Alcohol consumption enhances antiretroviral painful peripheral neuropathy by mitochondrial mechanisms

Abstract

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.