Pharmacological characterization of nalorphine, a kappa₃ analgesic

Nalorphine is an unusual opiate. Whereas low doses of nalorphine antagonize morphine analgesia, higher nalorphine doses are analgesic, with ED₅₀ values (95% CL) of 13.4 (11.5, 15.8) mg/kg in the writhing and 39.5 (26.6, 60.1) mg/kg in the tail-flick assay. Although nalorphine analgesia is sensitive to naloxone, implying an opioid mechanism, neither β-funaltrexamine, naltrindole nor nor-binaltorphomine antagonized nalorphine analgesia in the tail-flick assay at doses which reversed equianalgesic doses of their respective selective agonists. Nalorphine and the kappa₃ opiate naloxone benzoylhydrazone demonstrated analgesic cross-tolerance regardless of whether the mice were treated chronically with either nalorphine or naloxone benzyolhydrazone. Animals tolerant to nalorphine were not tolerant to either morphine or U50,488H {trans-3,4-dichloro-N-methyl-N-[2-(pyrrolindinyl)-cyclohexyl]-benzenea cetamide}. Furthermore, nalorphine retained its analgesic potency in animals tolerant to U50,488H. Nalorphine exerts its analgesia predominently through supraspinal mechanisms. Against systemically administered nalorphine, the opiate antagonist WIN44,441 {[2,6,11S-(-)-1-cyclopentyl-5-(1,2,3,4,5,6-hexahydro-8-hydroxy-3,6,11- trimethyl-2,6-methano-e-benazocine-11-yl)-3-pentanone methylsulfonate} reversed nalorphine analgesia 1500-fold more potently when administered i.c.v. (ID₅₀, 0.1 ng) than when given intrathecally (ID₅₀, 159 ng). Together these results indicate that nalorphine analgesia in the tail-flick assay does not involve mu, delta or the U50,488h-sensitive kappa₁ receptor and strongly suggest a role for supraspinal kappa₃ receptors.