Antianalgesic action of dynorphin A mediated by spinal cholecystokinin

Previous work indicates that the antianalgesic action of pentobarbital and neurotensin administered intracerebroventricularly in mice arises from acti vation of a descending system to release cholecystokinin (CCK) in the spina l cord where CCK is known to antagonize morphine analgesia. Spinal dynorphi n, like CCK, has an antianalgesic action against intrathecally administered morphine. This dynorphin action is indirect; even though it is initiated i n the spinal cord, it requires the involvement of an ascending pathway to t he brain and a descending pathway to the spinal cord where an antianalgesic mediator works, The aim of the present investigation was to determine if t he antianalgesic action of intrathecal dynorphin A involved spinal CCK. All drugs were administered intrathecally to mice in the tail flick test, Morp hine analgesia was inhibited by dynorphin as shown by a rightward shift of the morphine dose-response curve, The effect of dynorphin was eliminated by administration of the CCK receptor antagonists lorglumide and PD135 158, O ne hour pretreatment with CCK antiserum also eliminated the action of dynor phin, On the other hand, the antianalgesic action of CCK was not affected b y dynorphin antiserum. Thus, CCK did not release dynorphin, Both CCK and dy norphin were antianalgesic against DSLET but not DPDPE, delta(2), and delta (1), opioid receptor peptide agonists, respectively The results suggest tha t the antianalgesic action of dynorphin occurred through an indirect mechan ism ultimately dependent on the action of spinal CCK.