A major problem associated with diabetes is the complication of chronic non-healing wounds that can lead to the formation of debilitating ulcers, and can progress to more serious problems including amputation. There is no fully effective prevention of these complications, constituting an unmet medical need to understand the pathophysiology and treatment of wound healing in diabetes. This study determined whether blockade of opioid receptors from opioid peptides, known to inhibit cell proliferation and be overexpressed in diabetes, by topical application of the opioid antagonist naltrexone (NTX) reverses delays in wound closure. Rats with streptozotocin-induced type 1 diabetes (T1D) received topical applications of NTX (10(-4)-10(-6) mol/L) or vehicle in a variety of carriers; DNA synthesis was evaluated 12 h later. DNA synthesis in the epithelium of T1D rats was significantly reduced from normal animals. Both systemic and topical application of NTX increased DNA synthesis (up to 2-fold higher) within 12 h of administration. In a second study, diabetic and normal rats received full-thickness cutaneous wounds and were treated three times daily with either 10(-5) mol/L NTX or vehicle in topical carriers. Wound sizes were analyzed, and BrdU (5-bromo-2'-deoxyuridine) labeling in the skin was evaluated to determine DNA synthesis. Application of NTX in a variety of carriers to rats with full-thickness wounds resulted in significantly smaller wound areas relative to T1D animals receiving vehicle, and comparable to that of normal rats. Wound contraction in T1D animals was 50% of that in normal rats, with NTX-treated wounds restoring wound contraction to that of normal cohorts. DNA synthesis was also enhanced in NTX-treated T1D animals compared with T1D vehicle controls. These data suggest that topical application of NTX is a non-toxic and efficacious facilitator for healing full thickness wounds in T1D, with wound contraction serving as a particular target of NTX action.