A selective CCKB receptor antagonist potentiates, mu-, but not delta-opioid receptor-mediated antinociception in the formalin test.

The endogenous peptides enkephalins and cholecystokinin appear to play an opposite role in the control of pain. In this work, the effect of the selective CCKB receptor antagonist PD-134,308 on antinociceptive effects induced by morphine or by a complete inhibitor of enkephalin-metabolizing enzymes, RB 101, was studied using the formalin test. In mice, s.c. injection of formalin into the dorsal surface of the hindpaw had a biphasic effect: an early nociceptive response followed by a late response. Morphine (2 mg/kg i.p.) caused naloxone (0.5 mg/kg s.c.) but not naltrindole (0.5 mg/kg s.c.) reversible antinociceptive responses in the early and late phases of the assay, suggesting a preferential involvement of mu-opioid receptors in these responses. In contrast, RB 101 (50 mg/kg i.p.) produced antinociceptive effects in the early and late phases which were both antagonized by the delta-selective opioid receptor antagonist naltrindole (0.5 mg/kg s.c.). The antinociceptive response elicited by morphine on the late but not the early phase of the formalin test was potentiated by the CCKB antagonist PD-134,308 (1 mg/kg i.p.). This compound was unable to facilitate the analgesic effects produced by RB 101 on both phases, in contrast to what was observed in the hot plate test with mice and the tail flick test with rats. Therefore, in the formalin test with mice, the facilitating effects of opiate-induced analgesia by CCKB receptor antagonists seem to be restricted to mu-opioid receptor-mediated responses.