In rats, acute morphine dependence results in antagonist-induced response suppression of intracranial self-stimulation

Abstract

Rationale

Lower (0.001–1.0 mg/kg) doses of the opioid antagonist naltrexone produce few behavioral effects in otherwise drug-free rats responding for ICSS, but reduce response rates by up to 75% after a single dose of morphine.

Objectives

The present study represents an effort to verify that other opioid antagonists produce this acute opioid dependence effect, and to characterize their relative pharmacological profiles.

Methods

We implanted bipolar electrodes in the lateral hypothalamus of adult male rats, and then trained them to lever-press on an “autotitration” ICSS schedule, where responding on a “reset” lever allows the rat to control the frequency of stimulation; performance stabilized at approximately 1.5 responses/s.

Results

During twice-weekly test sessions, cumulative doses of five of seven opioid antagonists produced significant response rate decreases (30–80%) in saline-pretreated rats; nalorphine (ED25=15.6 mg/kg) > naltrexone (ED25=13.1 mg/kg)>naloxone (ED25=7.3 mg/kg)>levallorphan (ED25=13.96 mg/kg)>(−)cyclazocine (ED25=0.028 mg/kg). A single MOR pretreatment (10 mg/kg, 4 h) significantly enhanced the rate-decreasing effects of six of the seven agonists tested; by 10-fold (−) cyclazocine>13-fold (nalorphine)>93-fold (levallorphan)>972-fold (naloxone)>2190-fold (naltrexone). The pure non-selective antagonist diprenorphine potently decreased rates after MOR pretreatment (ED25=0.01 mg/kg), but did not after saline pretreatment. The mixed opioid agonist-antagonist drug nalbuphine (1.0–30 mg/kg) did not affect responding after either saline or MOR.

Conclusions

Antagonists with a high affinity for, and a lack of intrinsic activity at, the μ-opioid receptor precipitate the greatest behavioral changes in rats acutely dependent on MOR.

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Acknowledgments

The authors are grateful to Christina Kittipatarin for expert technical assistance, and to Merck & Co., Roche Laboratories, and the National Institute on Drug Abuse for generously providing some of the drugs that were used in this study. This investigation was supported by grant DA00541 and by Senior Scientist Award K05 DA00008, both from the National Institutes of Health. Portions of this work were presented at the 62nd annual meeting of the College on Problems of Drug Dependence (2000, San Juan, PR).

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Correspondence to Keith W. Easterling.

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Easterling, K.W., Holtzman, S.G. In rats, acute morphine dependence results in antagonist-induced response suppression of intracranial self-stimulation. Psychopharmacology 175, 287–295 (2004). https://doi.org/10.1007/s00213-004-1829-3

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Keywords

  • Intracranial self-stimulation
  • Sensitization
  • Naltrexone
  • Morphine
  • Physical dependence
  • Opioid withdrawal
  • Levallorphan
  • Nalbuphine
  • Nalorphine
  • Cyclazocine
  • Diprenorphine