Dissociation of tolerance and dependence to morphine: a possible role for cholecystokinin

Since cholecystokinin (CCK) has been suggested to be an endogenous opiate antagonist, we tried to evaluate if this peptide could be involved in the development of tolerance to morphine. Naive rats were chronically administered morphine, either alone or concomitantly with proglumide or benzotript, two putative CCK receptor antagonists. Chronic treatments with both CCK antagonists alone were also established. Drugs were administered by the oral route, dissolved in the drinking water. At the end of the chronic treatments, the development of tolerance to morphine was assessed by an evaluation of the analgesic responses evoked by graded doses of acutely injected morphine in the tail-flick and hot plate tests. Proglumide and benzotript were able to inhibit the shift to the right of the dose-response curve for morphine, i.e. they prevented the development of tolerance to morphine-induced analgesia. Chronically given alone, the two CCK antagonists never modified the responses to the acute challenge with morphine. We also determined the development of physical dependence by looking at the withdrawal syndrome precipitated by graded doses of acutely injected naloxone. In these experiments the concomitant treatment with morphine and proglumide or benzotript did not modify the occurrence of dependence. These observations are consistent with the hypothesis of CCK being an endogenous opiate antagonist, involved in the development of tolerance to morphine-induced analgesia but not of dependence. Moreover, tolerance to and dependence on morphine can be pharmacologically dissociated.