Abstract
8-Methyl-N-vanillyl-6-nonenamide (capsaicin) was locally applied in the tail of rhesus monkeys to evoke a nociceptive response, thermal allodynia, which was manifested as reduced tail-withdrawal latencies in normally innocuous 46°C water. Coadministration of threeκ opioid ligands, U50,488 (3.2–100 μg), bremazocine (0.1–3.2 μg), and dynorphin A(1–13) (3.2–100 μg), with capsaicin in the tail dose-dependently inhibited capsaicin-induced allodynia. This local antinociception was antagonized by a small dose of an opioid antagonist, quadazocine; (0.32 mg), applied in the tail; however, this dose of quadazocine injected s.c. in the back did not antagonize local U50,488. Comparing the relative potency of either agonist or antagonist after local and systemic administration confirmed that the site of action of locally applied κ opioid agonists is in the tail. In addition, local nor-binaltorphimine (0.32 mg) and oxilorphan (0.1–10 μg) antagonist studies raised the possibility of κ opioid receptor subtypes in the periphery, which indicated that U50,488 produced local antinociception by acting on κ1 receptors, but bremazocine acted probably on non-κ1 receptors. These results provide functional evidence that activation of peripheral κ opioid receptors can diminish capsaicin-induced allodynia in primates. This experimental pain model is a useful tool for evaluating peripherally antinociceptive actions of κ agonists without central side effects and suggests new approaches for opioid pain management.
Footnotes
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Send reprint requests to: Mei-Chuan Ko, Ph.D., Department of Pharmacology, University of Michigan, 1301 MSRB III, Ann Arbor, MI 48109–0632. E-mail:mko{at}umich.edu
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↵1 Support for this research was provided by United States Public Health Services Grant DA00254. Preliminary results were presented at the 60th annual meeting of College on Problems of Drug Dependence, Scottsdale, AZ, June 13–18, 1998.
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↵2 Present address: Rockefeller University, New York, NY
- Abbreviations:
- Capsaican
- 8-methyl-N-vanillyl-6-nonenamide
- DYN A(1–13)
- dynorphin A(1–13)
- nor-BNI
- nor-binaltorphimine
- % MPE
- percentage of maximum possible effect
- CGRP
- calcitonin gene-related peptide
- U50
- 488,(trans)-3,4-dichloro-N-methyl-N[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide
- Received August 31, 1998.
- Accepted October 30, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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