Abstract
Topically administered capsaicin produces thermal allodynia, and this effect has been used to investigate pain transduction and its pharmacological modulation. This study investigated the parameters of topical capsaicin-induced thermal allodynia in unanesthetized rhesus monkeys and its pharmacological modulation by centrally acting compounds [a κ-opioid agonist: (5α,7α,8β)-(+)-N-methyl-N-(7-[1-pyrrolidinyl]-1-oxaspiro [4.5]dec-8-yl)-benzeneacetamide (U69,593); and noncompetitive N-methyl-d-aspartate (NMDA) antagonists: ketamine and MK-801 (dizocilpine)]. Rhesus monkeys (n = 4) were studied within the warm water tail withdrawal assay (20-s maximum latency), using thermal stimuli that are normally not noxious (38 and 42°C). Capsaicin was applied topically on the tail (0.0013 and 0.004 M capsaicin solution on a 1-cm2 patch; 15-min contact). Topical capsaicin produced concentration-dependent thermal allodynia in both temperatures, robustly detected 15 to 90 min after topical capsaicin removal. A similar allodynic profile was observed with topical administration of the “endovanilloid” N-arachidonoyl-dopamine. The κ-agonist U69,593 (0.01-0.1 mg/kg, s.c.) dose dependently prevented capsaicin (0.004 M)-induced allodynia in 38 and 42°C, and the largest U69,593 dose also reversed ongoing allodynia within this model. Two NMDA antagonists, ketamine and MK-801 (0.32-1.8 and 0.032-0.056 mg/kg, respectively), also prevented capsaicin-induced allodynia in 38°C, but only variably in 42°C, at doses that did not cause robust thermal antinociceptive effects. At the largest doses studied, ketamine but not MK-801 also briefly reversed ongoing capsaicin-induced allodynia. The present model of topical capsaicin administration may be used to study antiallodynic effects of opioid and nonopioid compounds, as well as their ability to prevent and reverse allodynia, in unanesthetized nonhuman primates in the absence of tissue disruption.
Footnotes
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This work was supported by National Institutes of Health/National Institute on Drug Abuse Grants DA11113 (E.R.B.), DA 00049, and DA05130 (M.J.K.). Portions of these studies were presented in preliminary form at the 33rd International Narcotics Research Conference (Pacific Grove, CA) July 9 -14, 2002.
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The present studies were reviewed by the Rockefeller University Institutional Animal Care and Use Committee (IACUC) and are in accordance with the Guide for the Care and Use of Laboratory Animals, as promulgated by the U.S. National Institutes of Health.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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DOI: 10.1124/jpet.103.052381.
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ABBREVIATIONS. U69,593, 5α,7α,8β)-(+)-N-methyl-N-(7-[1-pyrrolidinyl]-1-oxaspiro[4.5]dec-8-yl)-benzeneacetamide; MK-801, dizocilpine; NADA, N-arachidonoyl-dopamine; ANOVA, analysis of variance; NMDA, N-methyl-d-aspartate; E-2078, N-methyl-Tyr1,N-methyl-Arg7,d-Leu8dynorphin A[1-8]ethylamide.
- Received April 5, 2003.
- Accepted June 6, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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