The aim of this study was to investigate local opioid effects in the inflamed skin of healthy human volunteers. To induce inflammation, the circular tip of a 10-mm-diameter probe was heated to 48 degrees C and applied for 120 seconds to a site on each forearm of 24 healthy participants. Thirty minutes later, 0.2 mL of normal saline was injected subcutaneously into 1 inflamed site, and the opioid antagonist naloxone hydrochloride (80 mu g in 0.2 mL) was injected subcutaneously into the other inflamed site. Participants completed tests of pain sensitivity (heat pain thresholds, heat pain ratings, and mechanical pain ratings) before and after the injections. Fentanyl citrate (10 mu g in 0.2 mL) was then injected into the pretreated sites, and pain sensitivity was measured again. The thermal injuries produced thermal and mechanical hyperalgesia that did not differ between the saline and naloxone sites. After the fentanyl injections, decreases in thermal and mechanical hyperalgesia were greater at the saline site than the naloxone site. These findings demonstrate that pretreatment with naloxone blocks local opioid effects produced by the subcutaneous injection of a low dose of fentanyl in the inflamed skin of healthy humans. Thus, peripheral opioid receptors could be a therapeutic target for painful cutaneous disorders.Perspective: This article demonstrates that activation of opioid receptors in the skin inhibits sensitivity to painful mechanical and thermal stimuli. Thus, local application of low-dose opioid medications could relieve painful skin disorders. (c) 2007 by the American Pain Society.