ENHANCEMENT OF MORPHINE ANTINOCICEPTION BY A CCKB ANTAGONIST IN MICE IS MEDIATED VIA OPIOID-DELTA RECEPTORS

This study investigated the possible involvement of opioid delta recep tors in the modulation of morphine antinociceptive potency produced by L365,260, a CCKB antagonist. Intracerebroventricular (i.c.v.), intrat hecal (i.th.) or subcutaneous (s.c.) L365,260 alone did not produce an y antinociceptive actions in the mouse warm-water tail-flick test. Tre atment with L365,260 by any of these routes produced a leftward shift of the corresponding morphine dose-effect curve that was blocked by pr etreatment with a receptor-selective dose of s.c. naltrindole, an opio id delta receptor antagonist. Pretreatment with i.c.v. antisera to [Le u(5)]enkephalin also blocked the leftward displacement of the i.c.v. m orphine dose-effect curve resulting from L365,260 but did not directly alter the i.c.v. morphine dose-effect curve; antisera to [Met(5)]enke phalin did not alter the effects of morphine or the modulation of morp hine antinociception produced by L365,260. Repeated pretreatment with L365,260 resulted in a progressive decrease in the magnitude of the mo rphine modulatory action (i.e., L365,260 ''tolerance''). In these ''L3 65,260-tolerant'' mice, the dose-effect curve for i.c.v. [D-Ala(2), Gl u(4)]deltorphin (a selective delta agonist) was displaced to the right by approximately 8.2-fold. The i.c.v. administration of [Leu(5)]enkep halin produced a leftward displacement of the i.c.v. morphine dose;eff ect curve that diminished after repeated administration (i.e., [Leu(5) ]enkephalin ''tolerance''). In ''[Leu(5)]enkephalin-tolerant'' mice, L 365,260 failed to produce the leftward shift of the morphine dose-effe ct curve seen in central animals. That is, two-way antinociceptive cro ss-tolerance was observed between an opioid delta agonist and a CCKB r eceptor antagonist. Intracerebroventricular thiorphan, a peptidase inh ibitor, did not elicit antinociception directly. Co-administration of thiorphan with L365,260 elicited significant antinociception that was blocked by naltrindole or antisera to [Leu(5)]enkephalin; antisera to [Met(5)]enkephalin had no effect. Repeated administration of i.c.v. [D -Ala(2), Glu(4)]deltorphin resulted in a progressively decreasing anti nociceptive effect (i.e., [D-Ala(2), Glu(4)]deltorphin ''tolerance''). In ''[D-Ala(2), Glu(4)]deltorphin-tolerant'' mice, the thiorphan/L365 ,260 antinociceptive effect was inhibited. Collectively, these data su ggest that CCK interacts at the CCKB receptor to inhibit tonically the release and/or availability of an endogenous substance acting at opio id delta receptors. The subsequent enhancement of morphine antinocicep tive potency may reflect the well-known modulation of morphine antinoc iception produced by opioid delta receptor agonists. In this case, the latter may be [Leu(5)]enkephalin or a [Leu(5)]enkephalin-like substan ce.