CCK₂ receptor antagonism attenuates negative motivational properties and physical signs of morphine withdrawal

CI988, a cholecytokinin receptor (CCK2) antagonist, is known to increase central enkephalin levels. CI 988 itself has not been shown to possess any direct positive motivational properties. We have used conditioned place aversion, in addition to recording physical signs, to determine whether CI 988 modifies the negative symptoms associated with naloxone-induced morphine withdrawal. We found that CI 988 attenuated the negative motivational properties of naloxone (NLX) precipitated morphine withdrawal as assessed by conditioned place aversion. Some somatic signs of NLX-precipitated morphine withdrawal: jumps, vocalization and salivation, were also ameliorated after both acute and chronic treatment with CI 988. However, wet dog shake behaviour significantly increased following acute CI 988 (5 mg/kg) treatment. Although CI 988 (5 mg/kg) elicited a trend towards conditioned place preference, this did not reach statistical significance. These results suggest that CI 988 may be a useful agent in reducing the severity of morphine withdrawal, possibly through its ability to facilitate endogenous enkephalin activity.