Development of new pharmacological strategies to treat wound pain will require a better understanding of the network of molecular events within nociceptive primary afferents that sensitize these nerve fibers. We have recently obtained compelling evidence that the integrins, a family of cell-surface receptor proteins not previously implicated in pain pathophysiology, plays a pivotal role in nociceptor sensitization. Specifically, integrins are essential in hyperalgesia mediated by both the PKA and PKC pathways activated by inflammatory mediators that are present in wounds. Furthermore, we have determined that integrins are a key element in the molecular events underlying the transition from acute inflammatory hyperalgesia to a state of chronic nociceptive hypersensitivity. Integrin molecules are heterodimers of alpha and beta subunits; the relatively large family of integrin proteins (containing at least two dozen members) and their specific interactions with hyperalgesic pathways present a rich prospect for the discovery of new pharmacological targets for analgesic therapy. The possibility of developing anti-integrin analgesics for use in humans seems very feasible, since such drugs are already being tested in clinical trials for treatment of a wide variety of other pathologies. Toward the ultimate goal of facilitating the rational design of highly specific analgesics to disrupt integrin-dependent mechanisms of wound pain, we propose a detailed analysis of the contributions of integrin subunits to acute and chronic hyperalgesia in the rat. This study will employ ah interdisciplinary approach utilizing behavioral and electrophysiological methods in concert to pharmacologically dissect apart the differential roles of individual integrin subunits in the acute and chronic wound-related pain, with emphasis on pain associated with partial thickness burn injury. ? ? ?
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