THE NMDA RECEPTOR ANTAGONIST, NPC-12626, REDUCES THE PRONOCICEPTIVE EFFECTS OF ORPHANIN FQ AND KAPPA-OPIATE ANTINOCICEPTION IN THE LAND SNAIL, CEPAEA-NEMORALIS

The heptadecapeptide, orphanin FQ or nociceptin -Gly-Ala-Arg-Lys-Ser-A la-Arg-Lys-Leu-Ala-Asn-Gln), originally isolated from rat brain has be en identified as an endogenous ligand for the orphan opioid-like recep tor. Although orphanin FQ shares some sequence and structural homology with kappa-opioid peptides, it has been speculated to exert its effec ts through novel nonopioid mechanisms. Kappa opioids have also been su ggested to have nonopioid actions in rodents involving the N-methyl-D- aspartate (NMDA) receptor. The present study examined the effects of t he competitive NMDA antagonist, NPC 12626, on the antinociceptive effe cts of the specific kappa-opiate receptor agonist, U69,593, and the pr onociceptive effects of orphanin FQ in an invertebrate system, the lan d snail, Cepaea nemoralis. NPC 12626 had no effect on the basal nocice ptive sensitivity of snails, as measured by the latency of response to a thermal (40 degrees C) surface. As reported for rodents, NPC 12626 dose-dependently reduced U69,593-induced antinociception in a manner c omparable to that produced by the specific kappa-opiate antagonist, no r-binaltorphimine, while slightly enhancing the antinociceptive effect s of the predominately mu-opiate agonist, morphine. Similarly, NPC 126 26 dose-dependently reduced the pronociceptive effects of orphanin FQ. These findings with the snail, Cepaea, indicate that NMDA systems/rec eptors are associated with the mediation of the nociceptive effects of both kappa opioids and orphanin FQ. They suggest an early evolutionar y development and phylogenetic continuity of NMDA opioid and related n europeptide interactions in the mediation of nociception. (C) 1997 Els evier Science Inc.