Differential cross-tolerance to opioid agonists in morphine-tolerant squirrel monkeys responding under a schedule of food presentation

Differential cross-tolerance to opioid agonists in morphine-tolerant squirrel monkeys responding under a schedule of food presentation

European Journal of Pharmacology, 174 (1989) 171-180 171 Elsevier EJP 51070 Differential cross-tolerance to opioid agonists in morphine-tolerant sq...

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European Journal of Pharmacology, 174 (1989) 171-180

171

Elsevier EJP 51070

Differential cross-tolerance to opioid agonists in morphine-tolerant squirrel monkeys responding under a schedule of food presentation Pamela Doty

1, Mitchell

J. Picker 1 a n d L i n d a A. D y k s t r a 1.2

1 Department of Psychology, 2 Department of Pharmacology, Unwerstty of North Carohna at Chapel Hdl, Chapel Hdl, NC 27599-3270, U S A

Received 29 June 1989, revised MS received 12 September 1989, accepted 19 September 1989

The effects of various /t and x opiold agonists were evaluated m three sqmrrel monkeys responding under a fixed-ratio 30 schedule of food presentation before, during and after a regimen of chronic morphine admxnistration. Imtlally, dose-effect curves for the/~ oplold agonlsts morphine and 1-methadone, the K oploid agonlsts U50,488 and tifluadom, the rmxed /t/x oplold agonist ethylketocyclazoclne, and the non-op~o~d compound pentobarhital were determined in non-tolerant squirrel monkeys. Subsequently, monkeys were adnunistered up to 3.0 mg/kg of morphine twice daily for 8-9 weeks, which resulted in a 1/2 to 3/4 log unit shift to the nght of the morphine dose-effect curve relative to its prechronlc position. During the chromc morphine regimen, the 1-methadone dose-effect curve shifted to the right approximately 3/4 log umt, while the U50,488 and pentobarb~tal dose-effect curves did not change. In contrast, the ethylketocyclazocme and tifluadom dose-effect curves shifted to the left approximately 1/4 and 3/4 log unit, respectively. The lack of cross-tolerance between tt and r agonists m morphine-tolerant sqmrrel monkeys observed in the present study provides further support for the differentiation of/x and K agomsts. The occurrence of leftward shifts in the dose-effect curves of some oplold compounds w~th x agonist actlxaty dunng the regimen of chronic morphine administration suggests that morphine tolerance modulates their rate-decreasing effects. /t Opiolds; ~ Oploids; Tolerance/cross-tolerance; Schedule-controlled behavior; Squirrel monkeys

1. Introduction Pharmacological and behavioral data suggest that a distinction can be made between various opioids proposed to interact with different opioid receptor subtypes. Although compounds acting at the /~ or x opioid receptor site both produce analgesia (VonVoigtlander et al., 1983; Dykstra and Massie, 1988), they produce opposite effects on diuresis (Leander, 1983; VonVoigtlander et al., 1983), locomotor activity (VonVoigtlander et al., 1983), and dopamine activity in the rat nucleus

Correspondence to P Doty, CB No. 3270, Davae Hall, Department of Psychology,Umversityof North Carohna, Chapel Hill, NC 27599, U.S.A.

accumbens, dorsal caudate and substantia nigra (D1 Chiara and Imperato, 1988; Walker et al., 1987). Moreover, /~ and x agomsts have been differentiated on the basis of their discriminative (Tang and Collins, 1985), reinforcing (Woods et al., 1982) and dependence-producing properties (Gmerek et al., 1987). Tolerance/cross-tolerance procedures provide another way to differentiate between /~ and x agonists. It is well known that the repeated administration of oploids such as morphine produces tolerance to its behavioral effects, as well as cross-tolerance to other morphme-like drugs (Jaffe and Martin, 1985; Schulz et al., 1981; Solomon et al., 1988). Thus, it is inferred that compounds that exhibit cross-tolerance share a similar mechanism

0014-2999/89/$03 50 © 1989 Elsevier Science Pubhshers B.V (Biomedical Dlvaslon)

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of action. Previous reports have shown that in xsolated tissue preparations (Schulz et al., 1981), thermal analgesia tests (Sherman et al., 1988), and tests of locomotor activity (Brady and Holtzman, 1981), the repeated administration of ~t agonists such as morphine, fentanyl and sufentanyl produced tolerance to their own effects as well as cross-tolerance to other /~ agonists. In contrast, tolerance to the effects of /~ agonlsts such as morphine and fentanyl does not confer crosstolerance to K agonlsts such as U50,488, or tifluadom or to the mixed /~/K agonlst ethylketocyclazocme in ~solated tissue preparations (Schulz et al., 1981) or m tests of analgesia or sedatmn (VonVolgtlander et al., 1983; Gmerek et al., 1987; Dykstra, 1983). However, cross-tolerance between morphine and the mixed /~/x agomst ethylketocyclazocine has been demonstrated in some mstances (Porreca et al., 1982; VonVoigtlander and Lewis, 1982; VonVolgtlander et al., 1983). These discrepant results may refect species or procedural differences, or may be related to the nonselective profde of ethylketocyclazocine. Since a variety of opmid agonists have been shown to decrease response rate under schedules of food presentation (Harris, 1980; Leander, 1978), the purpose of the present study was to determine whether the rate-decreasing effects of /z and K oploids could be differentiated in morphinetolerant sqmrrel monkeys, thereby suggesting that /~ and x agonists alter rate of responding in this procedure through actions at different oplold receptor types In addition, since recent data have suggested that ~¢ agomsts modulate morphine-induced analgesia differentmlly in morphine-naive and morphine-tolerant rodents (Tulunay et al., 1981; Schmauss and Herz, 1987; Ramarao et al., 1988), a second purpose of this study was to determine whether morphine tolerance altered the rate-decreasing effects of x oploids. In order to make these comparisons, the rate-decreasing effects of the/~ agonist 1-methadone, the x agonists U50,488 and tlfluadom, and the mixed/~/x agonist ethylketocyclazocine were evaluated before, during and after a regimen of chronic morphine administration. In additmn, cross-tolerance to pentobarbltal was evaluated as a nonopiold control.

U50,488 was selected for examination on the basis of its profile as a highly selective ~¢ agonist with low affinity for ~t receptors (Lahtl et al, 1982; VonVoigtlander and Lewis, 1982; Clark and Pasternak, 1988). Similarly, tifluadom which is a 1,4-benzodlazepine with no affinity for benzodiazeplne binding sites was selected on the basis of its selective x agonist profile (Romer et al., 1982). Ethylketocyclazoclne, on the other hand, is known to bind both/z and x receptors (Lahtl et al., 1982; Clark and Pasternak, 1988) as well as to possess some/~ agonist properties, particularly m rats and pigeons (Porreca et al., 1982; VonVoigtlander et al., 1983; Picker and Dykstra, 1987).

2. Materials and methods

2 1 SubJects Three experimentally naive adult male squirrel monkeys (Saimlrl sctureus) were maintained at approximately 80% of their free-feeding body weights (750-800 g). Body weights were maintained by Purina monkey chow and their diets were supplemented with fresh fruit. The monkeys were individually housed in a colony room maretamed on a 12 h : 12 h hght : dark cycle and were gxven continuous access to water.

2.2. Apparatus Two small primate cockpits ( B R S / L V E 142-11) were used to hold the monkeys in the seated position during the experimental session. On the front wall of each chamber was a centrally mounted lever 2.75 cm long located 9.5 cm directly below a recessed stimulus light which was yellow when illuminated. When operated, a pellet dispenser could deliver a 90 mg Noyes food pellet (P.J. Noyes Co., Lancaster, NH) into a pellet trough located 7.5 cm directly below the response lever. The cockpit was enclosed in a ventilated chamber equipped with white masking noise and two houselights When illuminated the houselights in one chamber were red and green and in second chamber were red and blue. Scheduling of experi-

173 mental events and data collection were controlled by a TRS model III microcomputer.

2.3. Behavzoral procedure Sqmrrel monkeys were trained on a fixed ratio (FR) schedule of food presentation. Initially every response was followed by food presentation and then the response requirement was gradually increased until 30 responses were required for food presentation (FR30). Daily sessions consisted of 4 FR components. The beginning of each FR component was signalled by the illumination of the yellow stimulus light. The component terminated when the monkey had received 15 food pellets or after 15 rain had elapsed. The 4 FR components were separated by a 5-min intertrial interval (ITI) during which the stimulus hght was off and responding had no programmed consequences. The ITI was lengthened to 15 rain on test days to accommodate drug administration. Sessions were conducted 5 days/week and cumulative dose-effect curves were typically obtained on Tuesdays and Fridays.

2.4 Pharmacological procedure Once rates of responding had stabilized, cumulative dose-effect curves were determined for morphine, 1-methadone, U50,488, ethylketocyclazocine, tifluadom and pentobarbital. In the cumulative dosing procedure, the first dose of a drug was administered 15-min prior to the start of the session and subsequent doses were administered at the beginning of each 15 mln ITI. The dose of each drug increased the total cumulative dose by either 1 / 4 or 1 / 2 log unit. Following the determination of these initial dose-effect curves (prechromc stage), monkeys were administered morphine according to the following chronic regimen. First, monkeys were administered a dose of morphine (1.0 mg/kg) which reduced rates of responding to approximately 70% of control. This dose of morphine was administered 15 min prior to the daily session. Then the dose of morphine was gradually increased to 3.0 m g / k g on an individual basis over a period of 41-81 sessions. Subsequently, to facilitate the de-

velopment of tolerance, morphine was admimstered twice daily with one injection occurring 2-4 h prior to the experimental session and a second injection occurring 10-12 h later. Initially, the twice daily dose of morphine was 1.7 mg/kg; then this dose was increased gradually to 3.0 m g / k g twice daily over 34-44 sessions. The morphine dose-effect curve was redetermined on a weekly basis to evaluate the development of tolerance. Once the morphine dose-effect curve had shifted 1 / 2 to 3 / 4 log unit to the right, dose-effect curves for 1-methadone, U50,488, ethylketocyclazocine, tlfluadom and pentobarbital were redetern'nned. For two of the monkeys, 6-4 and 6-14, water control and dose-effect determinations were made in the absence of the first maintenance dose of 3.0 m g / k g morpbane which was usually administered 2-4 h prior to the experimental session. The second maintenance dose of 3.0 m g / k g morphine (which was usually administered 6-8 h postsesslon) continued to be admimstered following water control sessions as well as following sessions in which the U50,488, ethylketocyclazocine and tifluadom dose-effect deternunatlons were made. To avoid possible toxicity, the postsession maintenance dose of morphine was not admlmstered on days on which the morphine, 1-methadone or pentobarbital curves were obtained. The maintenance regimen was the same in the third monkey (6-3) except that the presession maintenance dose of 3.0 m g / k g morphine was not eliminated in this monkey. Following redetermination of all dose-effect curves, the monkeys were taken off the chronic regimen. Three weeks to one month later when the morphine dose-effect curve had shifted back to its original position, the dose-effect curves for 1methadone, U50,488, ethylketocyclazocine, tlfluadom and pentobarbltal were redeterrmned once agam.

2 5. Drugs Morphine sulfate (National Institute on Drug Abuse, Rockville, MD), 1-methadone HC1 (Eli Lilly and Co., Indianapolis, IN), U50,488 (trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl] benzeneacetamide methanesulfonate hydrate)

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(Upjohn Co., Kalamazoo, MI) and ethylketocyclazocine methanesulfonate (Sterling-Winthrop Research Institute, Rensselaer, NY) were dissolved in distilled water. Pentobarbltal HC1 (Sigma Chemical Co., St Louis, MO) was dissolved in distilled water and a small amount of ethanol. dl-Tifluadom HC1 (Dr. M. Rance, Imperial Chemical Industries, Inc., Wilmslow, Cheshire, England) was dissolved in diazepam placebo. Doses for these drugs are expressed as the salt. Distilled water was used for control injections. Injections were administered i.m. into the thigh in an injection volume of 1 m l / k g of body weight.

2.6. Data analysts Rates of responding were determined for each monkey by dividing the number of responses that occurred during each FR component by the time spent in that component and expressing these as responses per second. Rates of responding were determined separately for each of the four F R components. Control rates of responding were obtained for each FR component on days on which water injections were administered. Dose-effect curves in which absolute rates of responding were expressed as a function of dose were then obtamed. For each dose-effect curve obtained, the dose that reduced rates of responding to 50% of the control rates was derived mathematically by log-linear interpolation using only those points on the dose-effect curve that were immediately above and below the dose that produced a 50% reduction in rate of responding. Changes in the dose that reduced rates of responding to 50% of control from prechronic to chronic and from prechronic to postchronic phases were determined for each monkey by subtracting the log of the prechronic dose from the log of the chronic or the postchronic dose, respectively.

TABLE 1 Mean response rates (R/s) measured for mdwldual monkeys (6-4, 6-3 and 6-14) on water control days dunng prechromc (9-11 control days), chromc (3-4 control days), and postchromc (3-4 control days) phases. Mean values are gwen with S.E. m parentheses Phase

Monkey 6-4

6-3

6-14

1 72 (0 05) 2.09 (0.04) 2.17 (0 07) 2 26 (0 11)

1 41 (0 05) 1 34 (0 05) 1 43 (0.07) 1.59 (0 11)

3.76 (0.05) 3.85 (0 04) 3 95 (0.11) 3 92 (0 05)

2.06 (0.14)

1 44 (0 06)

3 87 (0 05)

1 72 (0.37) 2.17 (0.17) 2 18 (0 19) 2 20 (0 08)

1 62 (0 03) 1 61 (0 12) 1 57 (0.15) 1 49 (0 11)

3 06 (0 34) 3 00 (0 33) 3 17 (0 36) 3 37 (0.45)

2.07 (0.13)

1 57 (0 03)

3.15 (0 09)

2 11 (0.06) 2 25 (0 16) 2 52 (0.25) 2 58 (0 18)

1.45 (0 03) 1 70 (0.06) 1 81 (0 05) 1 68 (0 07)

3 50 (0 17) 3 79 (0.19) 3 95 (0 09) 3 99 (0 15)

2 37 (0 13)

1 66 (0 09)

3.81 (0.13)

Prechrontc

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Mean Postchromc

Component Component Component Component Mean

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a Each component terrmnated when the monkey had received 15 food pellets or after 15 nun had elapsed A session consisted of four FR components

components within a daily session. Mean rates of responding were obtained by averaging across water control sessions that preceded test days. In general, control rates of responding for individual monkeys were similar during the prechronic, chronic and postchronlc phases of the study, differing by no more than 15%. Mean rates of responding for individual monkeys were generally consistent across components within a session, differing by no more than 16%.

3.2. Effects of i~ opwtd agomsts 3. Results

3 1. Control rates of respondmg Table 1 shows the mean rates of responding of individual monkeys for each of the four FR

Fxgure 1 shows the effects of the /~ opioid agonists morphine and 1-methadone on absolute rates of responding for each monkey during the prechronic, chronic and postchronic phases. During the prechronic phase, morptune (0.3-3.0

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of the study. The dose of morphine that reduced rates of responding to 50% of control rates during the chromc phase was 4-6 times larger than that obtained during the prechronic phase (see table 2). Redetermination of the morphine dose-effect curve 4-5 weeks after the termination of the chromc phase, showed decreases in rates of responding similar to those seen during the prechronic phase. For two monkeys (6-4, 6-14), the dose that ehminated responding and the dose that reduced rates of responding to 50% of control rates determined during the postchronic phase were equivTABLE 2

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Fig. 1 Rate of responding (responses/second) plotted as a function of the dose of morplune (left panels) or l-methadone (right panels) determaned prior to, dunng, and following a regimen of chronic morptune adrmmstrauon. Data represent one determination of each dose-effect curve for m&vldual monkeys 6-4, 6-3 and 6-14 The points at the far left represent the mean rate of responding on water control days d u n n g the prechromc (9-11 control days), chrome (3-4 control days) and postchronlc (3-4 control days) phases of the study. Ttus value was based on the mean rate of responding for each of the four components averaged across all water control days d u n n g each phase of the study, brackets represent the range of mean response rates across these components.

mg/kg) produced dose-dependent decreases in rates of responding in all three monkeys. Rates of responding following the administration of 1.0 mg/kg of morphine were decreased to approxamately 70% of control and were virtually eliminated following the administration of 1.7 mg/kg of morphine. Following several months of daily morphine administration, there was 1/2 to 3/4 log unit shift to the right in the morphine dose-effect curve (1.0-10.0 mg/kg). As seen in fig. 1, a dose of 10.0 mg/kg of morphine was required to eliminate responding in all three monkeys during the chronic phase of the experiment. Table 2 shows the dose of each agonist that reduced rates of responding by 50% in individual monkeys during each phase

The dose a ( m g / k g ) of each c o m p o u n d that reduced rates of responding to 50% of control rates determaned for individual monkeys (6-4, 6-3 and 6-14) during prechromc, chromc and postchromc phases Drug

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6-3

6-14

1.297 7 971 1 372

1 036 6 182 1.969

1.133 4 646 1 019

0 195 0 851 0 386

0.197 1 217 0 457

0 150 0.524 0 167

0.443 0 775 0 656

0 811 0 048 0 794

0 631 1 118 0 369

0 016 0 017 0 006

0 019 0 006 0.018

0.015 0 005 0.014

0.057 0.014 0 054

0 069 0 005 0 066

0 017 0 006 0 013

5.327 6.088 6 351

5.651 5 477 5 249

5 345 4.929 5.342

Morphine Prechromc Chromc Postchromc

l-Methadone Prechromc Chronic Postchromc

U50.488 Prechromc Chronic Postchromc

EKC Prechromc Chronic Postchronlc

Ttfluadom Prechromc Chronic Postchromc

Pentobarbttal Prechronxc Chrome Postcnromc

a Dose estimates for each drug were derived mathematxcally by log-hnear interpolation using only those points on the dose-effect curve that were lmmedmtely above and below the dose of each c o m p o u n d that reduced rates of responding to 50% of control rates

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methadone during the chromc phase was 4.4 (6-4), 6.1 (6-3), and 3.5 (6-14) times greater than that determined for 1-methadone dunng the prechronic phase (see table 2). When the 1-methadone doseeffect curve was again redetermined subsequent to the regimen of chronic morphine admimstration, it was shifted back to within approximately 1/4 log unit of its original position (see table 2).

alent to those determined prior to the regimen of chronic morphine administration. In the third monkey (6-3), the postchronic morphine dose that reduced rates of responding to 50% of control rates was approximately 1/4 log unit larger than that obtained prior to the regimen of chronic morphine administration. Figure I also shows the effects of 1-methadone (0.03-0.56 mg/kg) on rates of responding prior to, during and subsequent to the regimen of chronic morphine administration. During the prechronic phase of the study, 1-methadone decreased rates of responding in a manner simdar to morphine, except that 1-methadone was approximately 5 times more potent than morphine. During the regimen of chronic morphine administration, the 1-methadone dose-effect curve was shifted to the right approximately 1/2 to 3/4 log unit of that obtained prior to the chromc phase. For individual monkeys, the dose that reduced rates of responding to 50% of control rates determined for 1-

3.3. Effects of ~ optold agomsts Figure 2 shows the effects of two x opiold agonists, U50,488 and tifluadom, and the mixed /~/K agonist ethylketocyclazocine on absolute rates of responding for each monkey during the prechronic, chronic and postchronic phases of the study. Prior to the regimen of chronic morphine administration, U50,488 (0.1-1.0 mg/kg), ethylketocyclazocine (0.001-0.03 mg/kg) and tifluadom (0.003-0.1 mg/kg) produced dose-dependent decreases in rates of responding in all three monkeys. Tifluadom was slightly more potent in decreasing

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Fig 2. Rate of responding (responses/s) plotted as a function of the dose of U50,488 (left panels), ethylketocyclazocme (center panels) and tlfluadom (right panels) determined pnor to, dunng, and following a r e . m e n of chromc morphine adrmmstratlon Detads are as explamed in fig 1

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rates of responding than ethylketocyclazocine, which was approximately 30 times more potent than U50,488. Dose-effect curves obtained for U50,488 during the regimen of chronic morphine administration did not shift consistently across monkeys. In one monkey (6-3) the U50,488 dose-effect curve shifted to the left approximately 1 1 / 4 log units and the dose that reduced rates of responding to 50% of control rates determined during the chronic phase was 16 times less than that determined prior to the chromc phase (see table 2). In the other two monkeys, the U50,488 dose-effect curve shifted to the right 1 / 4 log unit. The dose that reduced rates of responding to 50% of control rates was 1.7 (6-4) and 1.8 (6-14) times greater than that determined for U50,488 during the prechronic phase (see table 2). During the postchromc phase, the U50,488 dose-effect curves and accompanying doses that reduced rates of responding to 50% of control rates for all three monkeys were equivalent to those determined prior to the chronic phase. Figure 2 also shows that during the chronic morphine phase the ethylketocyclazocine dose-effect curve shifted to the left approximately 1 / 2 log unit in two monkeys (6-3, 6-14) and did not change in the third monkey (6-4). The dose that reduced rates of responding to 50% of control rates determined during the chronic phase was 3 and 4 times less than that determined prior to the regimen of chronic morphine administration for monkeys 6-3 and 6-14, respectively (see table 2). In general, the ethylketocyclazocine dose-effect curves determined following the chronic phase were equivalent to those determined during the prechronic phase. Furthermore, fig. 2 shows that during the regimen of chronic morphine adnunistration, the tlfluadom dose-effect curve shifted to the left approximately 1/2 to 1 log unit. The dose that reduced rates of responding to 50% of control rates during the chronic regimen was either 3 (6-14), 6 (6-4) or 14 (6-3) times less than that determined prior to the chronic morphine regimen (see table 2). The doses that reduced rates of responding to 50% of control rates determined during the postchronic phase were equivalent to those determined during the prechronlc phase.

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PENTOBARBITAL(mq/kg) Fig. 3 Rate of responding (responses/s) plotted as a function of the dose of pentobarbltal determined prior to, during, and following a regimen of chromc morphine admlntstrat]on. Details are as explmnedm fig 1.

3.4. Effects of non-optmd compound Figure 3 shows the effects of pentobarbital on rates of responding obtained prior to, during and subsequent to the regimen of chronic morphine administration. Pentobarbital produced similar dose-dependent decreases in rates of responding during all phases of the study. Table 2 indicates that the doses that reduced rates of responding to 50% of control rates determined during and following the chromc phase were nearly identical to those determined during the prechronic phase.

4. Discussion

The present study demonstrates that chronic admimstratlon of morphine to squirrel monkeys

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responding under a schedule of food presentation produced tolerance, as evidenced by a 1/2 to 3/4 log unit shift to the right of the morphine dose-effect curve relative to its prechronic posiUon. Tolerance to morphine conferred cross-tolerance to another It opioid agomst, 1-methadone. In contrast, chronic administration of morphine did not result in cross-tolerance to the non-opioid pentobarbital, to the K opioid agonists U50,488 or tifluadom, or to the mixed It/x opioid agonist ethylketocyclazocine. Following termination of the regimen of chromc morphine administration, the dose-effect curves for all the drugs examined shifted back to within 1/4 log unit of their original positions suggesting that the shifts in the dose-effect curves observed during the chronic phase of the study resulted from the regimen of chronic morphine admimstration. The fact that morphine's effects on rates of responding were attenuated by repeated morphine administration is consistent with previous reports examining morphine's rate-decreasing effects on schedule-controlled responding in a number of species (Leander, 1978; Witkin et al., 1983; Sannerud and Young, 1986). Moreover, morphinetolerant squirrel monkeys were cross-tolerant to the It agonist 1-methadone and the magnitude of tolerance that developed to morphme and 1methadone was comparable. The present results parallel previous investigations in isolated tissue preparations (Schulz et al., 1981), as well as in various behavioral procedures with rodents and pigeons (Leander et al., 1975; Leander, 1978), which have shown that tolerance to the effects of It agonists such as morphine, fentanyl, or methadone, confers cross-tolerance to the effects of various other It agonists. In contrast, changes in the pentobarbital dose-effect curve were not observed during any phase of the study, thus indicating that these effects were pharmacologically specific. The finding that morphine-tolerant monkeys were not cross-tolerant to the K agonists U50,488 or tifluadom, nor to the mixed It/r agonist ethylketocyclazocine correlates well with previous research in monkeys that revealed marked differences between tt and x agonists, including distinct discriminative stimulus, reinforcing, and dependence-producing properties (Woods, 1982;

Tang and Collins, 1985; Gmerek et al., 1987). The present data also correlate well with data from analgesic assays showing a lack of cross-tolerance between morphine and U50,488 in rodents (VonVolgtlander and Lewis, 1982; VonVoigtlander et al., 1983), and between morphine and ethylketocyclazocine in squirrel monkeys (Dykstra, 1983). Furthermore, procedures evaluating either sedation or schedule-controlled behavior in morphine-dependent rhesus monkeys have demonstrated that tolerance to morphine does not confer cross-tolerance to various K agonists (Llewellyn, 1978; Gmerek et al., 1987). Thus, it appears that in squirrel monkeys the x agonists U50,488 and tifluadom and the mixed It/K agonlst ethylketocyclazocine produce their rate-decreasing effects by a mechanism which is distinct from the mechamsm mediating the effects of the It agonists morphine and 1-methadone. Although morphine-tolerant monkeys were not cross-tolerant to tifhiadom, ethylketocyclazocine or U50,488, chronic morphine treatment did modulate their rate-decreasing effects as evidenced by the presence of leftward shifts in their dose-effect curves during the regimen of chromc morphine administration. During the chronic phase of the study, the tifluadom dose-effect curve shifted to the left in all three monkeys, the ethylketocyclazocine dose-effect curve shifted leftward in two of three monkeys and the U50,488 dose-effect curve shifted leftward in one monkey. Although only a few studies have evaluated the effects of opioid compounds with K agonlst activity on schedule-controlled behavior in morphine-tolerant animals, leftward shifts in the ethylketocyclazocine dose-effect curve have been reported following tolerance to either morphine-induced rate decreases in rodents or morphine-induced analgesia in squirrel monkeys (Dykstra, 1983; Solomon et al., 1988); however, exceptions to these findings have also been reported (Craft and Dykstra, 1989). One possible interpretation of the leftward shifts is that they represent opioid antagonist activity. Previous investigations have shown that the doseeffect curves for the pure opioid antagonists naloxone and naltrexone shift to the left in morphine-tolerant animals (Leander et al., 1975; Sannerud and Young, 1986; Oliveto et al., 1989).

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For example, the naloxone dose-effect curve shifted 3 log units to the left in morphine-tolerant squirrel monkeys responding under a schedule of food presentation (Oliveto et al., 1989), an effect considerably greater than that obtained in the present investigation. In addition, Leander et al. (1975) reported that in morphine-treated rodents, the dose-effect curves of the mixed agonist/antagonists nalorphine, cyclazocine and pentazocine shifted to the left in a manner that paralleled their potency as antagonists in other tests (McMlllan et al., 1970). Recently, enhanced sensitivity to the rate-decreasing effects of several mixed agonist/ antagonists was reported in both morphinetolerant pigeons and morphine-tolerant squirrel monkeys responding under a schedule of food presentation, and the rank order of leftward shifts agreed with their relative agonist to antagonist activity in other procedures (Craft et al., 1989; Oliveto et al., 1989). The opioid compounds with x agonist activity examined in the present study, U50,488, ethylketocyclazocine and tifluadom, have been shown to antagonize the effects of/~ opiolds in a variety of procedures (Wood, 1983; Porreca and Tortella, 1987; Sheldon et al., 1987; Ramarao, 1988). Thus, the shifts to the left of the tifluadom, ethylketocyclazocine and U50,488 dose-effect curves may be an indication of their/~ antagonist properties. However, the ability of r agonists to antagonize morphine's rate-decreasing effects has not been demonstrated with squirrel monkeys in this procedure. In summary, the lack of cross-tolerance between /~ and K agonists in morphine-tolerant squirrel monkeys observed in the present study provides further support for the differentiation of /~ and K agomsts. The occurrence of leftward shifts in the dose-effect curves of some opioid compounds with x agonist activity during the regimen of chronic morphine administration suggests that tolerance to morphine modulates their rate-decreasing effects.

Acknowledgements Ttus work was supported by U.S. Public Service Grant DA02749 from the National Institute on Drug Abuse L A D

is a recipient of Research Scientist Award KO5-DA00033 A prehrmnary report of this work appears m Pharmacol. BIochem. Behav. 30 557, 1988 (APA Abstracts). The authors wash to thank Rebecca Craft, John Helse, Chfford Massle and Alison Ohveto for their assistance during the chromc phase of the study

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