Effects of R-84760, a selective kappa-opioid receptor agonist, on nociceptive reflex in isolated neonatal rat spinal cord.

We tested the effects of (3 R)-3-(1-pyrrolidinylmethyl)-4-[(1S)-5,6-dichloro-1-indancarbony l]-2,3,5,6-tetrahydro-1,4-thiazine hydrochloride (R-84760), a selective kappa-opioid receptor agonist, on the slow ventral root potential in the isolated spinal cord of neonatal rats. R-84760 at 10 nM decreased the slow ventral root potential to 35% of the control, leaving the monosynaptic reflex unaffected. The depressant effect of R-84760 progressed slowly for 60 min to the maximum and recovered slightly after removal of the drug from the perfusing solution. This contrasts with [D-Ala2, MePhe4, Gly-ol5]enkephalin (DAMGO) or [MeTyr1, MeArg7, D-Leu-NHEt8]dynorphin A-(1-8) (E-2078) which attained their maximum depressant effect within 15 min with recovery immediately after washout. Reversibility of the R-84760 effect was observed in vivo in antinociceptive tests in mice. R-84760 reduced the depolarization induced by substance P or L-glutamate in the normal solution, but not in the presence of tetrodotoxin at 0.3 microM. Naloxone inhibited the effect of R-84760 at a higher concentration (1 microM) than that (0.1 microM) needed to antagonize the effect of DAMGO. In contrast, R-84760 was more sensitive to nor-binaltorphimine than was DAMGO. The results show that R-84760 selectively inhibits the nociceptive response presynaptically through kappa-opioid receptors and that the inhibitory effect is characteristic, with long duration, in the neonatal rat spinal cord.