Reversal of tolerance to morphine but no potentiation of morphine-induced analgesia by antiserum against cholecystokinin octapeptide

Abstract

Tolerance to morphine analgesia was induced in rats by chronic treatment with morphine (5-30 mg/kg, t.i.d. for 6 days). Intracerebroventricular (i.c.v.) injection of antiserum against cholecystokinin octapeptide (CCK-8) reversed tolerance to morphine by 50% (P less than 0.001). Intrathecal (ith) injection of the CCK-8 antiserum produced a similar, although less marked, reversal of tolerance to morphine. Rats made tolerant to analgesia induced by morphine developed a cross tolerance to electroacupuncture-induced analgesia. This cross tolerance was also reversed by the CCK-8 antiserum by more than 50% (P less than 0.001). Intracerebroventricular or intrathecal injection of the CCK-8 antiserum per se produced no significant changes in the basal level of the latency of the tail flick response, nor did it affect the analgesia induced by morphine in naive rats. The results suggest that prolonged activation of opioid receptors may trigger the CCK-8 system in the central nervous system to exert a negative feedback control, which may constitute one of the mechanisms for the development of tolerance to opioids.