SNF9007 - A NOVEL ANALGESIC THAT ACTS SIMULTANEOUSLY AT DELTA(1), DELTA(2), AND MU-OPIOID RECEPTORS

Intracerebroventricular administration of the synthetic cholecystokini n analog SNF9007 (Asp-Tyr-D-Phe-Gly-Trp-[NMe]-Nle-Asp-Phe-NH2) produce d antinociception in the mouse hot-plate and warm water tail-flick tes ts. The mechanisms of its analgesic actions were assessed by administe ring antagonists selective for CCK (cholecystokinin octapeptide, sulfa ted)-A and CCK-B receptors, as well as specific antagonists for the mu opioid receptor (D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2, 1 mu g i.c. v.), the delta-1 opioid receptor [D-Ala(2)-Leu(5), Cys(6)]enkephalin, 4.57 nmol i.c.v., 24 hr pretreatment), the delta-2 opioid receptor (na ltrindole benzofuran, 25 pmol i.c.v.) and the kappa opioid receptor (n or-binaltorphimine, 10 mg/kg s.c.). The antinociceptive activity of SN F9007 was not a result of the activation of CCK receptors, as treatmen t with either CCK-A or CCK-B receptor antagonist was ineffective in bl ocking SNF9007 antinociception. Nor-binaltorphimine and naltrindole be nzofuran were completely ineffective in blocking SNF9007 antinocicepti on when administered alone or in combination. However, co-administrati on of delta-1 or delta-2 opioid receptor antagonists with the mu opioi d receptor antagonist D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 resulted in a dramatic reduction in analgesic responses to SNF9007. Furthermor e, the co-administration of mu + delta-1 + delta-2 opioid receptor ant agonists resulted in an even greater inhibition of SNF9007 antinocicep tion (>10-fold shift). We conclude that SNF9007 acts simultaneously at brain delta-1, delta-2 and mu opioid receptors to induce antinocicept ive effects in mice.