Alcohol consumption enhances antiretroviral painful peripheral neuropathy by mitochondrial mechanisms.
A major dose-limiting side effect of human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) chemotherapies, such as the nucleoside reverse transcriptase inhibitors (NRTIs), is a small-fiber painful peripheral neuropathy, mediated by its mitochondrial toxicity. Co-morbid conditions may also contribute to this dose-limiting effect of HIV/AIDS treatment. Alcohol abuse, which alone also produces painful neuropathy, is one of the most important co-morbid risk factors for peripheral neuropathy in patients with HIV/AIDS. Despite the prevalence of this problem and its serious impact on the quality of life and continued therapy in HIV/AIDS patients, the mechanisms by which alcohol abuse exacerbates highly active antiretroviral therapy (HAART)-induced neuropathic pain has not been demonstrated. In this study, performed in rats, we investigated the cellular mechanism by which consumed alcohol impacts antiretroviral-induced neuropathic pain. NRTI 2',3'-dideoxycytidine (ddC; 50 mg/kg) neuropathy was mitochondrial-dependent and PKCε-independent, and alcohol-induced painful neuropathy was PKCε-dependent and mitochondrial-independent. At low doses, ddC (5 mg/kg) and alcohol (6.5% ethanol diet for 1 week), which alone do not affect nociception, together produce profound mechanical hyperalgesia. This hyperalgesia is mitochondrial-dependent but PKCε-independent. These experiments, which provide the first model for studying the impact of co-morbidity in painful neuropathy, support the clinical impression that alcohol consumption enhances HIV/AIDS therapy neuropathy, and provide evidence for a role of mitochondrial mechanisms underlying this interaction.
Ferrari
Luiz F
LF
NIH Pain Center (UCSF), Division of Neuroscience and Biomedical Sciences Program, University of California at San Francisco, San Francisco, CA 94143, USA.
Levine
Jon D
JD
D020269:Alcoholic Neuropathy / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D000818:Animals; D019380:Anti-HIV Agents / Q000009:adverse effects*; D004195:Disease Models, Animal; D004347:Drug Interactions; D045222:Electron Transport Chain Complex Proteins / Q000037:antagonists & inhibitors; D000431:Ethanol / Q000494:pharmacology*; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy; D008297:Male; D008928:Mitochondria / Q000378:metabolism*; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology / Q000627:therapeutic use; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D051744:Protein Kinase C-epsilon / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016047:Zalcitabine / Q000009:adverse effects*
D019380:Anti-HIV Agents; D045222:Electron Transport Chain Complex Proteins; D020319:Oligodeoxyribonucleotides, Antisense; D000431:Ethanol; D016047:Zalcitabine; D051744:Protein Kinase C-epsilon