significant effects; for LY274614 see A second category of drugs that have been shown to Tiseo and Inturrisi (1993); Tiseo et al. (1994) in rats, and effect opioid withdrawal are the competitive NMDA Elliott et al. (1994b) in mice; for NPC17742 see Koles­ receptor antagonists that inhibit the binding of gluta­ nikov et al. (1993a) in mice; for LY235959 see Mat­ mate at the glutamate recognition site of the NMDA wyshyn and Bhargava (1995) in mice], although there NEUROPSYCHOPHARMACOLOGY 1995- VOL. 13, NO. 4 Glutamatergic Systems in Opioid Tolerance and Withdrawal 279

Table 4. Effects of Competitive NMDA Receptor Antagonists on Mu (Morphine), Kappa1 (U50488H), and Kappa3 (Na!BzoH) Opioid Tolerance and Withdrawal

Species Inhibition of Reversal of Inhibition of Drug Name Investigators Tested Mu Tolerance Mu Tolerance Mu Withdrawal LY274614 Rasmussen et al. (1991) Rats NT NT Yes Tiseo & lnturrisi (1993) Rats Yes Yes NT Tiseo et al. (1994) Rats Yes NT NT Elliott et al. (19946) Mice Yes NT NT NPC17742 Kolesnikov et al. (1993a) Mice Yes NT NT LY235959 Matwyshyn & Bhargava Mice Yes NT No (1995) Inhibition of Inhibition of Inhibition of Kappa1 Tolerance Kappa3 Tolerance Kappa Withdrawal

LY274614 Rasmussen et al. (1991) Rats NT NT NT Tiseo & lnturrisi (1993) Rats NT NT NT Tiseo et al. (1994) Rats NT NT NT Elliott et al. (19946) Mice No No NT NPC17742 Kolesnikov et a I. (1993a) Mice Yes No NT LY235959 Thorat & Bhargava ( 1995) Mice Yes NT NT

NT not tested; ~o nll s1grnhcdnt etfed; 'res signihcdnt d!P, t

have been few attempts to determine whether these petitive NMDA receptor antagonists may be opioid­ agents can reverse mu opioid tolerance (Tiseo and ln­ receptor specific as both of these latter sets of investi­ turrisi 1993) or influence the expression of mu opiate gators failed to fmd a significant effect of competitive withdrawal symptoms (two reports, one significant NMD A receptor antagonists in inhibiting the develop­ (Rasmussen et al. 1991) in mice, one nonsignificant ment of kappa3 opioid receptor tolerance using the opi­ (Matwyshyn and Bhargava 1995) in mice]. There have oid agonist drug naloxone benzoylhydrazone (NalB­ been few studies on the effects of competitive NMDA zoH) (Kolesnikov et al. 1993a; Elliott et al. 1994b). The receptor antagonists on kappa opioid tolerance; two in­ effects of competitive NMDA receptor antagonists on dicated significant inhibition on tolerance (Kolesniko\ kappa I opioid receptor tolerance using the opioid et al. 1993a in mice; Thorat and Bhargava 1995 in mice), agonist U50488H have been examined in three studies, and the third was nonsignificant (Elliott et al. 1994b in and significant inhibition of tolerance for this agent was mice). Therefore, additional research is needed to de­ obtained by Kolesnikov et al. (1993a) using NPC17742 termine the specificity of these results to other opioid and by Thorat and Bhargava (1995) using LY235959, receptors, including the delta and kappa type. whereas no significant effects of LY274614 were de­ Tiseo and Inturrisi (1993) conducted the first series tected by Elliott et al. (1994b). of experiments demonstrating that the competitive Review of the Tiseo and Inturrisi (1993) findings is NMDA receptor antagonist LY274614 inhibits morphine instructive for providing a template for this type of de­ tolerance in rats (Elliott et al. this volume; see also Tiseo sign for other researchers and for noting the power and et al. 1994). Even more noteworthy, these researchers limitations of competitive NMDA receptor antagonists showed for the first time that both competitive (i.e., in inhibiting mu opioid receptor tolerance in rats. The LY274614) and noncompetitive (MK801) NMDA recep­ hot plate (HP) procedure was used to evaluate analge­ tor antagonists could reverse morphine tolerance after sia. Tolerance was produced by BID injections of mor­ it had been established. These former results appear phine (10 mg/kg SC) given daily for 6 to 10 days de­ to extend to other murine species, including mice. For pending on the experiment. The eff:tcacy of LY274614 example, competitive NMDA receptor antagonists have (24 mg/kg/24 h) or of MK801 (0.4 mg/kg 24 h) delivered been shown to inhibit morphine tolerance in CD-1 mice ziia osmotic minipumps was compared, This study in an investigation by Elliott et al. (1994b) using demonstrated three major effects of LY274614. (1) LY274614, in a second investigation by Kolesnikov et LY27 4614 as well as MK801 attenuated the development al. (1993a), using NPC17742 and CD-1 mice and in a of tolerance when coadministered with morphine, and recent investigation by Matwyshyn and Bhargava (1995) this inhibition of tolerance (and the retention of anal­ using LY235959 (the active isomer of LY274614) and gesic sensitivity to morphine) persisted for at least Swiss Webster mice. Furthermore, this effect of com- 7 days in the absence of continued administration of 280 B.H. Herman et al. NEUROPSYCHOPHARMACOLOGY 1995-VOL. 13, NO. 4

drug. (2) Subsequent administration of l Y274614 Ben-Eliyahu 1992; for competitive NMDA receptor an­ reversed mu opioid receptor tolerance if administered tagonists, see Tiseo and Inturrisi 1993; Kolesnikov et to already morphine-tolerant animals. Indeed, rats al. 1993a; Elliott et al. 1994a; Tiseo et al. 1994). This con­ receiving LY274614 for 1 week following the establish­ trasts with the effects of opiate receptor antagonists, ment of morphine tolerance (threefold dose-response which attenuate morphine tolerance only at doses that shift) showed a virtually complete return in sensitivity also block morphine analgesia. This includes narcotic to the analgesic effects of morphine. (3) Concurrent ad­ antagonists that block mu, delta, and kappa opiate recep­ ministration of LY274614 reversed morphine tolerance, tors such as naloxone (Mushlin and Cochin 1976; Smits and the reversal of tolerance persisted for at least 7 days 1976; Tremblay et al. 1976; Yano and Takemori 1977) after the cessation of LY274614. An important control and naltrexone (Bhargava 1978, 1994; Bhargava et al. was that neither l Y274614 nor MK801 administered 1994) and specific opiate receptor antagonists such as alone had significant analgesic effects, indicating that B-funaltrexamine (highly selective mu opioid receptor the NMDA receptor antagonists affected tolerance but antagonist; see Aceto et al. 1986). There are some bio­ not analgesia. In summary, the findings of Tiseo and chemical data suggesting that the NMDA receptor an­ Inturrisi (1993) suggested a unique and a specific role tagonists do not directly compete with any known opi­ of NMDA receptor antagonists in opiate tolerance. oid receptor (e.g., lufty et al. 1993; Tiseo et al. 1994; What are the differences between the inhibition and but see Bhargava et al. 1995b for effects on kappa opioid reversal of morphine tolerance produce by NMDA receptors) and do not alter the affinity or numbers of receptor antagonists compared with other drugs? [Note opioid receptors (Tiseo et al. 1994; but see Bhargava et that some of these differences have been described by al. 1995b for effects on kappa opioid receptors). Thus, Tiseo and Inturrisi (1993)]. One difference is that the the molecular mechanisms underlying the inhibition NMDA receptor antagonists appear to influence the of morphine tolerance by LY274614 is unknown at this "process" of tolerance itself rather than its "expression " time, and much further research will be needed to clar­ This does not appear to be the case for other agents such ify its biochemical basis. However, it does not appear as the cholecystokinin (CCK) antagonists. For exam­ to reflect a simple antagonism or change in mu brain ple, the reversal of morphine tolerance by proglumide opioid receptors. (a weak and nonselective CCK antagonist) has been A third characteristic that differentiates the NMDA reported to be immediate (Watkins et al. 1984), suggest­ receptor antagonists from other agents in the inhibi­ ing an influence in the "expression" of tolerance tion of morphine tolerance is that the effect outlasts the whereas the reversal of morphine tolerance by l Y274614 coadministration period for several days. Coadminis­ takes place over a number of days (Tiseo and Inturrisi tration of other agents have also been shown to inhibit 1993), suggesting an influence in the "process" of toler­ morphine tolerance without influencing morphine's an­ ance itself. The fact that the reversal achieved bv algesic effects. These agents include systemically ad­ l Y274614 is not immediate indicates that the NMDA ministered dynorphin A (1-13) or various Des-Tyr1 receptor is probably not involved in the final step in the nonopioid fragments of dynorphin A (Tulunay et al. elaboration of morphine tolerance. In addition, another 1981; Takemori et al. 1992, 1993). However, unlike the difference between NMDA receptor antagonists and delta opioid antagonists or the dynorphin A fragments, CCK antagonists is that CCK antagonists potentiate the NMDA receptor antagonists appear to be unique morphine analgesia (Watkins et al. 1984; Dourish et al. in producing a reversal of morphine tolerance that out­ 1988, 1990; O'Neill et al. 1989), making it difficult to lasts the coadministration period. This has important differentiate an additive effect of analgesia alone on clinical implications, and further preclinical studies are tolerance assessments in these studies. This difference needed to document the specific noncompetitive and is in marked contrast with the NMDA receptor antago­ competitive NMDA receptor antagonists that are capa­ nists that do not potentiate morphine analgesia (see ble of reversing, not just inhibiting, morphine tolerance. below). Additional studies are also needed to determine the lon­ Second, unlike other drugs (e.g., narcotic antag(1- gevity of the reversal in morphine tolerance produced nists), pharmacological evidence suggests that this by the NMDA receptor antagonists. effect of NMDA receptor antagonists on morphine toler­ ance does not reflect a simple antagonism of any of the COMPETITIVE NMDA RECEPTOR ANTAGONIST known opioid receptors. Using behavioral pharmaco­ AND OPIOID WITHDRAWAL logical approaches, several investigators have shown that NMDA receptor antagonists inhibit morphine toler­ The effects of l Y274614 as compared with MK801 on ance without antagonizing the analgesic effects of mor­ inhibiting naltrexone-induced withdrawal symptoms phine (for noncompetitive NMDA receptor antagonists, in morphine-dependent rats have been investigated by see Marek et al. 1991a, 1991b; Trujillo and Akil 1991; Rasmussen et al. (1991). (See Rasmussen in this vol- NEUROPSYCHOPHARMACOLOGY 1995-VOL. 13, NO. 4 Glutamatergic Systems in Opioid Tolerance and Withdrawal 281

ume for further details and for a research update.) logical effects of competitive and noncompetitive Pretreatment with LY274614 (50 and 100 mg/kg IP) or NMDA receptor antagonists and glycine antagonists MK801 (0.1 and 1.0 mg/kg SC) significantly decreased on opiate withdrawal are needed to determine the relia­ a number of opiate withdrawal symptoms, including bility of this finding across different drugs of these teeth chattering, chewing action, ptosis, erections, di­ classes and different species. arrhea, and weight loss. However, both LY274614 and MK801 failed to affect significantly jumping, writhes, EFFECTS OF NMDA RECEPTOR ANTAGONISTS and salivation. The lack of effect of competitive NMDA ACTING AS AGONISTS receptor antagonists on narcotic antagonist-provoked OR ANTAGONISTS AT THE GLYCINE SITE OF THE NMDA-RC opiate withdrawal "jumping" is notable and may indi­ ON OPIOID TOLERANCE AND WITHDRAWAL cate that this class of drugs have limited clinical poten­ tial for treating the "hyperactivity" versus gastroentero­ A group of NMDA receptor antagonists with possible logical (e.g., weight loss) elements of opiate withdrawal. clinical potential for the treatment of opiate addiction Indeed, as shown in Table 4, a recent investigation by comprise agents that act as partial glycine site agonists Matwyshyn and Bhargava (1995) has failed to find a at the strychnine-insensitive glycine site of the NMDA­ significant effect of the competitive NMDA receptor an­ RC, including I-aminocyclopanecarboxylic acid (ACPC), tagonist, LY235959 on naltrexone-precipitated with­ D-cycloserine, 3-amino-I-hydroxypyrrolid-z-oe (HA- drawal from morphine. 966), or as antagonists at the glycine site, including Rasmussen and co-workers ( 1991 and this volume) 1-amino-cyclobutylcarboxylic acid (ACBC), 7-chloro­ have attempted to delineate the neuroanatomical/neu­ k ynureate, 5-nitro-6, 7-dimethyl-1,4-dihydro-2,3-qui­ rochemical substrate for this effect by recording cellu­ noxalinedione (ACEA-1328), felbamate (Felbatol) and lar activity in the locus coeruleus (LC). As previously memantine (Foster and Kemp 1988; Huettner 1989; documented (Aghajanian 1978; Rasmussen et al. 1990), Marvizon et al. 1989; Hood et al. 1989, 1990, 1992; Wat­ increased &ring was produced in the cells of the LC as son and Lanthorn 1990; Baron et al. 1994; Boje 1994; a consequence of narcotic antagonist administration in Lufty et al. 1995). The glycine antagonists are agents the opiate-dependent rat. However, unlike the inhibi­ that prevent glycine from binding to the glycine regula­ tion in the behavioral symptoms of opioid withdrawal, tory site of the NMDA receptor (Johnson and Ascher LY274614 failed to inhibit this increased LC firing. An 1987; Williams et al. 1991), and these agents effectively earlier study by Rasmussen and Aghajanian (1989) had prevent glutamate from activating the NMDA-RC be­ indicated that intracerebroventricular injections of the cause the glycine site acts as a coagonist site with the nonspecific excitatory amino acid (EAA) antagonist (also glutamate binding site. Unlike some noncompetitive glycine antagonist), kynurenic acid, inhibited naloxone­ NMDA receptor antagonists, the glycine site antago­ precipitated LC opioid withdrawal. In addition, Akaoka nists do not show discriminative generalization to PCP and Aston-Jones (1991) reported that an inhibition in !Singh et al. 1990) or produce PCP-like motor effects naloxone-induced increases in LC firing rate of the in rodents (Koek and Colpaert 1990). morphine-dependent rat could be produced by a num­ Kolesnikov et al. (1994) recently reported that the ber of NMDA receptor antagonist, including kynure­ partial glycine agonist ACPC prevented tolerance to a ate (nonspecific NMDA receptor and glycine an­ mu opioid agonist (morphine) and to a delta opioid tagonist), 6-cy ano-7-dinitroquinoxaline -2, 3-dione agonist [D-Pen2,D-Pen5]enkephalin (DPDPE) when [CNQX; (nonNMDA receptor antagonists and a gly­ coadministered with either of these opioids in CD-1 cine antagonist)], and AP5 (competitive NMDA recep­ mice. In addition, ACPC reversed morphine tolerance. tor antagonist). Interestingly, in the Akaoka and Aston­ ACPC did not significantly inhibit tolerance to either Jones (1991) study, AP5 was the least effective NMDA a kappa 1 opioid (U50,488H) or a kappa3 opioid (NalB­ antagonist, suggesting, in combination with the _zoH). ACPC had no analgesic effects when given alone. findings of Rasmussen et al. (1991), that competitive Thus, these effects parallel the influence of the NMDA NMDA receptor antagonists do not appear to be as receptor antagonists and NOS inhibitors on mu and effective as noncompetitive NMDA receptor antagonists kappa opioid tolerance obtained by these investigators in inhibiting naloxone-precipitated opioid withdrawal in other studies (Kolesnikov et al. 1993a and 1993b; LC &ring. The results of the Akaoka and Aston-Jones Babey et al. 1994). As noted by the authors, ACPC has (1991) study indicate that a substantial component promising clinical potential because it appears relatively of the LC hyperactivity occurring during narcotic free of side effects and has a number of other poten­ antagonist-induced opioid withdrawal is mediated by tially positive effects in rodents such as acting as both an augmented glutamatergic input to the LC that can an antidepressant and anxiolytic in appropriate animal be blocked by brain injections of noncompetitive models (Trullas et al. 1991). Similarly, Lufty et al. (1995) NMDA or glycine receptor antagonists. More preclini­ recently reported that ACEA-1328, a novel NMDA cal studies examining the behavioral and electrophysio- receptor/glycine site antagonist, inhibited morphine 282 B.H. Herman et al. NEUROPSYCHOPHARMACOLOGY 1995-VOL. 13, NO. 4

tolerance in mice without affecting the basal nocicep­ although it is an unconventional neurotransmitter and tive response. simply diffuses out to its target site (Martin and Gillespie Kosten et al. (this volume) has found that felbamate 1990; Bredt and Snyder 1992; Culotta and Koshland significantly decreased the severity of opioid with­ 1992). The immunocytochemical distribution of brain drawal symptoms in rats chronically treated with mor­ NOS (amygdala, central grey, spinal tract of the trigerni­ phine and then administered a narcotic antagonist. Un­ nal nerve and the substantia gelatinosa of the spinal fortunately, at the present time the clinical fate of cord) is consistent with a role for NOS in some aspect felbamate is somewhat problematic. Specifi.cally, al­ of the mu opioid analgesia/ tolerance/ withdrawal pro­ though felbamate was approved by the FDA in 1994 cess (Bredt et al. 1990, 1991; Synder and Bredt 1991). for the treatment of intractable epilepsy in children, its The link between NO and NMDA receptors is de­ clinical use was greatly curtailed by reports of deaths rived from research suggesting that NMDA can elicit from a plastic anemia associated with this use. This is increases in cGMP levels in rat hippocampal slice prepa­ thought to be an isolated effect associated with this rations and that these can be blocked by NOS inhibi­ specific agent and one that is not common to all glycine tors (Garthwaite et al. 1988, 1989). In addition, a rela­ site antagonists. tionship between NOS inhibitors, glutamate, and Thus, glycine agonists and antagonists may be con­ neuronal toxicity was illustrated in a study by Dawson sidered as clinical entities for the treatment of opiate et al. (1991) demonstrating that NOS inhibitors can pro­ addiction in the future. However, much further preclin­ tect rat embryonic cortical cells in culture from NMDA ical research is to clarify their effects in both opioid toler­ neurotoxicity. Indeed, the relationship between NOS ance and withdrawal. and the NMDA-RC and the results of the Dawson et al. (1991) study inspired several research groups to in­ NITRIC OXIDE SYNTHASE INHIBITORS vestigate the effects of NOS inhibitors on opioid toler­ ,rnce and withdrawal. NMDA receptor antagonists appear to inhibit both opi­ oid tolerance and withdrawal. Although the biological mechanism underlying these pharmacologic effects is NITRIC OXIDE SYNTHASE INHIBITORS AND presumed to be blockade of the NMDA receptor com­ OPIOID TOLERANCE plex (NMDA-RC), other related molecular mechanisms may be involved. Stimulation of neuronal nitric oxide Direct NOS inhibitors such as L-NG-nitroarginine (NO) may occur during opioid tolerance and with­ (L-NNA) have been reported by at least two laborato­ drawal. Activation of the NMDA-RC stimulates the en­ ries to inhibit and even reverse morphine tolerance in zymatic production of NO, and, therefore, NMDA mice (Kolesnikov et al. 1992, 1993b; Elliott et al. 1994b), receptor antagonists can indirectly reduce the activity and at least one laboratory has recently shown that of NOS (see Garthwaite 1991 for a review). NO appears L-NC-monomethylarginine (L-NMMA) inhibits mor­ to be a neurotransmitter and a messenger in target cells, phine tolerance in rats (Bhargava 1995a; see Table 5).

Table 5. Effects of 1\'itnc Ux1de ':ivnthase Inhibitors un Mu (Morphine) Opioid Tolerance and Withdrawal ·····------· Inhibition of Inhibition of Increase Vascular Clinical Drug Name Abbreviation Mu Tolerance Mu Withdrawal BP NOS Potential

1 L-Nc;-nitroarginine L-NNA Ye~" ' Yes" c.d,e.f Noa, Yesd Yes Possibly L-NG-monomethylarginint· L-NMMA Ye~" Yescr,\ Noc NT Yes Possibly L-Ne,-nitroarginine methyl ester L-NAME \:1 Yes'·d c.f Yesd Yes No N (5)-(1-Iminoeth yl- L-( irnth 1ne) L-NIO \:1 Yes.t Yesd Yes No 7-nitroindazole 7-1\:l '\T Yes.I Nod No Yes Methylene blue (indirect) MB ) es" NT NT No Yes

BP = blood pressure as 1t occur, durmg withdrawal from chronically administered mu opioid agonists such as morphine; vascular NOS = effects on vascular epithelial NOS; clinical potential = refers only to treatment of a specific aspect of opiate addiction. "Kolesnikov et al. (1993b). 1' Elliott et al. ( 1994b) ' Kimes et al. (1993). d Vaupel et al. ( 1995) ' Cappendijk et al. (1993) ! Thora! et al. (1994). ' Bhargava (1995a). h Babey et al. (1994) NEUROPSYCHOPHARMACOLOGY 19<.J'i- VOL. 13, '.\:O. 4 Glutamatergic Systems in Opioid Tolerance and Withdrawal 283

These groups capitalized on the action of L-NNA to in­ opioid analgesic effects. Both Kolesnikov et al. (19936) hibit irreversibly NOS (Dwyer et al. 1991) by showing and Elliott et al. (19946) examined the effects of L-NNA the longevity of inhibition of tolerance produced by on the tolerance to the analgesic effects induced by two L-NNA weeks after its administration. (For further de­ kappa opioid agonists: a kappa1 ligand, U50488H, and tails, see Pasternak et al. this volume and Elliott this a kappa3 ligand, NalBzoH, and results of both investi­ volume). In addition, a third study (Babey et al. 1994) gations indicated that L-NNA did not prevent the toler­ has demonstrated that the indirect NOS inhibitor meth­ ance to the analgesia mediated by either of these kappa ylene blue (MB) signi&cantly inhibits morphine toler­ agonists. On the other hand, a different NOS inhibi­ ance in mice. Therefore as indicated in Table 5, some tor, L-NMMA, has been reported to inhibit the toler­ NOS inhibitors (L-NNA, L-NMMA, MB) should have ance of the analgesic actions of U50488H in both the been reported to inhibit mu opioid tolerance. mouse (Thorat et al. 1993) and the rat (Bhargava 1994). One of the first investigations into the effects of The nature of this difference in results is not clear but L-NNA on opioid tolerance was reported by Kolesnikov may reflect the specific mouse or rat strain employed et al. (19936) using CD-1 mice (see also Kolesnikov et or some subtle pharmacological difference between al. 1992). These experiments demonstrated the follow­ L-NNA versus L-NMMA. ing four characteristics of L-NNA and morphine tol­ Babey et cJ.l. (1994) have explored the intermediary erance: biochemical steps underlying this effect of L-NNA on morphine tolerance in CD-1 mice. Rather surprisingly, 1. L-NNA inhibited the development of morphine tolerance these investigators failed to fmd a signi&cant effect of in mice. Tolerance to morphine was produced by im­ chronic morphine administration on NOS levels in ei­ planting a morphine pellet (75 mg SC) in mice. Coad­ ther brainstem or cerebellum and/or on levels of NOS ministration of L-NNA (4 mg/kg IP) for 5 days mRNA in a variety of brain regions. These results con­ markedly inhibited the development of tolerance trast with signi&cant upregulation of NOS obtained of (e.g., 50% of mice were analgesic on day 5). Similar NOS obtained in certain brain regions obtained by inhibitory effects of L-NN A on morphine tolerance others in a preliminary report (Barjavel and Bhargava in CD-1 mice were also obtained by Elliott et al. 1994). However, a role of L-arginine (a reciprocal NOS (19946). manipulation) in the NOS/opioid tolerance process was 2. The effects of L-NNA in inhibiting tlze development of mor­ indicated in the Babey et al. (1994) study. Indeed, L-argi­ phine tolerance were long-lasting. Tolerance was in­ nine was found to accelerate morphine tolerance, and duced by daily injections of morphine (5 mgikg SC). this effect was blocked by L-NNA. By comparison, Administration of a daily dose of 2 mg/kg of L-NNA L-arginine had no signi&cant effects on the tolerance maintained the analgesic response to morphine for to kappa1 and kappa3 opioid agonists, indicating once over 4 weeks. again a role of the NO system in mu, but not in kappa, 3. L-NNA slowly reversed morplzine tolerance after it occurred opioid systems. over 5 days. Inded, L-NNA reversed tolerance in a In addition, Babey et al. (1994) described the results superior fashion than complete withdrawal from lit an interesting experiment that MB (1 and 10 mg/kg morphine! SC), an indirect NOS inhibitor, blocked the tolerance 4. The effects of L-NNA were speciti,· to tolerance and cannot to morphine's analgesic effects in CD-1 mice. The clini­ be explained as a pharmacological additive response on cal importance of this observation is that MB is already analgesia plus tolerance. L-NNA (2 mg/kg IP) by itself on the market in the United States as tablets to be ad­ failed to produce an analgesic response when ad­ ministered orally in several forms. These medications ministered either acutely or chronically, and it also containing MB are approved by the FDA for the relief failed signifi.cantly to influence the analgesic potency of discomfort of the lower urinary tract caused by hyper­ of morphine in opiate-naive mice (Elliott et al. 19946). motility resulting from inflammation associated with cys­ Therefore, these effects cannot represent a simple t is tis, urethritis, or trigonitis. Thus, the proven safety summation of separate analgesic effects of two agents of MB makes it an excellent clinical candidate for as­ (morphine, L-NNA). sessing the role of NOS inhibitors in opioid tolerance ,md withdrawal. These results document the unusual pharmacological feature of NMDA receptor antagonists and NOS inhib­ itors that when using these agents a separation can be NITRIC OXIDE SYNTHASE INHIBITORS achieved between morphine analgesia and tolerance. AND OPIOID WITHDRAWAL The speci&city of these effects of NOS inhibitors to mu versus kappa opioid tolerance is more controversial. There are at least six separate reports indicating that On the one hand, some researchers have failed to find '.\JOS inhibitors [L-NNA, L-NMMA, L-NG-nitroargi­ significant effects of L-NNA on the tolerance to kapra ninemethylester (L-NAME), N(5)-I-iminoethyl-L-orni- 284 B.H. Herman et al. NEUROPSYCHOPHARMACOLOGY 1995-VOL. 13, NO. 4

thine (L-NIO), 7-nitroindazole (7-NI)] inhibit the devel­ tension, is produced by the majority of NOS inhibitors opment of morphine opioid withdrawal in murine because they inhibit the production of NOS in vascu­ species. NOS inhbitors have been shown to attenuate lar epithelial tissue (Babbedge et al. 1993; Moore et al. some of the symptoms of opioid withdrawal in rats 1993a, 1993b). An important finding of the Vaupel et (Kimes et al. 1991, 1993; Vaupel et al. 1995 and this vol­ al. (1995) study in rats was that three of the NOS inhib­ ume; Bhargava 1995a) and in mice [Cappendijk 1993; itors (L-NAME, L-NNA, L-NIO) induced significant in­ (some measures) Kolesnikov et al. 1993b; Matwyshyn creases in BP with the sole exception of 7-NI. These et al. 1993; Thorat et al. 1994] and to reverse already results suggest that 7-NI may be of particular interest established opiate dependence (i.e., withdrawal symp­ in human treatment trials for certain aspects of opiate toms) in mice (Kolesnikov et al. 1993b) (see Table 5). addiction (see below). In contrast with Vaupel et al. For further details see Vaupel et al. this volume and (1995), Kolesnikov et al. (1993b) failed to find a Pasternak et al. this volume. significant effect of L-NNA on mean arterial blood pres­ Kimes et al. (1993) (preliminary report in Kimes et sure (MAP) in mice. This may represent a species differ­ al. 1991) showed that L-NNA (7.5 mg/kg IP) inhibited ence between rats and mice, since Kolesnikov et al. certain naloxone-precipitated opioid withdraw al symp­ (1993b) also report a dramatic elevation in MAP with toms, including wet dog shakes and weight loss, in L-NNA in rats. morphine-dependent rats. L-NAME was 10-fold less Support for these findings has also been obtained potent than L-NNA in producing these effects. Depen­ by Kolesnikov et al. (1993b) in CD-1 mice. Jumping was dence was induced by implanting three 75-mg mor­ used to assess the effects of L-NNA on naloxone­ phine pellets in rats. The NOS inhibitors were ad­ precipitated (1 mg/kg SC) opioid withdrawal in mice ministered during these days, and withdrawal was chronically administered morphine (5 mg/kg SC). L-NNA precipitated with naloxone (0.5 mg/kg SC). There were induced dose-dependent decreases in naloxone-precip­ several other opioid withdrawal responses that were itated jumping. Although the overall interpretation is not significantly affected by L-NNA (i.e., naloxone­ similar to that made by Kimes et al. (1993) that L-NNA induced hyperactivity and jumping). The relative inhibits naloxone-precipitated morphine withdrawal, potencies of L-NNA and L-NAME in inhibiting certain it is of interest that "jumping" was not significantly types of opioid withdrawal show a relationship to the influenced by L-NNA in the Kimes et al. (1993) study efficacy of these drugs as NOS inhibitors (Rees et al or in the follow-up investigation by Vaupel et al. (1995). 1990; Lambert et al. 1991). Careful examination of data presented by Kimes et al. In a follow-up study Vaupel et al. (1995) reported (1993, Table 1 of that paper) suggests that the differ­ on the efficacy of four NOS inhibitors to decrease ences in results between the two studies are probably naloxone-precipitated morphine withdrawal in rats not due to a species difference in rats versus mice but, (one 75-mg morphine pellet) was used to induce de­ rather, due to subtle differences in methodology or post pendency). Results indicated that 7-NI, L-NIO, L-NAME, hoc statistical analyses. Accordingly, it would be valu­ and L-NNA all produced significant dose-related de­ able to conduct a side-by-side comparison in mice versus creases in weight loss, diarrhea, wet dog shakes, and rats for L-NNA on naloxone-precipitated morphine grooming. However, other severe symptoms of with­ withdrawal jumping in the same laboratory to resolve drawal, such as "hyperactivity," were not inhibited. these discrepancies across investigations. Opioid-dependent rats showed about three-fold in­ Results similar to the effects of NOS inhibitors on creases (day 4) in exploratory activity, and this "opioid narcotic antogonist-induced opioid withdrawal in mice withdrawal hyperactivity" was significantly increased found by Kolesnikov et al. (1993b) have been reported (worsened) by 7-NI, L-NIO, and L-NNA while L-NAME by other investigators (Cappendijk et al. 1993; Mat­ had no effect. A positive control. clonidine (an alpha- wyshyn et al. 1993; Thorat et al. 1994), and each of these 2-adrenergic agonist commonly used "off-label" for the studies indicates that withdrawal "jumping" in mice is treatment of opioid withdrawal), showed that the in­ inhibited by L-NNA and L-NAME while the effects of hibitory effects induced by 7-NI on opioid withdrawal L-NMMA are more controversial. Cappendijk et al. symptoms were comparable to those obtained with this (1993) failed to find a significant effect of L-NMMA (3.5 medication. Clonidine also increased the "hyperactivitv to 100 mg/kg) on morphine withdrawal symptoms in of opioid withdrawal." However, clonidine significantly mice. This latter result differs from that reported by reduced blood pressure (BP), an effect not observed Thorat et al. (1994) who found that L-NMMA (0.02 to with 7-NI. 4.0 mg/kg SC) reduced withdrawal jumping (but no Effects on BP is a side effect of great clinical sig­ other symptoms) in morphine-dependent (one 75-mg nificance in the development of NOS inhibitors. NO pellet) mice. Methodological differences (e.g., in the produces hypotension through its activation of vascu­ dose of morphine or narcotic antagonist used) may un­ lar epithelial NOS (Garthwaite et al. 1988; Bredt and derlie some of the differences obtained for L-NMMA Synder 1992; Xie et al. 1992). The reverse state, hvper- (Bhargava 1994). NEUROPSYCHOPHARMACOLOCY 1995-VOL. 13, NO. 4 Glutamatergic Systems in Opioid Tolerance and Withdrawal 285

Results of the Kolesnikov et al. (1993b) investiga­ L-NAME, and L-NIO all affect vascular epithelial NOS tion also revealed that L-NNA reversed previously es­ and have been shown significantly to increase BP in ro­ tablished morphine dependence. Mice receiving L-NNA dents (Babbedge et al. 1993; Moore et al. 1993a, 1993b; for 5 days with continued morphine administration Vaupel et al. 1995 and this volume). MB appears to be showed essentially little or no naloxone-precipitated the lead candidate for indirect NOS inhibitors for this withdrawal jumping in comparison with mice receiv­ indication (Babey et al. 1994), also because of the prob­ ing just morphine for this period. Therefore, NOS in­ able lack of effect on blood pressure. hibitors may not have to be administered during the development of mu opioid agonist dependence to effec­ tively inhibit opioid withdrawal. However, none of the NEUROTOXICITY ISSUES ASSOCIATED WITH investigations address the question of whether NOS inhibitors can inhibit morphine withdrawal once it is NMDA RECEPTOR ANTAGONISTS expressed. Indeed, heroin addicts are typically referred A pivotal issue concerning the therapeutic use of for medical intervention when they are actively express­ :\IMDA receptor antagonists is neurotoxicity and other ing opioid withdrawal symptoms, not when they are serious side effects that have been associated with this in a stable opioid state. Of course, this does not pre­ class of drugs. Because of these concerns, the clinical clude initially stabilizine an opioid-dependent individ­ development of NMDA receptor antagonists (and NOS ual with an orally administered opioid agonist along inhibitors) has been slowed over the last several years with a NOS inhibitor for several days and then with­ and the clinical development of these agents for the drawing the opioid agonist. treatment of stroke, head trauma, epilepsy, chronic Overall, there is striking evidence across at least pain, Parkinson's disease, and drug addiction remains four different laboratories that NOS inhibitors decrease poised for the resolution of these important issues. A narcotic-induced abstinence in both mice (Cappendijk review of these neurotoxicity issues was sponsored by et al. 1993; Kolesnikov et al. 1993b; Matwyshyn et al. the National Institute of Mental Health-Psychothera­ 1993; Thorat et al. 1994) and in rats (Kimes et al. 1993; peutic Medications Development Program (NIMH­ Vaupel et al. 1995 and this volume; Bhargava 1995a). PMDP) in 1994, and results of this conference are re­ Further research is needed to determine whether there ported in Psychopharmacology Bulletin. Included in these is a murine species difference in the capacity of NOS reports is a summary by the conference organizer (Hai­ inhibitors to effect "jumping" versus other opioid with­ gler 1994) and a review of the salient regulatory issues drawal responses. Such differentiation may provide a underlying FDA approval of these drugs (Leber 1994). preclinical tool for predicting the efficacy of NOS in­ ( Fur details of the potential neurotoxicity of NMDA hibitors in influencing the "hyperactivity" versus other receptor antagonists, see Olney et al. this volume). symptoms (gastroenterological, psychological) of opi· It has been clearly demonstrated that noncompeti­ oid withdrawal in humans. t 1ve NMDA receptor antagonists can cause acute neu­ As indicated in Table 5, there are reports on at least runal vacuolization in a small number of neurons in the five NOS inhibitors and opioid withdrawal in rodents, nngulate and retrosplenial cortex of rodent brain (Ol­ and all indicate that these drugs inhibit opioid with­ ney et al. 1989, 1991; Auer and Coulter 1994) and that drawal in either mice or rats. Three (L-NNA, L-NMMA, a small proportion of these affected neurons can un­ MB) of these agents have been investigated for their dergo necrosis (Fix et al. 1993). However, very recent effects on opioid tolerance, and results of three studies research has questioned the clinical significance of these indicate that L-NNA or MB inhibits morphine tolerancl' results. First, vacuole formation does not occur if fro­ (Kolesnikov et al. 1993b; Babey et al. 1994; Elliott et ,1en, rather than aldehyde-fixed, rodent brain is exam­ al. 1994b; Bhargava 1995a). 7-NI (and probably MB) are med (Auer 1994; Auer and Coulter 1994), suggesting the only NOS inhibitors tested to date that would not the possibility that the previously reported neurotoxic be expected to have hypertensive side effects, and, effects of NMDA receptor antagonists in rodent brain therefore, have clinical potential relative to other NOS may reflect a "fixative artifact." Second, the vacuole for­ inhibitors pending results of future investigations. Ot mation associated with NMDA receptor antagonists ap­ all the direct NOS inhibitors, 7-NI appears to be in the pears to be reversed over time and, paradoxically, oc­ lead as a clinical candidate for the treatment of opioid curs only when NMDA receptor antagonists are acutely withdrawal because it does not appear to affect vascu­ ucrsus chronically administered (Olney et al. 1989, 1991; lar epithelial NOS (Babbedge et al. 1993; Moore et al. Auer and Coulter 1994). In addition, vacuolization is 1993a and 1993b) and as a consequence does not have inhibited by pretreatment with a variety of pharmaco­ any significant effects on BP in either opioid-naive mice logical agents (Olney et al. 1991; Olney 1994). Third, (Moore et al. 1993b) or in opioid-dependent rats under­ and most important, there is now evidence that this going opioid antagonist-precipitated withdrawal (Vaupel effect may be specific to rodents, because vacuolization et al. 1995 and this volume). In contrast, L-NNA has not been obtained in squirrel monkeys given a high 286 B.H. Herman et al. NEUROPSYCHOPHARMACOLOGY 1995-VOL. 13, NO. 4

dose of MK801 (Auer 1994). These issues and related reaction in some medium to large-size neurons oflayers ones are discussed in greater detail in the following. III and IV of the cingulate and retrosplenial cortex of The neurotoxic effect of glutamate in brain and the adult Sprague-Dawley rats (Olney et al. 1989; Auer and protection afforded by NMDA receptor antagonists Coulter 1994). Electron microscopy of affected neurons have been clearly demonstrated. Following the discov­ revealed that the vacuoles were formed from saccules ery that iontophoretic application of glutamate excited of endoplasmic reticulum and were incorporating mi­ nerve cells (Curtis and Watkins 1963), it was reported tochondria and other cytoplasmic organelles. This pro­ that systemic administration of glutamate produced cess continued until the vacuoles had apparently hypothalamic lesions in the infant mouse (Olney 1969) digested the mitochondria. The potency of this effect and in infant primates (Olney et al. 1972). Further evi­ was in direct relation to their potencies for the PCP bind­ dence for a glutamatergically mediated toxicity to neu­ ing site of the NMDA receptor complex. Other investi­ rons was inferred by demonstrating that pharmacolog­ gators (Fix 1994) have reported that dose-dependent in­ ically active glutamate analogues produced toxicity in creases in GFAP are produced in some neurons of the parallel potency to their excitatory actions whereas in­ posterior cingulate/retrosplenial cortex of rats treated active analogues lacked toxicity (Olney 1971). Con­ with MK801 (Fix 1994), suggesting an astroglial re­ tinued evaluation of structural analogues of glutamate sponse to the damaged neurons. revealed two important features: differential sensitiv­ The ability of MK801 to protect against ischemic in­ ity to the agonists kainic acid quisqualate and NMDA farct and its possible neurotoxic effects was investigated (which has demonstrated utility in subtyping glutamate in the squirrel monkey using a middle cerebral artery receptors) and the usefulness of NMDA receptor an­ occlusion paradigm (Auer 1994). Although the 1-mg/kg tagonists to prevent this toxicity (Watkins 1978; Wat­ dose of MK801 produced behavioral effects similar to kins and Evans 1981). a catalepic state for 24 hours, it failed to reduce infarct The NMDA receptor antagonists a-aminoadipate size. (This is a very high dose of MK801, approximately and D-2-amino-5-phosphonopentanoate were shown equivalent to 5 mg/kg of MK801 in rats.) No lesions were to afford protection from the neurotoxic effect of noted in the cingulate or retrosplenial cortex. Although NMDA-mediated activity in the mouse (Olney et al. this work reflects the results of only one study, it does 1979, 1981). Potency screening for the capacity of com­ suggest that the NMDA receptor antagonist process of petitive and noncompetitive NMDA antagonists to cerebral vacuolization may be murine specific and may inhibit the effects of glutamate and NMDA in in vitro not generalize to primates. preparations has been summarized (Olney 1991). The second issue that must be considered in the Moreover, the neurotoxic effects of glutamate appear possible development of NMDA antagonists is be­ to be a consequence of (possibly excessive) NMDA havioral toxicity. PCP and ketamine have psychotorni­ receptor activation following ischemic or traumatic metic properties. It is not clear whether all NMDA events (Choi 1988). The mechanism is thought to be ex­ antagonists would share this disturbing property or cessive or prolonged opening of the ion channel that whether it is limited to noncompetitive NMDA antag­ allows Ca+ + ions to accumulate and begin a cascade (_mists. As reviewed, behavioral studies in rodents have of neuronal processes leading to cell injury and death. suggested that these PCP-like behavioral effects appear Given the possible benefits to be derived from NMDA to be limited to noncompetitive rather than competi­ antagonists in the clinical states that may involve tive NMDA receptor antagonists (Willetts et al. 1990; glutamate-induced neurotoxicity, there has been justified Rasmussen et al. 1991). However, there is some clini­ interest in pursuing this group of compounds for their cal evidence that competitive NMDA receptor antago­ therapeutic potential. nists also share this property. The competitive antago­ However, clear concerns must be addressed before nists CPP (Kristensen et al. 1992), CPPene (Herrling the possible testing of certain NMDA antagonists in hu­ 1994), and CGS19755 (Grotta 1994) have been reported man populations can proceed. The first issue is whether to elicit psychotic responses in human subjects. It is not NMDA antagonists are safe to administer to human clear whether these PCP-like side effects occur only at subjects, that is, whether they could be expected to in­ certain high doses or whether this is a general feature duce neurotoxic effects similar to those found in rodent of other competitive NMDA receptor antagonists. It brain. As indicated, the regulations regarding the clin­ must be remembered that the NMDA receptor complex ical testing of NMDA receptor antagonists may be contains multiple binding sites for a variety of ligands modified based on the lack of neurotoxicity seen in non­ (e.g., glycine, polyamine). The actual site being inter­ human primate brain (Auer 1994). Subcutaneous ad­ acted with may determine the pharmacological re­ ministration of noncompetitive NMDA antagonists sponse elicited, and, accordingly, there is great interest (phencyclidine, ketamine, tiletamine, and MK801) have in the development of glycine and polyamine NMDA been shown to produce a dose-related vacuolization receptor antagonists. NEUROPSYCHOPHARMACOLOGY llJY5~ VOL. 13, NO. 4 Glutamatergic Systems in Opioid Tolerance and Withdrawal 287

A third issue that may influence the risk-benefit or NO system may be critically related to relapse. As considerations in the use of NMDA receptor antago­ indicated above, relapse is the major factor perpetuat­ nists is the degree of receptor antagonism necessary to ing opiate addiction (see Ball and Ross 1991). Evidence produce a desired response. Relative safety may be in­ to support studies for this indication includes data in ferred if levels of receptor occupancy are sufficient to rodents implicating the NMDA receptor system in long­ produce the desired pharmacological effect but below term potenhation (L TP) (Collingridge et al. 1983; Harris the level of occupancy necessary for the production of and Cotman 1986; Morris et al. 1986; Errington et al. a toxic response. 1987; Xie and Lewis 1991), a process that may relate to Coadministration of neuroactive agents may pro­ the intractability and high relapse rate associated with tect against NMDA antagonist "neurotoxicity" and 'be­ opiate addiction. Indeed, the interest in NMDA recep­ havioral psychosis" (Olney 1994). Diazepam has been tors has been stimulated by the linkage to LTP, a reported to suppress ketamine-induced emergence phenomenon that produces stable increases in synap­ reactions (Reich and Silvay 1989), suggesting that in­ tic efficacy and may be a neurobiological substrate in­ creased GABAergic transmission may modulate this be­ volved in learning and memory (Collingridge et al. 1983; havioral toxicity. Olney et al. (1991) have reported that Harris and Cotman 1986; Morris et al. 1986; Errington a variety of agents protect against NMDA receptor et al. 1987). For example, Xie and Lewis (1991) have ex­ antagonist neurotoxicity, including diazepam, m 1 amined the effects of opioid agonists, opioid antago­ muscarinic anticholinergic agents (e.g., scopolamine, nists, and NMDA receptor antagonists on elec­ atropine), and barbiturates (e.g., pentobarbital, seco­ trophysiological events on hippocampal slices and in barbital). Therefore, the combined administration of the lateral performant path (LPP) of rat brain after LTP NMDA receptor antagonists with one of these agents has been induced. These researchers found that a mu (e.g., diazepam) may be another method used to elim­ agonist (Pl017) reduced the threshold for LTP and in­ inate possible "neurotoxic" or "PCP-like" side effects creased the amount of LTP in the LPP and that these of the NMDA receptor antagonists. effects were blocked by either an opioid receptor an­ Interestingly, and an important point in the opiatt:' tagonist (naloxone) or a NMDA receptor antagonist addiction field, the effects uf opioid agonists on this (APS). These data suggested that exogenous opioids NMDA receptor antagonist neurotoxic effect remains enhanced the efficiency of LTP, and that LTP in this to be investigated (Olney et al. this volume). However, pathway can be blocked by either an opioid or NMDA given that MK801 potentiates morphine lethality in rats receptor antagonist. It is intriguing to speculate that LTP (Trujillo and Akil 19916), the combination of this type may underlie the prolonged changes in opiate respon­ of noncompetitive NMDA antagonist and an opiate may sitivity produced by chronically administered opioids be too dangerous for human use. On the other hand. and underlie relapse and that this process may be dis­ given its widespread availability as a nonprescription rupted by the administration of NMDA receptor antag­ medication, it is likely that DM (also a noncompetitive (mists. The possible production of LTP by opioids, its NMDA receptor antagonist) does not produce similar interaction with the NMDA-RC, and the relationship neurotoxic effects. Therefore, studies are needed to de­ to opioid tolerance, dependence, relapse, and drug­ termine whether DM induces vacuole formation in an­ seeking behavior warrants further investigation. imal brain (in both the opiate-naive and opiate­ However, apart from testing LTP, it will be difti.cult dependent animal) and if the combination of DM and to perform tests of this hypothesis in animals because morphine in humans differentially affects the analge­ of the paucity of agreed-upon preclinical models for as­ sic versus respiratory tolerance associated with chroni­ sessing the efficacy of medications for inhibiting relapse cally administered mu opiate agonists. to opiates. Information on the effects of these agents on preclinical models that appear to address some aspects of relapse (e.g., conditioned place preference) CONCLUSIONS: CLINICAL SIGNIFICANCE would be of interest, although it is notable that Trujillo The clinical signifiance of these results for the treatment and Aki] (1994) provided evidence that some of these of opiate addiction lies in the introduction of the NMDA agents (noncompetitive NMDA receptor antagonists) receptor antagonists and NOS inhibitors for at least appear to affect nonassociative rather than associative three indications related to opiate addiction. type of tolerance. In short, the fmdings of Trujillo and First, of great interest would be to determine the Akil (1994) suggest that the effects of the noncompeti­ efficacy of the NMDA receptor antagonists and the NOS tive NMDA receptor antagonists on conditioned cues inhibitors in the prevention of relapse to intravenously may not be critical in explaining their effects on certain administered opiates in individuals previously medi­ aspects of opiate addiction (at least in rodents). Finally, cally withdrawn from opiates. Such studies would pro­ as detailed, data on the efficacy of this class of medica­ vide powerful tests of the hypothesis that the NMDA tions to inhibit and/or to reverse the development of 288 B.H. Herman et al. NEUROPSYCHOPHARMACOLOGY 1995-VOL. 13, NO. 4

tolerance may also provide preclinical models of medi­ The high probability of this type of clinical interven­ cations to be used in relapse prevention. tion's working is based on the significant effects of DM The second indication is to utilize these medications (e.g., Elliott et al. 1994a), LY274614 (Tiseo and Inturrisi in the treatment of opioid withdrawal symptoms. Evi­ 1993; also see recent preliminary report of significant dence to support this indication includes the significant effects with LY235959 by Matwyshyn and Bhargava effects of noncompetitive NMDA receptor antagonists 1995), ACPC (Kolesnikov et al. 1994), L-NNA (Koles­ with clinical potential (e.g., DM), competitive NMDA nikov et al. 1993), L-NMMA (Bhargava 1995b), and MB receptor antagonists (e.g., LY274614), glycine antago­ (Babey et al. 1994) in inhibiting mu (morphine) opioid nists (e.g., felbamate, although see the problems with tolerance in the rodent. The safety profile and clincial this medication delineated above) and direct NOS in­ availability of DM and MB over these other medications hibitors (e.g., L-NNA, L-NMMA, 7-NI) in the treatment may provide an advantage of these agents for this novel of morphine withdrawal in rodents (e.g., Koyuncuoglu indication. et al. 1990; Rasmussen et al. 1991; Kimes et al. 1993; The importance of testing other NOS inhibitors Kolesnikov et al. 1993b; Kosten et al. this volume; such as 7-NI given its lack of side effects on BP (Vaupel Vaupel et al. 1995 and this volume; MB remains to be et al. 1995 and this volume) in the inhibition and rever­ tested for this effect; although see lack of effect reported sal of mu opioid tolerance in rodents is clearly indicated. for LY235959 by Matwyshun and Bhargava 1995). As If these 7-NI preclinical trials are successful, then simi­ a first step, it would seem reasonable to attempt to repli­ lar tests with nonhuman primates would be of interest. cate some of the OM, LY274614, felbamate, 7-NI studies Subsequently, trials of 7-NI in humans would be indi­ in opioid-dependent monkeys described before, since cated providing that the safety, toxicology, and phar­ there is high predictive validity for the efficacy for most macokinetics profile of this agent proves to be satisfac­ other classes of medications for the treatment of opioid tory considering that 7-NI is not yet approved by the withdrawal symptoms in rhesus monkeys for humans FDA for any indication. A drawback in the clinical de­ (Aceto et al. 1982, 1986, 1990). velopment of 7-NI is that it is currently only available In the case of 7-NI it may be reasonable to under­ as an injection, and that the availability of an oral or take a small inpatient trial to test this hypothesis using nasal route is critical for fostering a medication for the the injectable form of 7-NI as a first step to assess its treatment of any aspect of opiate addiction. efficacy for the treatment of opioid withdrawal in hu­ The future indicates that the clinical medication de­ mans. However, it is doubtful whether 7-NI will prove velopment of the various types of noncompetitive and more effective and with lower side effects than con­ competitive NMDA receptor antagonists, the glycine ventional treatments (e.g., medically supervised with­ antagonists, and the NOS inhibitors may proceed on drawal with methadone or alpha-2-adrenergic ago­ a faster track for the treatment of various aspects of opi­ nists). Indeed, it appears likely that 7-NI may exacerbate ate addiction than for any other indication, including certain opioid withdrawal symptoms, including the stroke, head trauma, epilepsy, or Parkinson's disease. "hyperactivity" of opioid withdrawal (e.g., Kimes et al. The reason for this is the substantial preclinical litera­ 1993; Vaupel et al. 1995 and this volume). Second, an ture already suggesting a role for these medications in advantgage of 7-NI for this indication would be sug­ the treatment of opiate addiction and that continued gested if 7-NI was found to affect the "psychological self-administration of intravenous opiates is associated distress" associated with opioid withdrawal and.1or if with considerable morbidity and mortality (e.g., AIDS). 7-NI was found to influence the more prolonged symp­ Therefore, it is of great relevance to medicine and to toms of opioid withdrawal that do not appear to be society in general to support pharmacological research affected by some other medications. Neither of these 1t1 this important area in the future. effects have been demonstrated for 7-NI, although a lack of effect of 7-NI versus clonidine on BP in humans would represent a strong third advantage (Vaupel et al. 199'i I Third, coadministering these medications with ap­ ACKNOWLEDGMENTS proved opiate agonist maintenance medications (e.g .. methadone, LAAM) could be used to decrease the toler­ The authors gratefully express their appreciation to Drs. E. Weber and H. Haigler and to Drs. K. Elliott, H. Heinemann, ance or dependence to mu opiates and eventually tu C Inturrisi, A. Kimes, T. Kosten, E. London, D. Mayer, help an individual achieve the transition from an opi­ J. Olnev, G. Pasternak, C. Rasmussen, R. Rosen, R. Rosse, ate agonist to an opiate antagonist type of therapy. K. Trujillo, and B. Vaupel for providing thoughtful discussion Medications with this type of potential include the non­ and intellectual guidance prior and during the NIDA Techni­ competitive NMDA receptor antagonists (e.g., DM), cal Review that led to this manuscript. Our appreciation to M. G. Palfreyman for sharing his published the competitive NMDA receptor antagonists schematic of the (e.g .. NMDA receptor complex. Expert assistance in medical library LY274614), the glycine antagonists (e.g., ACPC), and research was provided by Joanne Gampel, M.A., of MDD, the NOS inhibitors (e.g., 7-Nl, L-NNA, L-NMMA, MB) '\"IDA. assisted by LaQuanda Brown. Word processing as- NEUROPSYCHOPHARMACOLOGY 199'i-VOL. 13, NO. 4 Glutamatergic Systems in Opioid Tolerance and Withdrawal 289

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