Severe pain due to war-related injuries is difficult to treat, and current opioids i.e. mu opioid receptor agonists such as morphine cause unacceptable side effects including addiction. Injuries suffered most frequently by active military personnel include traumatic brain injury, nerve trauma, skin incision, and burn injury, and all these injuries are associated with acute cutaneous pain andor mechanical allodyniahypersensitivity. The goals of our research are to evaluate analgesics acting on delta opioid receptors DORs in animal models relevant to todays battlefield experience Specific Aim 2, and elucidate the mechanisms by which DOR agonists, administered in skin and acting on mechanosensory dorsal root ganglia neurons, relieve pain Specific Aim 1. We have determined the analgesic effect of two DOR agonists, deltorphin II and SNC80. We show that these compounds significantly elevate mechanical pain threshold, indicating their acute antinociceptive action. Furthermore, we found that in two models of injuries, namely skin incision and nerve trauma, a single injection of deltorphin II eliminates the mechanical hyper sensitivity caused by injury. We have also initiated studies aiming at identifying the peripheral sensory neurons that express DOR, a first step towards understanding the analgesic mechanism of action of DOR agonists. We are currently extending these findings by performing the other experiments described in our original proposal, without significant change in our plans and strategy. Importantly, our promising results support our hypothesis that DOR agonists, acting in the skin, represents an effective therapeutic strategy for blocking severe pain associated with injuries that can be suffered on the battlefield.