Mitochondrial electron transport in models of neuropathic and inflammatory pain

Although peripheral nerve function is strongly dependent on energy stores, the role of the mitochondrial electron transport chain, which drives ATP synthesis, in peripheral pain mechanisms, has not been examined. In models of HIV/AIDS therapy (dideoxycytidine), cancer chemotherapy (vincristine), and diabetes (streptozotocin)-induced neuropathy, inhibitors of mitochondrial electron transport chain complexes I, II, III, IV, and V significantly attenuated neuropathic pain-related behavior in rats. While inhibitors of all five complexes also attenuated tumor necrosis factor α-induced hyperalgesia, they had no effect on hyperalgesia induced by prostaglandin E2 and epinephrine. Two competitive inhibitors of ATP-dependent mechanisms, adenosine 5′-(β,γ-imido) triphosphate and P1,P4-di(adenosine-5′) tetraphosphate, attenuated dideoxycytidine, vincristine, and streptozotocin-induced hyperalgesia. Neither of these inhibitors, however, affected tumor necrosis factor α, prostaglandin E2 or epinephrine hyperalgesia. These experiments demonstrate a role of the mitochondrial electron transport chain in neuropathic and some forms of inflammatory pain. The contribution of the mitochondrial electron transport chain in neuropathic pain is ATP dependent.