We have recently observed that exogenous sulfated cholecystokinin octapeptide (CCK) can antagonize various forms of opiate analgesia and that the CCK receptor blocker proglumide potentiates morphine analgesia. These observations, plus the similarity in the distribution of CCK and opiate systems, suggest that endogenous CCK may act as a physiological opiate antagonist. We have extended these initial studies by examining the effect of CCK antagonists on opiate analgesia produced by release of endogenous opiates (front paw footshock induced analgesia) and by intrathecal administration of D-Ala-methionine enkephalinamide, a stable analogue of an endogenous opiate. Additionally, the specificity of proglumide's effect was examined by testing the effect of this drug on various forms of non-opiate analgesia. This series of experiments demonstrate that CCK antagonists can markedly potentiate analgesia induced by endogenous opiates and provide strong support for the hypothesis that endogenous CCK systems can oppose the analgesic effects of opiates. Potentiation of analgesia by CCK receptor blockers appears to be selective for opiate systems since proglumide typically attenuated or had no effect on various forms of non-opiate analgesia. These data suggest that CCK blockers may be clinically useful for enhancing the analgesic effects of procedures such as acupuncture, which may be mediated by release of endogenous opiates.