CCK antagonists enhance opiate analgesia & appear to reverse morphine tolerance

s353 CCK ANTAGONISTS ENHANCE OPIATE ANALGESIA & APPEAR TO REVERSE MORPHINE TOLERANCE. L. Watkinsl, I. Kinscheck**, J. Miller2" R. Coghil12* H. Frenk3 h D. Mayer2. Animal Physiol.i , Univ. of Caiif., Davis, CA 95616 U.S.A.; Physiol. h Bioph sics2, Med. Coll. VA, Richmond, VA 23298 U.S.A.; Psychology, Tel Aviv U.t;, Ramat Aviv, Israel. We have reported that the CCK antagonist proglumide (PR) enhances systemic, intracerebral & intrathecal (IT) morphine analgesia (Neurosci. Abs., 9 (1983) 792). Since PR (a) does not produce analgesia in the absence of opiates and (b) does not potentiate non-opiate analgesia, these data indicate that CCK systems selectively interact with opiates to return the organism toward basal pain sensitivity. We have extended these initial findings by examining the effect of (a) the order to delivery of morphine & PR, (b) CCK antagonists on IT D-alamethionine enkephalinamide (DALA) analgesia 8 (c) PR on systemic morphine tolerance in rats. In all studies, the tail flick test was used to assess pain thresholds. These studies show that (a) PR enhances morphine analgesia when PR is given prior to, with, or after morphine, (b) the CCK antagonists PR & benzotript each enhance IT DALA so the effect may be characteristic of CCK antagonists in general, (c) IT PR enhances IT DALA in a naltrexone reversible manner, & (d) PR appears to reverse tolerance to the analgesic effects of systemic morphine. The fact that increased doses of PR are required to 'reverse' tolerance in rats exposed to longer (10 vs 6 day) morphine tolerance regimens suggests that chronic morphine may induce CCK synthesis/release and that CCK may at least in part underlie the phenomenon of tolerance. These data have broad implications for the acute & chronic management of pain in man. Supported by the A. H. Robins Co. and DA 00576.