title: Role of Drp1, a key mitochondrial fission protein, in neuropathic pain.
abstract: While oxidative stress has been implicated in small-fiber painful peripheral neuropathies, antioxidants are only partially effective to treat patients. We have tested the hypothesis that Drp1 (dynamin-related protein 1), a GTPase that catalyzes the process of mitochondrial fission, which is a mechanism central for the effect and production of reactive oxygen species (ROS), plays a central role in these neuropathic pain syndromes. Intrathecal administration of oligodeoxynucleotide antisense against Drp1 produced a decrease in its expression in peripheral nerve and markedly attenuated neuropathic mechanical hyperalgesia caused by HIV/AIDS antiretroviral [ddC (2',3'-dideoxycytidine)] and anticancer (oxaliplatin) chemotherapy in male Sprague Dawley rats. To confirm the role of Drp1 in these models of neuropathic pain, as well as to demonstrate its contribution at the site of sensory transduction, we injected a highly selective Drp1 inhibitor, mdivi-1, at the site of nociceptive testing on the dorsum of the rat's hindpaw. mdivi-1 attenuated both forms of neuropathic pain. To evaluate the role of Drp1 in hyperalgesia induced by ROS, we demonstrated that intradermal hydrogen peroxide produced dose-dependent hyperalgesia that was inhibited by mdivi-1. Finally, mechanical hyperalgesia induced by diverse pronociceptive mediators involved in inflammatory and neuropathic pain-tumor necrosis factor α, glial-derived neurotrophic factor, and nitric oxide-was also inhibited by mdivi-1. These studies provide support for a substantial role of mitochondrial fission in preclinical models of inflammatory and neuropathic pain.
authors.affiliation: Department of Medicine, University of California at San Francisco, San Francisco, California 94143-0440, USA.
authors.forename: Luiz F
authors.initials: LF
authors.lastname: Ferrari
authors.forename: Adrienne
authors.initials: A
authors.lastname: Chum
authors.forename: Oliver
authors.initials: O
authors.lastname: Bogen
authors.forename: David B
authors.initials: DB
authors.lastname: Reichling
authors.forename: Jon D
authors.initials: JD
authors.lastname: Levine
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D019380:Anti-HIV Agents / Q000633:toxicity; D000970:Antineoplastic Agents / Q000633:toxicity; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D034281:Dynamins / Q000235:genetics / Q000378:metabolism*; D004837:Epinephrine / Q000627:therapeutic use; D005786:Gene Expression Regulation / Q000187:drug effects; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000627:therapeutic use; D006861:Hydrogen Peroxide; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D020932:Nerve Growth Factor / Q000627:therapeutic use; D009437:Neuralgia / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000633:toxicity; D009574:Nitro Compounds / Q000633:toxicity; D020319:Oligodeoxyribonucleotides, Antisense / Q000627:therapeutic use; D009944:Organoplatinum Compounds / Q000633:toxicity; D000077150:Oxaliplatin; D010147:Pain Measurement / Q000379:methods; D052999:Quinazolinones / Q000627:therapeutic use; D012333:RNA, Messenger; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000627:therapeutic use; D016047:Zalcitabine / Q000633:toxicity
chemical_list: C549041:3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone; D019380:Anti-HIV Agents; D000970:Antineoplastic Agents; D051100:Glial Cell Line-Derived Neurotrophic Factor; D020030:Nitric Oxide Donors; D009574:Nitro Compounds; D020319:Oligodeoxyribonucleotides, Antisense; D009944:Organoplatinum Compounds; D052999:Quinazolinones; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D000077150:Oxaliplatin; D016047:Zalcitabine; D020932:Nerve Growth Factor; C061872:FK 409; D006861:Hydrogen Peroxide; C519851:Dnm1l protein, rat; D034281:Dynamins; D004837:Epinephrine