Tolerance and selective cross-tolerance to the motivational effects of opioids

T. S. Shippenberg, M. W. Emmett-Oglesby, F. J. Ayesta, A. Herz

Research output: Contribution to journalArticlepeer-review

46 Scopus citations


The issue of whether tolerance develops to the motivational effects of opioids was addressed by use of an unbiased place preference conditioning procedure. Administration of the μ-opioid agonists morphine or fentanyl produced dose-related preferences for the drug-associated place in control rats. In contrast, the κ-opioid agonist, U-69593 produced conditioned place aversions. Non-contingent administration of morphine (5.0 mg/kg/12 h) for 4 days prior to conditioning resulted in tolerance to its reinforcing effects, and cross-tolerance to the effects of fentanyl. No cross-tolerance to the motivational effects of the psychostimulant d-amphetamine or the κ-opioid agonist U-69593 was observed. Chronic administration of U-69593 prior to conditioning produced tolerance to its aversive effects. This treatment did not, however, modify the reinforcement produced by morphine. These data demonstrate that tolerance develops to both the reinforcing and aversive properties of opioids and suggest that differential cross-tolerance may provide a useful method for determining the pharmacological basis underlying drug-induced motivational effects.

Original languageEnglish
Pages (from-to)110-115
Number of pages6
Issue number1
StatePublished - Sep 1988


  • Morphine
  • Opioids
  • Place conditioning
  • Rat
  • Reinforcement
  • Tolerance
  • U-69593
  • d-Amphetamine


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