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Discriminative stimulus effects of acute morphine followed by naltrexone in the squirrel monkey

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Abstract

Rationale

The discriminative stimulus effects of a combination of acute morphine followed by naltrexone have been described in rats.

Objective

The purpose of this study was to extend observations to a non-human primate.

Methods

Eight squirrel monkeys were trained in a discrete-trial avoidance/escape procedure to discriminate morphine (1.7 mg/kg, IM, 4 h) followed by naltrexone (0.1 mg/kg, IM, 0.25 h) (MOR→NTX) versus saline (1.0 ml/kg, IM, 4 h) followed by naltrexone (0.1 mg/kg, IM, 0.25 h) (SAL→NTX).

Results

Seven subjects acquired the discrimination in an average of 108±14 sessions. MOR→NTX-appropriate responding increased as an orderly function of increasing dose of morphine (0.56–1.7 mg/kg) and of naltrexone (0.01–10 mg/kg). The discrimination was also dependent upon interval between morphine and naltrexone administration. The MOR→NTX cue was fully generalized to the combination of levorphanol (0.3 mg/kg) followed by naltrexone, but not to the non-opioid stereoisomer of levorphanol, dextrorphan (0.3 and 3.0 mg/kg) or the kappa-opioid-receptor-selective agonist U69,593 (0.3 mg/kg) followed by naltrexone. Naltrexone administered 15 min before morphine dose-dependently blocked MOR→NTX-appropriate responding.

Conclusions

This is the first non-rodent study of the discriminative effects of MOR→NTX. MOR→NTX produces a unique interoceptive stimulus that is pharmacologically selective, requires occupation of opioid receptors, presumably mu, for some minimum period of time, and is reversible. This discrimination procedure might provide new insights into the early drug-receptor interactions that underlie the development of physical dependence upon morphine-like drugs.

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Acknowledgements

We thank Dr. Kelly R. Powell for conducting the preliminary experiments that led the way to this study. This research was supported by NIH grants DA00541 and K05 DA00008.

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Authors and Affiliations

  1. Department of Pharmacology, Emory University School of Medicine, Rollins Research Center, 1510 Clifton Road NE, Suite 5074, Atlanta, GA 30322, USA

    David A. White & Stephen G. Holtzman

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  1. David A. White
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  2. Stephen G. Holtzman
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Correspondence to David A. White.

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White, D.A., Holtzman, S.G. Discriminative stimulus effects of acute morphine followed by naltrexone in the squirrel monkey. Psychopharmacology 167, 203–210 (2003). https://doi.org/10.1007/s00213-002-1367-9

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  • DOI: https://doi.org/10.1007/s00213-002-1367-9

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