Abstract
Capsaicin produces thermal allodynia in animals and humans by acting as an agonist at vanilloid receptor subtype 1 [VR1; also known as transient receptor potential vanilloid type 1 (TRPV1)]. VR1 receptors are widely distributed in the periphery (e.g., on primary afferent neurons). These studies examined the ability of loperamide (0.1–1 mg/kg s.c.; a μ-opioid agonist that is peripherally selective after systemic administration), in preventing and reversing thermal allodynia caused by topical capsaicin (0.004 M) in rhesus monkeys, within a tail withdrawal assay (n = 4; 38°C and 42°C; normally non-noxious thermal stimuli). The effects of loperamide were compared with those of the centrally penetrating μ-agonist, fentanyl (0.0032–0.032 mg/kg s.c.). We also characterized the allodynic effects of the endogenous VR1 agonist (“endovanilloid”), N-oleoyldopamine (OLDA; 0.0013–0.004 M). In this model, loperamide and fentanyl produced dose-dependent prevention of capsaicin-induced allodynia, whereas only fentanyl produced robust reversal of ongoing allodynia. Antagonism experiments with naltrexone (0.1 mg/kg s.c.) or its analog, methylnaltrexone (0.32 mg/kg s.c.), which does not readily cross the blood-brain barrier, suggest that the antiallodynic effects of loperamide and fentanyl were predominantly mediated by peripherally and centrally located μ-receptors, respectively. Loperamide and fentanyl (1 mg/kg and 0.032 mg/kg, respectively) also prevented OLDA (0.004 M)-induced allodynia. Up to the largest dose studied, loperamide was devoid of thermal antinociceptive effects at 48°C (a noxious thermal stimulus, in the absence of capsaicin). By contrast, fentanyl (0.01–0.032 mg/kg) caused dose-dependent antinociception in this sensitive thermal antinociceptive assay (a presumed centrally mediated effect). These studies show that loperamide, acting as a peripherally selective μ-agonist after systemic administration, can prevent capsaicin-induced thermal allodynia in primates in vivo, in the absence of thermal antinociceptive effects.
Footnotes
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This work was supported By National Institutes of Health-National Institute on Drug Abuse Grants DA11113 (to E.R.B.) and DA00049 and DA05130 (to M.J.K.).
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The present studies were reviewed by the Rockefeller University Institutional Animal Care and Use Committee, 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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doi:10.1124/jpet.104.068411.
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ABBREVIATIONS: VR1, vanilloid receptor subtype 1; OLDA, N-oleoyldopamine; ANOVA, analysis of variance.
- Received March 14, 2004.
- Accepted May 19, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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