This study examined a possible peripheral site of action of opiates in the modulation of the response to noxious pressure on inflamed paws. Rats received an injection of Mycobacterium butyricum suspension into one hindpaw which resulted in an ipsilateral inflammatory response (swelling) and decreased threshold to noxious pressure within 1–2 days. Four days post-inoculation direct intraplantar injection of fentanyl resulted in a significant increase of paw pressure thresholds in inflamed, but not in non-inflamed paws. Intraplantar injection of (−)-naloxone but not (+)-naloxone reversed this effect. The action of fentanyl was dose dependent at doses of 0.1–1.2 μg. Equal doses of fentanyl given systemically as well as (−)-naloxone or (+)-naloxone given alone were inactive. These data show that fentanyl can modify the response to noxious pressure in inflamed but not non-inflamed paws via a peripheral site of action. Stereospecific reversibility by naloxone as well as dose dependency strongly indicate an opioid mechanism of action. This suggests a possible role for peripherally located opioid receptors in the modulation of nociception in inflamed tissue.