Vol. 289, Issue 1, 378-385, April 1999

Activation of Peripheral  Opioid Receptors Inhibits Capsaicin-Induced Thermal Nociception in Rhesus Monkeys¹

Mei-Chuan Ko, Eduardo R. Butelman² and James H. Woods

Departments of Pharmacology and Psychology, University of Michigan, Ann Arbor, Michigan

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 three 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 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 opioid receptor subtypes in the periphery, which indicated that U50,488 produced local antinociception by acting on ₁ receptors, but bremazocine acted probably on non-₁ receptors. These results provide functional evidence that activation of peripheral  opioid receptors can diminish capsaicin-induced allodynia in primates. This experimental pain model is a useful tool for evaluating peripherally antinociceptive actions of agonists without central side effects and suggests new approaches for opioid pain management.