Peripheral opioid modulation of pain and inflammation in the formalin test

The effects of local treatment with opioid receptor agonists on the early (0-10 min) and late (20-40 min) behavioural response and extravasation induced by intraplantar injection of 1% formalin in rats were examined. The mu-opioid receptor agonist [D-Ala2,N-Me-Phe4,Gly5-ol]enkephalin (DAMGO) depressed pain behaviour in the late phase, and extravasation in both phases. The kappa-opioid receptor agonist trans-(+/-)-3,4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl] benzeneacetamide methanesulfonate (U50,488H) suppressed the behavioural response in both phases, but extravasation was enhanced in the early phase and not altered in the late phase. The delta-opioid receptor agonist [D-Pen2,5]enkephalin (DPDPE) enhanced the behavioural response in the late phase, but inhibited extravasation in the both early and late phases. Systemic injection of the agonists had no effects, and pretreatment with s.c. naloxone methiodide reversed the effects of locally administered agonists. These data (1) support the notion that different pathophysiological mechanisms underlie the two phases of the formalin test, and (2) indicate that depending on the receptor specificity, opioid receptor agonists have both pro- and antinociceptive effects, as well as pro- and antiinflammatory activity.