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 alpha-induced hyperalgesia, they had no effect on hyperalgesia induced by prostaglandin E2 and epinephrine. Two competitive inhibitors of ATP-dependent mechanisms, adenosine 5'-(beta,gamma-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 alpha, 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.
Department of Medicine, Division of Neuroscience and Biomedical Sciences Program, University of California at San Francisco, 521 Parnassus Ave, Box # 0440/C522, San Francisco, CA 94143-0440, USA.
Elizabeth K
EK
Joseph
Jon D
JD
Levine
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D000968:Antimycin A / Q000031:analogs & derivatives / Q000494:pharmacology; D004195:Disease Models, Animal; D004347:Drug Interactions; D004579:Electron Transport / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006930:Hyperalgesia / Q000188:drug therapy / Q000201:enzymology* / Q000209:etiology*; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology*; D009097:Multienzyme Complexes / Q000378:metabolism*; D009437:Neuralgia / Q000139:chemically induced / Q000150:complications*; D020078:Neurogenic Inflammation / Q000139:chemically induced / Q000150:complications*; D010147:Pain Measurement / Q000379:methods; D017288:Pain Threshold / Q000187:drug effects; D010525:Peripheral Nerves / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012402:Rotenone / Q000494:pharmacology; D013311:Streptozocin; D013997:Time Factors; D014475:Uncoupling Agents / Q000494:pharmacology; D014750:Vincristine; D016047:Zalcitabine
D004791:Enzyme Inhibitors; D009097:Multienzyme Complexes; D014475:Uncoupling Agents; D012402:Rotenone; C032456:antimycin; D014750:Vincristine; D013311:Streptozocin; D000968:Antimycin A; D016047:Zalcitabine; D000255:Adenosine Triphosphate