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
Citation Impact
MSK Authors
  1. Gavril W Pasternak
    414 Pasternak
  2. Chaim G. Pick
    14 Pick
  3. Dennis J. Paul
    17 Paul