Pharmacological characterization of nalorphine, a kappa(3) analgesic Journal Article
| Authors: | Paul, D.; Pick, C. G.; Tive, L. A.; Pasternak, G. W. |
| Article Title: | Pharmacological characterization of nalorphine, a kappa(3) analgesic |
| Abstract: | 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. |
| Keywords: | nonhuman; mouse; animal; mice; classification; animal experiment; drug receptor binding; morphine; analgesics; analgesia; drug tolerance; receptors, opioid, mu; naloxone; beta funaltrexamine; naltrindole; pyrrolidines; cross tolerance; binding, competitive; 3,4 dichloro n methyl n [2 (1 pyrrolidinyl)cyclohexyl]benzeneacetamide methanesulfonate; kappa opiate receptor; receptor occupancy; receptors, opioid; intracerebroventricular drug administration; norbinaltorphimine; male; priority journal; article; nalorphine; receptors, opioid, kappa; support, non-u.s. gov't; support, u.s. gov't, p.h.s.; 3,4-dichloro-n-methyl-n-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-isomer; intrathecal drug administration; quadazocine |
| Journal Title: | Journal of Pharmacology and Experimental Therapeutics |
| Volume: | 257 |
| Issue: | 1 |
| ISSN: | 0022-3565 |
| Publisher: | American Society for Pharmacology and Experimental Therapeutics |
| Date Published: | 1991-04-01 |
| Start Page: | 1 |
| End Page: | 7 |
| Language: | English |
| PUBMED: | 1850462 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Source: Scopus |
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