SNF9007: A novel analgesic that acts simultaneously at delta₁, delta₂ and mu opioid receptors

Intracerebroventricular administration of the synthetic cholecystokinin analog SNF9007 (Asp-Tyr-D-Phe-Gly-Trp-[NMe]-Nle-Asp-Phe-NH₂) produced antinociception in the mouse hot-plate and warm water tail-flick tests. The mechanisms of its analgesic actions were assessed by administering antagonists selective for CCK (cholecystokinin octapeptide, sulfated)-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 μg i.c.v.), the delta-1 opioid receptor [D-Ala²-Leu⁵, Cys⁶)enkephalin, 4.57 nmol i.c.v., 24 hr pretreatment), the delta-2 opioid receptor (naltrindole benzofuran, 25 pmol i.c.v.) and the kappa opioid receptor (nor-binaltorphimine, 10 mg/kg s.c.). The antinociceptive activity of SNF9007 was not a result of the activation of CCK receptors, as treatment with either CCK-A or CCK-B receptor antagonist was ineffective in blocking SNF9007 antinociception. Nor-binaltorphimine and naltrindole benzofuran were completely ineffective in blocking SNF9007 antinociception when administered alone or in combination. However, co- administration of delta-1 or delta-2 opioid receptor antagonists with the mu opioid receptor antagonist D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH₂ resulted in a dramatic reduction in analgesic response to SNF9007. Furthermore, the co-administration of mu + delta-1 + delta-2 opioid receptor antagonists resulted in an even greater inhibition of SNF9007 antinociception (>10-fold shift). We conclude that SNF9007 acts simultaneously at brain delta-1, delta- 2 and mu opioid receptors to induce antinociceptive effects in mice.