Conditioned place preference: no tolerance to the rewarding properties of morphine

Naunyn Schmiedebergs Arch Pharmacol. 1997 May;355(5):589-94. doi: 10.1007/pl00004988.


The effect of repeated morphine administration on conditioned place preference (CPP) using a novel treatment schedule, i.e., drug treatment was always contingent with the conditioned environmental stimuli, was investigated. We also examined whether changes in the mu- and kappa-opioid receptor binding occurred in the brain of morphine-treated animals. Intraperitoneal (i.p.) administration of morphine (2 and 10 mg/kg) induced a place preference after 8 daily conditioning trials (4 morphine injections on alternate trials), the level of preference being the same with the two doses of the opiate. No change in place preference was observed in the morphine-treated rats at 2 mg/kg, when animals were further trained up to a total of 32 conditioning trials (16 morphine injections). Conversely, after 20 conditioning trials (10 morphine injections), a stronger CPP response developed in the morphine-treated rats at 10 mg/kg. Signs of morphine withdrawal were never detected in morphine-treated rats during the experiment. Loss of body weight (index of opiate dependence) was not observed either 24 h or 48 h after the last morphine administration. mu- and kappa-opioid receptor density and affinity were not affected by repeated morphine administrations at either dose. The results demonstrate that no tolerance develops to the rewarding properties of morphine. Indeed, a sensitisation effect may occur at increasing doses of the opiate. Furthermore, changes in the rewarding effect of morphine are not dependent upon alterations in opioid receptors involved in the reinforcing mechanisms.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Behavior, Animal / drug effects
  • Benzeneacetamides*
  • Body Weight / drug effects
  • Disease Models, Animal
  • Drug Tolerance
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
  • Enkephalins / metabolism
  • Injections, Intraperitoneal
  • Male
  • Morphine / administration & dosage
  • Morphine / metabolism
  • Morphine / toxicity*
  • Morphine Dependence* / physiopathology
  • Narcotics / administration & dosage
  • Narcotics / metabolism
  • Narcotics / toxicity*
  • Pyrrolidines / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Opioid, kappa / agonists
  • Receptors, Opioid, kappa / drug effects
  • Receptors, Opioid, kappa / metabolism
  • Receptors, Opioid, mu / agonists
  • Receptors, Opioid, mu / drug effects
  • Receptors, Opioid, mu / metabolism


  • Benzeneacetamides
  • Enkephalins
  • Narcotics
  • Pyrrolidines
  • Receptors, Opioid, kappa
  • Receptors, Opioid, mu
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
  • Morphine
  • U 69593