Psychopharmacology (1992) 106:189-194 Psychopharmacology Springer-Verlag 1992

Discriminative stimulus effects of cyclorphan: selective antagonism with naltrexone

Albert J. Berta|mio and James H. Woods Departments of Psychology and Pharmacology, University of Michigan, Ann Arbor, MI 48109-0626, USA Received June 4, 1990 / Final version September 13, 1990

Abstract. The opioid antagonist, naltrexone, was used to to discriminate ethylketazocine (EKC) yielded high levels identify some of the receptor mechanisms responsible for of EKC-appropriate responding. Nevertheless, the levels the discriminative stimulus effects of cyclorphan in the that were attained with/-cyclorphan were not as high as pigeon. Subjects were trained to discriminate 10 mg/kg those that were readily obtainable with EKC itself, i.e., IM injections of either morphine or dextrorphan from there was a "ceiling" effect. Thus, that study suggested saline injections in a two key drug discrimination that /-cyclorphan shares some properties with opioid procedure in which responding was maintained by food agonists, but it also suggested that/ocyclorphan differs presentation. The dextrorphan-trained birds generalized from drugs in the opioid agonist class in some way. In to/-cyclorphan at 10 mg/kg; naltrexone did not alter the another phase of the previous study pigeons were chron- /-cyclorphan dose-response curve for this effect. In the ically treated with morphine and trained to discriminate morphine-trained group, l-cyclorphan produced only injections of naltrexone. The morphine-treated nal- partial generalization, and naltrexone greatly increased trexone-trained pigeons generalized fully to /-cyclor- the dose of/-cyclorphan necessary to produce this effect. phan, indicating that /-cyclorphan also shares some These results are consistent with the conclusion that in properties with drugs in the opioid antagonist class. morphine-trained pigeons the partial generalization to Finally, cyclazocine-trained pigeons generalized com- /-cyclorphan is mediated by opioid receptors. Moreover, pletely to /-cyclorphan, which was taken to mean that limited intrinsic efficacy at mu opioid receptors may be /-cyclorphan also shares some properties with phency- the characteristic of /-cyclorphan that prevents full clidine(PCP)-like drugs in this species. generalization in morphine-trained pigeons, d-Cyclor- It was not clear what receptor mechanisms were re- phan produced partial generalization in both groups, but sponsible for the atypical pattern of discriminative stimu- the involvement of opioid receptor mechanisms could lus effects found with /-cyclorphan. In the pigeon, if a not be confirmed, as 1 mg/kg naltrexone did not an- drug produces high levels of EKC-appropriate respond- tagonize d-cyclorphan in either group. ing it is considered likely that it does so by acting at mu opioid receptors, rather than at kappa opioid receptors Key words: Cyclorphan - Naltrexone - Levorphanol - (e.g., Herling and Woods 1981). Nevertheless, the ceiling Dextrorphan - Opioid antagonism - Intrinsic efficacy - effect found with/-cyclorphan in EKC-trained pigeons Drug discrimination - Morphine cast some doubt on the involvement of any opioid recep- tor mechanism in the discriminative stimulus effects of /-cyclorphan. On the other hand, if mu opioid receptor mechanisms were actually involved in producing such In this study the opioid antagonist, naltrexone, was used EKC-appropriate responding as did occur, then it was to help identify some of the receptor mechanisms respon- not clear what factor was imposing a ceiling. It was sible for the discriminative stimulus effects of/-cyclor- hypothesized that effects of/-cyclorphan on the PCP phan in the pigeon. In a previous drug discrimination receptor system might produce a PCP- or cyclazocine- study /-cyclorphan exhibited a complex profile of like cue that limited the levels of EKC-appropriate re- pharmacological activity (Herling et al. 1982). In that sponding that could be obtained with/-cyclorphan (Hert- study administration of/-cyclorphan to pigeons trained ing et al. 1982). In some cases an opioid antagonist can be used as a Offprint requests to: A.J. Bertalmio, Department of Pharmacology, tool to determine whether or not a drug is producing a M6322 Medical Science Building I, University of Michigan Medical behavioral effect through an opioid receptor system, al- School, Ann Arbor, MI 48109~)626, USA though it cannot be safely assumed that this will univer- 190

sally be the case (e.g., Young and Woods 1981). In the Following the injection the subject was placed in the experimental present study the discriminative stimulus and rate-reduc- chamber for the TO, during which the chamber was unilluminated ing effects of l- and d-cyclorphan were determined in and responses had no programmed consequences. During the re- sponse period the houselight was illuminated, the center and right pigeons trained to discriminate either the mu opioid keys were transilluminated, and reinforcement contingencies were receptor agonist, morphine, or the PCP receptor ligand, in effect. dextrorphan, i.e., drugs which in this species share dis- Some subjects were trained with 10 mg/kg morphine; others criminative stimulus properties with EKC and cyclazo- were trained with 10 mg/kg dextrorphan. The single trial of a cine, respectively (Herling et al. 1980, 1983). Then nal- training session was initiated with an injection of either the training trexone was given in combination with l- and with d- drug or a saline solution, i.e., the vehicle for the training drug. During the response period of a training session, emission of 20 cyclorphan in an attempt to reveal the opioid receptor- consecutive responses (CR 20) on the key that had been designated specific component of the mechanism of action of cyclor- as correct for that session activated the feeder for a 4-s period. While phan in these preparations. For reference, results from the feeder was activated the subject had access to grain. these antagonism experiments were compared to results For sessions initiated with a training drug injection, the right key from antagonism experiments in which naltrexone was was designated as correct; the center key was designated as correct used in combination with dextrorphan and its optical for saline injection sessions. Incorrect responses reset the response requirement on the correct key to 20. Response periods were stereoisomer levorphanol. Levorphanol and dextrorphan scheduled to be 60 min in duration, but if the subject gained access are close congeners of l- and d-cyclorphan, respectively. to food 32 times prior to the expiration of 60 min, the remainder Also, levorphanol, like morphine, is believed to act pref- of the response period was spent under TO conditions. Performance erentially at the mu opioid receptor, but levorphanol, in the response period of a training session was considered to be unlike l-cyclorphan, substitutes fully in morphine-trained adequate if the subject met a series of criteria which included pigeons. making no more than 39 responses prior to the first food presenta- tion and making at least 90% of all responses on the key that had been designated as correct for that session. Successive training sessions were scheduled until the subject met the performance Materials and methods criteria for eight consecutive sessions; then testing was initiated. Test sessions differed from training sessions in that they consist- Subjects. Pigeons (Colurnba livia) of the White Carneaux variety ed of a number of discrete trials. In a test trial the response period were individually housed, with water and grit freely available. To was 5 min in duration; ifa subject obtained access to food 10 times maintain the weights of the birds at no less than 80 % of free feeding before the expiration of 5 min, the remainder of the response period levels, Purina Pigeon Checkers and/or a mix of grains was provided was spent under TO conditions. Also, during the response period daily in the home cage, subsequent to any participation in the of a test trial, completion of a CR 20 on either key led to food experiment scheduled for that day. All subjects had previously been presentation. A test session was scheduled only if the subject had used in other experiments. In general, the eight birds in the mor- performed adequately for two successive training sessions, i.e., a phine-trained group had been exposed to opioid agonists, convul- training drug injection session and a saline injection session. If a sants and anticonvulsants, PCP-like drugs, and a few other drugs. subject failed to satisfy the criteria for adequacy in one of these In the dextrorphan-trained group the six subjects had been exposed sessions, testing was postponed and additional training sessions to other PCP-like drugs, to opioid agonists and antagonists, and to were run until the subject again met the criteria. All sessions were some other drugs. run at approximately the same time of day. Apparatus. Experiments were performed in 25 cm • 28 cm x (height) Data analysis. Data are presented only for contingent responding, 30 cm test cages (model El0-10, Coulbouru Instruments Inc. (CI), i.e., responding occurring on the two transilluminated keys during Lehigh Valley, PA), which were enclosed in ventilated isolation the response period. Data for the discriminative stimulus effects of chambers (model E 10-20, CI). A horizontal array of three translu- drugs are presented as the percent training-drug-appropriate re- cent plastic bird-pecking response keys (modified model E21-17, sponding, i.e., the number of responses made on the right key CI) was centered in one end wall of each test cage, 22 cm above the divided by the sum of the responses made on both the center and floor. Each key was approximately 2.5 cm in diameter; the lateral right keys, with the resultant fraction being multiplied by 100. Also keys were separated from the central key by approximately 5.5 cm. included are data on the overall rate of responding expressed as Each key could be transilluminated with a red 7 W bulb that was responses per second, i.e., the total number of responses made on located directly behind it. Exertion of sufficient pressure on a key both transilluminated keys, divided by the number of seconds to activate the electrical switch behind it was defined as emission of elapsed until either ten food presentations were attained or the an operant response on that key. Directly below the central key, 5-min response period expired. 9 cm above the cage floor, was a 5.7 cm x 6.3 cm rectangular aper- Data were computed for each subject on each trial of the test ture, and directly behind the aperture was a solenoid-operated session. If a test was repeated in a subject, results were averaged. feeder (model G5610, Ralph Gerbrands Co., Arlington, MA), Any data available on the discriminative stimulus effects of drugs which contained a mix of grains. A houselight (model E10-O1, CI) obtained when the rate of responding of a subject was reduced to was located in the upper right corner of the end wall. Programming less than 0.1 response per second were discarded. of experimental contingencies was accomplished with a digital com- Group data are the average of the data from all the subjects puter (model 960A, Texas Instruments Inc., Dallas, TX); data participating in a test, unweighted for any differences in the number collection was accomplished with the computer and cumulative of times the test was repeated across subjects. For any given trial recorders (Ralph Gerbrands Co.). of a test, group data for the discriminative stimulus effects of drugs are not presented unless data were available from at least two Procedure. The subjects performed in a two key operant drug subjects. Rate data for the group represent all of the animals in a discrimination procedure in which there was one trial during train- test for all trials in the test, e.g., if an animal stopped responding ing sessions but multiple discrete trials during test sessions. All trials earlier in a test than did the other animals, that animal was assigned of both training and test sessions consisted of an injection, a 10-rain a rate of zero for all the remaining trials of the test. In cases where time out (TO) period, and a period for responding. multiple injections of a test drug were administered during a session The injection at the start of the trial was made into the pectoral (i.e., cumulative dosing), results are expressed as the total amount muscle while the subject was hand-held outside of the chamber. of that drug that had been administered from the start of the session 191

through the trial on which the data were collected. When cumula- MORPHINE-TRAINED DEXTRORPHAN-TRAINED tive dosing was used, replications of the test were not averaged if different dosing regimens were used across tests; in this case the results obtained with only one of the dosing regimens were selected to represent all of the data for that test. .~. 6ol 6O 40 Drugs. The drugs used in the study included dextrorphan tartrate, r- 2 ,. levorphanol tartrate, and l- and d-cyclorphan hydrochloride, all of . . ! ~/ . which were provided by Hoffman-La Roche, Inc., Nutley, NJ. C 0.3 1 3 10 30 C 0,3 1 3 10 30 Naltrexone hydrochloride was provided by Endo Laboratories, Garden City, NY. Morphine sulfate was purchased from Mallinc- krodt Chemical Works, St Louis, MO. All drugs were dissolved in 4~ ~--~. 1 4.o sterile, 0.9% saline solution. 3:o r--?-- !2oI 20 Results ~-~ 1.0t 1.0 "'I'-.. o, co:3 i 3 fo 31o o co:3 i 5 ~o 30 The discriminative stimulus and rate-reducing effects of CUMULATIVE DOSE (MG/KG) morphine and dextrorphan were evaluated in two groups Fig. 1. Dose-response curves for the discriminative stimulus (upper of pigeons, one group trained to discriminate morphine panels) and rate-reducing (lower panels) effects of morphine and (Fig. 1, left panels) and the other trained to discriminate dextrorphan in pigeons trained to discriminate injections of either dextrorphan (Fig. 1, right panels). For each group, in- morphine (left panels) or dextrorphan (right panels) from saline creasing the dose of the drug with which that group had injections. The upper panel ordinates indicate the percentage of all responses made that were made on the training-drug-appropriate been trained yielded monotonic increases in percent key. Lower panel ordinates indicate the rate of responding. The drug-appropriate responding. In morphine-trained sub- abscissae represent cumulative drug dose. The scale of the abscissae jects morphine produced over 90% morphine-appro- are logarithmic. Any points at C represent control values from the priate responding at a cumulative dose of 10 mg/kg, the first trial of the session, in which the drug vehicle alone was injected ; acute dose used in training. In dextrorphan-trained sub- control data were not obtained in all cases. Data represent tests jects dextrorphan produced over 90% dextrorphan- conducted in at least four subjects. Vertical bars indicate +/--SE. Some points have been slightly laterally displaced to improve clarity appropriate responding only at a cumulative dose of 20 mg/kg, i.e., one quarter log unit higher than the acute dose with which the subjects in this group had been trained. At the lowest dose that yielded over 90% injected on the first trial of a test session and sham training-drug-appropriate responding, neither morphine injections were given at the start of each of the remaining nor dextrorphan substantially suppressed rates of re- trials, rates of responding did not differ substantially sponding, i.e., rates were not suppressed to less than half from the rates obtained when saline was injected on all of the rates found at lower doses. trials. In the dextrorphan-trained birds the 0.1 and When morphine was tested in the dextrorphan-trained 1 mg/kg doses did not produce more than 10% drug- group and dextrorphan was tested in the morphine- appropriate responding on any trial. In the morphine trained group, neither produced more than 25% training- group the 0.1 and 1 mg/kg doses produced less than 10% drug-appropriate responding, even though each was test- training-drug-appropriate responding on the first five ed up to doses that completely suppressed responding. trials of the session, but on the sixth they produced 23% Both morphine and dextrorphan were about one quarter and 33 %, respectively. In the morphine-trained group the log unit less potent in reducing rates of responding in the 10 mg/kg dose of naltrexone substantially suppressed subjects that had been trained to discriminate them than responding, and it also produced 24% and 36% drug- they were in reducing rates of responding in the other appropriate responding on the fifth and sixth trials, re- group of subjects. spectively. In the dextrorphan group the 10 mg/kg dose The discriminative stimulus and rate-modulating ef- had no greater effect than did the 1 mg/kg dose. fects of repeated saline injections and the time course of The effects of naltrexone on the discriminative stimu- the discriminative stimulus and rate-modulating effects lus properties of dextrorphan and those of its optical of 0.1, 1 and 10 mg/kg doses of naltrexone were also stereoisomer, ievorphanol, were determined in both mor- determined in both groups of subjects (data not shown). phine-trained and dextrorphan-trained pigeons (Fig. 2). Test sessions in which saline was injected for six suc- The effects of levorphanol in these preparations resem- cessive trials were held at various times over the course bled those produced by morphine, except that levor- of the study. In these tests one bird in each group re- phanol was approximately one half log unit more potent sponded predominantly on the training-drug-appro- than morphine in producing morphine-like discrimina- priate key during some of the test trials; all data from tive stimulus effects; it was also slightly more potent than these two birds were, therefore, excluded from the study. morphine in suppressing responding (data not shown). The remaining subjects in both groups responded almost On the first trial of the antagonism tests, i.e., with only exclusively on the saline-injection-appropriate key naltrexone having been administered, results were gener- during all six trials of such sessions, and their rates of ally similar to those observed during the first trial of the responding varied little from trial to trial. control experiments conducted with naltrexone alone, In both groups when 0.1 or 1 mg/kg naltrexone was except that in the morphine-trained group the 10 mg/kg 192

LEVORPHANOL DEXTRORPHAN I-CYCLORPHAN d-CYCLORPHAN MORPHINE-TRAiNED MORPHiNE-TRAINED 1 e--QALONE 7" I O01 I--OALONE 1001 O-- O ,',LONE 9 A+ Ol NLT 9 Ae 0,1NLT '~ I v- v+ i Ntr S0 T-- V§ I NLT V-- V* 1NLf t)--"O+ 1o NLT 'b---- e * 10NLT a01 o~ o~, ~! 6o 60 ~ 6~l 6O 40 // 4O ~ 40 t 40 2 2

:E O| 9 I C0.3 I 3 10 30 C0.3 1 3 10 30 C 0.1 0.3 1 3 10 30 C 0.1 0.3 1 3 10 30 OlEXTRORPHAN--TRAINED ,o, 4 '~176 ,~176 80 8~ I OOJ ~ 6oi 60 40 o~ 20 l 2O ol- o-- I, cola i 5 (o 30 co.a i 3 io ao C 0.1 0.3 1 3 10 30 C 0.1 0.3 1 3 10 30 CUMULATIVE DOSE (MG/KG) CUMULATIVE DOSE OJG/KG) Fig. 2. Dose-response curves for the discriminative stimulus effects Fig. 3. Dose-response curves for the discriminative stimulus effects of levorphanol (left panels) and dextrorphan (right panels) in of l-cyclorphan (left panels) and d-cyclorphan (right panels) in morphine-trained pigeons (upper panels) and dextrorphan-trained morphine-trained pigeons (upper panels) and dextrorphan-trained pigeons (lower panels), and modulation of these dose-response pigeons (lower panels), and modulation of these dose-response curves by naltrexone. For the antagonism studies, control points at curves by naltrexone. Other details as in Figs. l and 2 C represent results obtained with the indicated dose of naltrexone alone, given on the first trial of the test. For tests performed with the agonist alone, if control observations were made, the points at C represent an injection of the drug vehicle alone on the first trial gressively higher doses (Fig. 2, lower left panel). With the of test. The effects of dextrorphan alone in the dextrorphan-trained 10 mg/kg dose of naltrexone there was an upward shift pigeons are repeated from Fig. l, for easier reference. Other details as in Fig. 1 in the curve, as has been shown in other studies (e.g., Herling et al. 1983); with this dose of naltrexone, levor- phanol produced over 90% dextrorphan-appropriate re- sponding at a cumulative dose of 20 mg/kg. As was the dose of naltrexone produced intermediate levels of mor- case in the morphine-trained birds, naltrexone had no phine-appropriate responding (Fig. 2, upper panels). systematic effects on the dose-response curves for dex- The pattern of modulatory effects exerted by nal- trorphan in this preparation (Fig. 2, lower right panel). trexone differed depending on the agonist, the prepara- The discriminative stimulus effects of the stereoiso- tion, and the effect being observed. In the morphine- mers of cyclorphan are displayed in both morphine- trained group naltrexone failed to produce an increase in trained and dextrorphan-trained subjects in Fig. 3. In the the dose of levorphanol necessary to suppress respond- morphine-trained group over the range of cumulative ing; if anything, naltrexone acted synergistically in re- doses from 0.3 to 10 mg/kg, l-cyclorphan produced be- ducing rates (rate data not shown). Consequently, in this tween 50% and 68% training-drug-appropriate respond- preparation a surmountable antagonism of the mor- ing (Fig. 3, upper left panel); at 20 mg/kg it produced a phine-like discriminative stimulus effects of levorphanol slightly higher level of morphine-appropriate respond- could not be demonstrated; the actual pattern observed ing, but this dose also suppressed rates to 0.25 responses was a non-dose-dependent insurmountable antagonism per second. In the dextrorphan-trained group,/-cyclor- (Fig. 2, upper left panel). Naltrexone had no systematic phan produced a dose-dependent increase in drug-appro- effect on either the discriminative stimulus (Fig. 2, upper priate responding, with over 90% of responding occur- right panel) or rate-modulating properties of dextror- ring on the drug-appropriate key at 10 mg/kg (Fig. 3, phan in the morphine-trained group of subjects. lower left panel). In both groups d-cyclorphan produced In contrast to the case found in the morphine-trained intermediate levels of training-drug-appropriate re- group, in dextrorphan-trained subjects the 0.1 and sponding (Fig. 3, fight panels), but only at doses that also 1 mg/kg doses of naltrexone progressively increased the substantially reduced rates of responding. In each group dose of levorphanol that was required to suppress re- it was approximately one half log unit less potent than sponding (rate data not shown). Nevertheless, the /-cyclorphan in reducing rates. 10 mg/kg dose of naltrexone produced no further shift. The effect of naltrexone on cyclorphan dose-response When 1 or I0 mg/kg naltrexone was given in this group, curves was specific for the isomer, effect, and prepara- the doses of levorphanol required to suppress responding tion. In the morphine-trained group the 1 mg/kg dose of were 10-fold greater than the doses required to suppress naltrexone shifted the/-cyclorphan dose-response curve responding when these same doses of naltrexone were for producing intermediate levels of training-drug- used in the morphine-trained subjects. The 0.1 and appropriate responding to over 30-fotd higher doses of 1 mg/kg doses of naltrexone also shifted the levorphanol /-cyclorphan (Fig. 3, upper left panel). The/-cyclorphan dose-response curve for the production of intermediate dose-response curve for rate reduction was not shifted by levels of dextrorphan-appropriate responding to pro- naltrexone; in the presence of the 1 mg/kg dose, l- cyclor- 193

phan totally suppressed rates at 20 mg/kg. In the dextror- effect. This was a situation in which one would expect phan-trained pigeons, the 1 mg/kg dose of naltrexone that it would be difficult to demonstrate a "textbook" had no effect on either the discriminative stimulus (Fig. case of competitive antagonism; in this regard this 3, lower left panel) or rate-modulating effects of/-cyclor- preparation resembled many other behavioral prepara- phan. Similarly, the 1 mg/kg dose of naltrexone had little tions (e.g., Young and Woods 1981). Nevertheless, this effect on dose-response curves for d-cyclorphan in either was not the case with/-cyclorphan, which produced over morphine-trained or dextrorphan-trained subjects. The 60% morphine-appropriate responding at 0.3 mg/kg, but 1 mg/kg dose of naltrexone was used with cyclorphan which began to reduce rates only at a dose of 10 mg/kg. because a higher dose (i.e., I0 mg/kg) appeared to Thus, it was easier to demonstrate antagonism of the produce substantial response suppression in the mor- morphine-like discriminative stimulus effects of/-cyclor- phine-trained group and intermediate levels of mor- phan, because the rate-reducing effects of/-cyclorphan phine-appropriate responding in some cases (e.g., Fig 2., did not have to be simultaneously antagonized. upper panels). Although the antagonism of the discriminative stimu- lus effects of l-cyclorphan in the morphine-trained group appeared to be specific, it was not completely clear that Discussion it was" truly surmountable. The increases in morphine- appropriate responding that occurred in the presence of In this study the opioid antagonist, naltrexone, was used 1 mg/kg naltrexone occurred at doses of/-cyclorphan to confirm that the high levels of training-drug-appro- that also had effects on rates of responding, and, in the priate responding which /-cyclorphan is capable of presence of naltrexone, intermediate levels of morphine- producing in pigeons trained to discriminate morphine appropriate responding also occurred with rate-reducing are the result of the action of/-cyclorphan on opioid doses of dextrorphan (Fig. 2, upper right panel). Thus, receptors. This conclusion could not be reached from the it was not clear whether or not the intermediate levels of data for/-cyclorphan alone, because/-cyclorphan does morphine-appropriate responding that were produced by not substitute completely for morphine, and interpreta- /-cyclorphan when 1 mg/kg naltrexone was given were tion of intermediate levels of morphine-appropriate re- the result of stimulation of opioid receptors. sponding was made difficult because fairly high levels of The ceiling on the level of morphine-appropriate re- morphine-appropriate responding can be produced by sponding obtainable with/-cyclorphan may be due either mechanisms other than opioid agonism, e.g., by com- wholly or in part to a limitation in the intrinsic efficacy binations of dextrorphan and naltrexone (Fig. 2, upper of this drug at mu opioid receptors. Specifically,/-cyclor- right panel) or even by naltrexone alone (Fig. 2, upper phan may not have sufficient intrinsic efficacy at these panels) (also, see Koek and Woods 1989). Nevertheless, receptors to produce a level of stimulation equivalent to naltrexone antagonized the discriminative stimulus effect that produced by 10 mg/kg morphine - even when l- of/-cyclorphan in the morphine-trained subjects (Fig. 3, cyclorphan is given in doses high enough to completely upper left panel), and this established the opioid nature saturate the relevant receptor pool. Indeed, there is in- of the mechanism by which/-cyclorphan produced mor- dependent evidence that the intrinsic efficacy of/-cyclor- phine-appropriate responding. Moreover, there was ade- phan at mu opioid receptors is limited. The observation quate reason to believe that this effect of naltrexone that morphine-treated pigeons trained to discriminate resulted from an opioid receptor-specific action of this naltrexone injections generalize to/-cyclorphan (Herling antagonist. The changes naltrexone produced in the et al. 1982) indicates that the intrinsic efficacy of this dose-response curve for discriminative stimulus effects of compound at mu opioid receptors is limited. Originally /-cyclorphan in the morphine-trained group were dis- it was hypothesized that the PCP-like effects of/-cyclor- tinctly different from its effects on the dose-response phan were responsible for the ceiling effect (Herling et al. curve for dextrorphan in the morphine-trained group 1982), and it must still be considered possible that these (Fig. 2, upper right panel) and on the dose-response effects of/-cyclorphan do contribute to the ceiling effect. curve for/-cyclorphan in the dextrorphan-trained group Nevertheless, in another study ketamine, a PCP receptor (Fig. 3, lower left panel). Thus, it was confirmed that drug, failed to reliably antagonize the discriminative naltrexone did not spuriously produce the appearance of stimulus effects of morphine (Koek. and Woods 1989). an antagonism when a drug produced morphine-appro- This finding makes it seem less likely that the PCP recep- priate responding by a non-opioid mechanism or when tor-mediated effects of/-cyclorphan are solely responsi- /-cyclorphan produced a non-opioid effect. ble for imposing a ceiling on the morphine-like discrimi- The failure of the naltrexone-levorphanol data to native stimulus effects that can also be obtained with this provide a positive control for antagonism of opioid dis- drug. criminative stimulus effects in the morphine-trained pi- In the preparations used in this study, d-cyclorphan geons was not considered to argue strongly against the did not appear to act simply by opioid or PCP receptor opioid nature of the interaction between naltrexone and mechanisms. In the morphine-trained group this drug /-cyclorphan. Levorphanol reduced rates of responding produced only intermediate levels of training-drug- at doses just above those that substituted for morphine. appropriate responding, and 1 mg/kg naltrexone failed Thus, to shift the dose-response curve for the morphine- to antagonize this effect. Thus, an opioid mechanism of like discriminative stimulus effect of this agonist, nal- action could not be confirmed for d-cyclorphan in this trexone would have also had to shift its rate-reducing preparation. In the dextrorphan-trained group d-cyclor- 194 phan produced levels of dextrorphan-appropriate re- References sponding that were greater than chance, although it was less efficacious than l-cyclorphan. The level of dextror- Herling S, Coale EH Jr, Valentino R J, Hein DW, Woods JH (1980) phan-appropriate responding was probably high enough Narcotic discrimination in pigeons. J Pharmacol Exp Ther 214:139-146 to indicate that this compound acts at PCP receptors. Its Herling S, Hein DW, Nemeth MA, Valentino RJ, Woods JH (1982) failure to fully substitute for dextrorphan may indicate Discriminative stimulus, antagonist, and rate-decreasing effects that there are a number of elements to the dextrorphan of cyclorphan: multiple modes of action. Life Sci 30:331-341 cue and that d-cyclorphan mimics only some of these Herling S, Solomon RE, Woods JH (1983) Discriminative stimulus elements. Alternatively, the failure to substitute may effects of dextrorphan in pigeons. J Pharmacol Exp Ther indicate that d-cyclorphan has actions not shared by 227: 723-731 Herling S, Woods JH (1981) Discriminative stimulus effects of dextrorphan and that these actions prevent full sub- narcotics: evidence for multiple receptor-mediated actions. Life stitution. Sci 28:1571-1584 Koek W, Woods JH (1989) Partial generalization in pigeons trained Acknowledoements. This work was supported by US Public Health to discriminate morphine from saline: applications of receptor Service Grant DA05325. The authors wish to express their ap- theory. Drug Dev Res 16:169-181 preciation for the expert technical assistance rendered by Rodney Young AM, Woods JH (1981) Limitations on the antagonistic D. Clark. actions of opioid antagonists. Fed Proc 41:2333-2338