Stimulus effects of morphine in the monkey: Quantitative analysis of antagonism

doi:10.1016/0091-3057(80)90193-8

Pharmacology Biochemistry and Behavior

Volume 12, Issue 4, April 1980, Pages 587-593

https://doi.org/10.1016/0091-3057(80)90193-8 Get rights and content

Abstract

The ability of narcotic antagonists to block the discriminative stimulus effects of 3.0 mg/kg (IM) of morphine was evaluated quantitatively in the squirrel monkey using a two-choice discrete-trial avoidance paradigm. The time-course and relative potency of naloxone and naltrexone for antagonizing morphine's stimulus effects in the squirrel monkey were similar to those determined in rats and pigeons. Complete blockade of morphine's effects was attained with 0.03 mg/kg of either antagonist when given simultaneously with morphine, but only naltrexone completely blocked the stimulus effects of morphine when the pretreatment interval was extended to 12 and 18 hr. A Schild plot derived from the degree of antagonism of graded doses of morphine by graded doses of naltrexone (0.003−0.1 mg/kg) yielded a line with a slope of −0.63 ± 0.2 and an apparent pA₂ value of 8.25 ± 0.2. These results demonstrate the feasibility of quantitatively assessing the drug-receptor interactions that subserve the discriminative stimulus effects of morphine in the squirrel monkey.

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Morphine is an effective training drug in drug discrimination procedures. In subsequent generalization tests in which other opioids are administered, mu opioid agonists selectively substitute for the training drug. Given the relative selectivity of morphine for the mu receptor, such substitution patterns suggest that the mu opioid receptor is mediating the discriminative control of this compound. The present study assessed this selective mediation by examining the ability of the delta opioid agonist SNC80 to substitute for (and the delta opioid antagonist naltrindole to antagonize) morphine stimulus effects in rats trained to discriminate morphine from its vehicle in the conditioned taste aversion baseline of drug discrimination learning. Although morphine and methadone produced dose-related substitution for morphine (10 mg/kg), there was no evidence of substitution for morphine by SNC80 at any dose tested. Further, although naloxone (3.2 mg/kg) completely blocked the discriminative effects of morphine, naltrindole (3.2–10 mg/kg) did not significantly affect the morphine stimulus. These data suggest that the discriminative control established to morphine is mediated by its activity at the mu, but not the delta, receptor.
Quantitative analysis of naloxone antagonism of the discriminative stimulus properties of morphine in the pigeon
1986, Pharmacology, Biochemistry and Behavior
Pigeons were trained to discriminate morphine (5.0 mg/kg) from saline under a second-order fixed ratio 10 (fixed-ratio 5) color-tracking schedule for food reinforcement. After reliable stimulus control was established, cumulative graded doses of morphine (0.3–30.0 mg/kg) were tested and resulted in dose-dependent increases in morphine-appropriate key pecking and decreases in response rate. Cumulative doses of naloxone (0.1–10.0 mg/kg) or consecutive injections of saline did not elicit morphine-appropriate responding or affect response rate. Pre-treatment with naloxone (0.1-1.0 mg/kg) before determination of cumulative dose-effect curves for morphine caused the morphine generalization curves to be shifted, in a parallel manner, rightward. Dose-ratio analysis of naloxone antagonism of morphine generalization, using a Schild plot with the slope constrained to −1, gave an apparent pA₂ value (95% confidence limits) of 6.53 (6.18-6.89).
Morphine discrimination in the pigeon using a color tracking procedure
1986, Pharmacology, Biochemistry and Behavior
Pigeons were trained to discriminate 5.0 mg/kg morphine from saline. After morphine, subjects tracked the location of red response keys and after saline, the location of green keys. When stimulus generalization to other drugs was investigated dl-methadone produced morphine-like responding and this response generalization was primarily due to the l-isomer. Pretreatment with 1.0 mg/kg naloxone shifted the morphine generalization curve 10-fold to the right but only shifted the rate suppression curve 3-fold to the right. dl-Cyclazocine generated dose-related increases in responding on the red key location and in 3 of 5 birds, responses after 1.0 mg/kg were indistinguishable from those after morphine training doses. Meperidine did not produce responding on the red keys, nor did diazepam, cocaine, d-amphetamine, phencyclidine or pentobarbital. The discriminative stimulus effects of morphine are thus stereo-selective and pharmacologically specific. Generalization of responding to dl-cyclazocine but not to phencyclidine suggests that the morphine-like discriminative dl-cyclazocine cue was not due to interaction at sigma opiate receptors.
Drug discrimination studies
1985, Drug and Alcohol Dependence
Opioid agonists and agonist/antagonists comprise a heterogeneous body of compounds that can be partitioned into at least three groups on the basis of their discriminative stimulus properties in several animal species: (1) stimulus effects similar to those of morphine or fentanyl and blocked completely by low doses of antagonists, such as naloxone and naltrexone; (2) stimulus effects similar to those of ethylketocyclazocine or nalorphine and blocked by higher doses of antagonists; (3) stimulus effects similar to those N-allylnormetazocine or phencyclidine and not blocked by antagonists. This diversity of stimulus properties is consistent with other evidence that multiple populations of receptors mediate the actions of opioids. In man, drugs in group 1 produce subjective effects that are entirely morphine-like and highly reinforcing whereas drugs in groups 2 and 3 produce dysphoric and psychotomimetic subjective effects. Thus, discriminative stimulus properties of opioids appear to reflect drug actions at the neuronal level that are directly relevant to potential for abuse in man.
Quantitative analysis of the interaction between the agonist and antagonist isomers of picenadol (LY150720) on electric shock titration in the squirrel monkey
1984, European Journal of Pharmacology
The opioid mixed agonist-antagonist picenadol (LY150720) is a racemate whose resolution results in a highly stereospecific separation of opioid agonist and antagonist activity. Attenuation of the antinociceptive effects of the agonist (dextro) isomer LY136596 by the antagonist (levo) isomer LY136595 was evaluated quantitatively in squirrel monkeys responding under a schedule of electric shock titration through the use of a dose-ratio analysis. LY136596 (0.3–3.0 mg/kg) produced a dose-related increase in the intensity at which monkeys maintained the shock. Increases in shock intensity produced by LY136596 were antagonized by LY136596 (0.1–10.0 mg/kg); dose-response curves for LY136596 were shifted to the right in a parallel manner by increasing doses of LY136595. An apparent pA₂ (Schild) plot obtained from these data yielded a line with a slope of −0.60 ± 0.05 and an apparent pA₂ value of 5.67 ± 0.07. These data support previous suggestions that the antinociceptive activity of picenadol (LY150720) resides in the d-isomer (LY136596) and that the l-isomer (LY136595) acts to limit the analgesic efficacy of the racemate.
Acute tolerance to the discriminative stimulus properties of morphine
1982, Pharmacology, Biochemistry and Behavior
Two pigeons were trained to discriminate intramuscular injections of 1.0 mg/kg morphine from water by presenting food after keypeck responses on one key when morphine was administered and after responses on a second key when water was administered. Following training, close to 100% of responses occurred on the appropriate key following administration of 1.0 mg/kg morphine or water. Morphine (0.1–5.6 mg/kg) produced dose-dependent increases in the percentage of morphine-appropriate responses (discriminative stimulus properties) and decreases in the rate of responding. A shift to the right of the morphine dose-effect curve for the discriminative stimulus properties of morphine resulted from a single injection of morphine (10.0 mg/kg) 24 hrs prior to testing (i.e., acute tolerance) but not from a single injection of pentobarbital (17.0 mg/kg). Tolerance to the discriminative stimulus properties of morphine was reversible within five days of the single injection. Tolerance did not develop to the effects of morphine on response rate. Naloxone antagonized both the discriminative stimulus properties and the response rate-decreasing effects of morphine. Thus, a single administration of morphine can alter morphine discriminability without affecting other aspects of behavior.

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^☆: This investigation was supported in part by U.S. Public Health Service Grants GM00179, DA00541, and Research Scientist Development Award K02 DA00008 to S.G.H.

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Stimulus effects of morphine in the monkey: Quantitative analysis of antagonism☆

Abstract

Pharmac. Biochem. Behav.

Pharmac. Biochem. Behav.

Eur. J. Pharmac.

Eur. J. Pharmac.

Eur. J. Pharmac.

pDx, pAx and pD'x values in the analysis of pharmacodynamics

Archs int. Pharmacodyn.

Some quantitative uses of drug antagonists

Br. J. Pharmac.

Receptor binding and pharmacological activity of opiates in the guinea-pig intestine

J. Pharmac. exp. Ther.

The urinary excretion profiles of naltrexone in man, monkey, rabbit, and rat

Drug Metab. Dispos.

Introduction to Statistical Analysis

Antagonism of morphine by long acting narcotic antagonists

Psychopharmacologia

Comparative in vivo distribution of opiate agonists and antagonists by means of double isotope techniques

Life Sci.

Narcotic antagonist activity of several metabolites of naloxone and naltrexone tested in morphine dependent mice (38558)

Some behavioral effects of morphine, naloxone and nalorphine in the squirrel monkey and the pigeon

J. Pharmac exp. Ther.

Elementary Statistics

Effects of morphine and narcotic antagonists on avoidance behavior of the squirrel monkey

J. Pharmac. exp. Ther.

Morphine as a discriminative cue in gerbils: Drug generalization and antagonism

Psychopharmacology

Further studies on the enhanced affinity of opioid receptors for naloxone in morphine-dependent mice

J. Pharmac. exp. Ther.

Opioid antagonists

Pharmac. Rev.