Opioid antagonists and antisera to endogenous opioids increase the nociceptive response to formalin: Demonstration of an opioid kappa and delta inhibitory tone

Michael H. Ossipov, Carl J. Kovelowski, Helen Wheeler-Aceto, Alan Cowan, John C. Hunter, Josephine Lai, T. Philip Malan, Frank Porreca

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The present experiments explored the role of endogenous opioids in the behavioral response to a formalin-induced nociceptive stimulus in the rat. Flinching was taken as a measure of the intensity of the nociceptive stimulus after the administration of formalin into the dorsal surface of the paw of control animals, or in animals receiving i.p. administration of receptor- selective doses of opioid antagonists including naloxone, naltrindole (delta opioid antagonist), nor-binaltorphimine (kappa opioid antagonist) or β- funaltrexamine (mu opioid antagonist). Additionally, antisera to [Leu5]enkephalin, [Met5]enkephalin and dynorphin A (1-13) (dynorphin) were administered intrathecally before formalin to explore the contribution of endogenous opioids in modulation of the flinching response. Formalin-induced flinching was increased significantly by naloxone, and receptor selective doses of naltrindole and nor-binaltorphimine, but not β-funaltrexamine. Additionally, antisera to [Leu5]enkephalin and dynorphin also resulted in a significant increase in formalin-induced flinching, whereas antisera to [Met5]enkephalin had no effect. On the basis of significant increases in formalin-induced flinching produced by 1) receptor-selective doses of delta and kappa, but not mu, opioid antagonists and 2) antisera to [Leu5]enkephalin and dynorphin A, but not [Met5]enkephalin, these data suggest the presence of an opioid inhibitory tone which acts to limit the intensity of the pain signal. This tone appears to be mediated via activation of delta and kappa receptors, possibly by a [Leu5]enkephalin- and dynorphin- like substance, respectively.

Original languageEnglish (US)
Pages (from-to)784-788
Number of pages5
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number2
StatePublished - May 1 1996


ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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