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To Get This Paper in Adobe Acrobat PDF Format FEBS 23468 FEBS Letters 470 (2000) 309^314 Morphine-related metabolites di¡erentially activate adenylyl cyclase isozymes after acute and chronic administration Klaus Eckhardtb, Igal Nevoa, Rivka Levya, Gerd Mikusb;1, Michel Eichelbaumb, Zvi Vogela;* aDepartment of Neurobiology, The Weizmann Institute of Science, 76100 Rehovot, Israel bDr. Margarete Fischer Bosch Institute of Clinical Pharmacology, Auerbachstr. 112, 70376 Stuttgart, Germany Received 24 January 2000; received in revised form 28 February 2000 Edited by Shmuel Shaltiel shown that when these and several other G -coupled recep- Abstract Morphine-3- and morphine-6-glucuronide are mor- i=o phine's major metabolites. As morphine-6-glucuronide produces tors (e.g. D2-dopaminergic, m2- and m4-muscarinic, K2-adren- stronger analgesia than morphine, we investigated the effects of ergic, somatostatin) are chronically activated, there is an in- acute and chronic morphine glucuronides on adenylyl cyclase crease in cAMP accumulation, which is particularly apparent (AC) activity. Using COS-7 cells cotransfected with representa- upon withdrawal of the inhibitory agonist [3^11]. This phe- tives of the nine cloned AC isozymes, we show that AC-I and V nomenon has been referred to as AC sensitization, or super- are inhibited by acute morphine and morphine-6-glucuronide, and activation, and is believed to represent a possible biochemical undergo superactivation upon chronic exposure, while AC-II is substrate for the development of drug tolerance and depen- stimulated by acute and inhibited by chronic treatment. dence, commonly observed upon prolonged exposure to opi- Morphine-3-glucuronide had no effect. The weak opiate agonists ate drugs [3,12]. codeine and dihydrocodeine are also addictive. These opiates, in The opiate agonist morphine is metabolized in humans to contrast to their 3-O-demethylated metabolites morphine and dihydromorphine (formed by cytochrome P450 2D6), demon- morphine-3- and morphine-6-glucuronides. While it was pre- strated neither acute inhibition nor chronic-induced superactiva- viously considered that glucuronide metabolites are pharma- tion. These results suggest that metabolites of morphine cologically inactive and that their formation is a mechanism (morphine-6-glucuronide) and codeine/dihydrocodeine (mor- for the detoxi¢cation and elimination of the parent com- phine/dihydromorphine) may contribute to the development of pound, it is now recognized that their formation might have opiate addiction. important pharmacological implications. In animal experi- z 2000 Federation of European Biochemical Societies. ments, both glucuronides have been shown to in£uence the analgesic e¡ects of morphine. Morphine-6-glucuronide exhib- Key words: Morphine; Glucuronide; Codeine; ited both a higher analgesic potency [13^15] and an increased Dihydrocodeine; Opioid receptor; Adenylyl cyclase physical dependence [15] compared with morphine. These re- sults appear to be in contrast to binding studies in which morphine-6-glucuronide and morphine displayed comparable 1. Introduction binding to the W-receptor [13,16]. On the other hand, mor- phine-3-glucuronide showed only a poor a¤nity to the W-re- Opiate agonists are the drugs of choice for the treatment of ceptor and even antagonized morphine's analgesic e¡ect [17]. moderate and severe pain, although their use is limited due to Indeed, recent investigations point to a new binding site for side e¡ects, including the development of tolerance, respira- morphine-6-glucuronide, di¡erent than the known W-opioid tory depression and constipation. Pharmacological studies receptor type 1 (MOR-1) [18,19]. However, the role of have de¢ned three types of opioid receptors, termed W, N MOR-1 in mediating the acute and chronic signaling elicited and U, which di¡er in their a¤nity for various opioid ligands, by opiates, such as morphine-6-glucuronide and heroin, has their distribution in the nervous system, and their physiolog- not yet been systematically investigated. It was therefore of ical and behavioral pro¢les [1,2]. The three opioid receptors interest to determine whether the acute and chronic activation are members of the seven-transmembrane domain GTP-bind- of the W-receptor with such compounds in transfected Chinese ing protein (G protein)-coupled receptor superfamily. Activa- hamster ovary (CHO) and African green monkey kidney tion of these receptors inhibits the activity of adenylyl cyclase (COS-7) cells would yield results similar to those observed (AC) via the Gi=o type of G proteins. Yet, we and others have with morphine. Moreover, we have previously shown that not all of the nine isozymes of AC which have been identi¢ed to date [20,21] behave identically with respect to regulation by *Corresponding author. Fax: (972)-8-934 4131. morphine [11]. It was therefore of interest to study the regu- E-mail: [email protected] lation of these AC isozymes by morphine metabolites and derivatives. 1 Present address: Department of Internal Medicine VI, Clinical Pharmacology and Pharmacoepidemiology, Bergheimerstr. 58, 69115 Besides the strong opiate morphine, the weak and moderate Heidelberg, Germany. opiates codeine and dihydrocodeine (see formulas in Fig. 1) are used in the treatment of mild to moderate pain, as well as Abbreviations: AC, adenylyl cyclase; BSA, bovine serum albumin; in cough treatment. Prescription analgesics, including these CHO, Chinese hamster ovary; CYP2D6, cytochrome P450 2D6; opiates, are among the major classes of drugs prescribed DMEM, Dulbecco's modi¢ed Eagle's medium; FS, forskolin; G pro- tein, GTP-binding protein; IBMX, 1-methyl-3-isobutylxanthine; and used worldwide [22]. Codeine and dihydrocodeine, alone MOR, W-opioid receptor; TSH, thyroid-stimulating hormone or in combination with other drugs, are among the most 0014-5793 / 00 / $20.00 ß 2000 Federation of European Biochemical Societies. All rights reserved. PII: S0014-5793(00)01329-6 FEBS 23468 23-3-00 310 K. Eckhardt et al./FEBS Letters 470 (2000) 309^314 widely abused prescription drugs [22,23]. While these drugs moved and the reaction terminated by addition of perchloric acid present only weak binding to the W-receptor (probably due containing 0.1 mM unlabeled cAMP, followed by neutralization, and the amount of [3H]cAMP was determined by a two-step column to the blockage of the 3P OH position), they are metabolized separation procedure [10]. Chronic treatment was achieved by incu- by the enzyme cytochrome P450 2D6 (CYP2D6) to form the bating the cells for 4 h with the indicated concentrations of agonists, strong opiates morphine and dihydromorphine [24,25] (Fig. followed by agonist withdrawal (by quick removal of medium and 1). Consequently, the question arises of whether it are codeine addition of fresh medium containing 1 WM of the opiate antagonist naloxone) and the addition of the appropriate AC stimulator (see and dihydrocodeine themselves, or rather their 3-O-demethyl- above) to assay cAMP accumulation. The incubation with ated metabolites morphine and dihydromorphine, that lead to [3H]adenine took place during the last 2 h of the chronic exposure. addiction and withdrawal symptoms. We therefore investi- Uptake of [3H]adenine into the cells was not a¡ected by the chronic gated the e¡ects of codeine and dihydrocodeine in comparison agonist treatments. to the e¡ects of morphine and dihydromorphine on AC ac- Statistical analysis of the data was performed using the Student's t-test. Curve ¢tting and calculation of EC50 and IC50 were done by tivity in CHO cells stably transfected with the MOR. non-linear regression using the GraphPad software package (ISI Soft- ware, Philadelphia, PA, USA). 2. Materials and methods 2.1. Materials 3. Results [3H-2]Adenine (18.0 Ci/mmol) was purchased from American Ra- diolabeled Chemicals (St. Louis, MO, USA). Morphine and dihydro- 3.1. E¡ects of acute and chronic morphine and morphine morphine were obtained from the National Institute of Drug Abuse, glucuronides on AC activity Research Technology Branch (Rockville, MD, USA), and naloxone was purchased from Research Biochemical International (Natick, Dose^response curves for the e¡ects of acute and chronic MA, USA). Morphine-3- and morphine-6-glucuronide, codeine and agonist exposures on AC activity in CHO cells are depicted in 3-ethylmorphine, as well as forskolin (FS), cAMP and thyroid-stim- Fig. 2. Signi¢cant inhibition of FS-stimulated cAMP accumu- ulating hormone (TSH), were obtained from Sigma (St. Louis, MO, lation was observed in cells acutely treated with morphine or USA). Dihydrocodeine was obtained from Knoll Pharma (Lud- wigshafen, Germany). Ionomycin and the phosphodiesterase inhibi- morphine-6-glucuronide. Both materials showed similar ef- tors 1-methyl-3-isobutylxanthine (IBMX) and RO-20-1724 were from fects on AC inhibition with IC50 values of 92 þ 9 nM and Calbiochem (La Jolla, CA, USA). Tissue culture reagents were from 71 þ 25 nM, respectively (Fig. 2a). No signi¢cant inhibition Life Technologies (Gaithersburg, MD, USA). was observed for morphine-3-glucuronide. We have previously shown that chronic exposure to mor- 2.2. Plasmids Plasmids containing AC cDNAs (pXMD1-AC-I, pXMD1-AC-II phine followed by removal of the agonist by extensive wash or and pXMD1-AC-V), as well as pXMD1-gal, rat TSH receptor in the addition of the antagonist naloxone leads to AC super- pSG5, and rat MOR in pCMV-neo have previously been described activation [9]. Fig. 2b shows that chronic treatment of CHO-W [11]. cells by either morphine or morphine-6-glucuronide induces 2.3. Transfected cells AC superactivation. The level of superactivation is dependent The CHO cell line stably transfected with the rat MOR cDNA on the concentration of these ligands during the chronic ex- (CHO-W) was previously described [9]. The CHO-W cells were cultured posure prior to the agonist withdrawal. The EC50 values for in Dulbecco's modi¢ed Eagle's medium (DMEM) supplemented with AC superactivation by these opiate agonists appear to be 8% fetal calf serum, 2 mM glutamine, non-essential amino acids, similar to the IC values for inhibition: 127 þ 27 nM and 0.2 mg/ml G418, 100 U/ml penicillin and 100 Wg/ml streptomycin in 50 136 þ 56 nM, respectively.
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