Mechanisms of tactile hypersensitivity induced by chronic alcohol consumption

About This Grant

SUMMARY Individuals with alcohol use disorder (AUD) are more likely to suffer from chronic pain conditions and to report moderate to severe pain compared with AUD-free subjects. Importantly, pain is a significant risk factor for relapse back to alcohol use, and a reduction in pain is associated with reduced relapse. These clinical data strongly suggest that effective pain management during AUD treatment can facilitate abstinence. Our long- term goals are to delineate the mechanisms underlying the impact of chronic alcohol consumption on pain processing and to identify molecular targets for intervention strategies that selectively target pain in the context of AUD. We have established a behavioral paradigm that models the effects of chronic alcohol on nociception and persistent pain. Our preliminary data indicate that repeated cycles of chronic alcohol consumption and withdrawal resulted in alcohol-induced hypersensitivity (AIH). Moreover, chronic alcohol consumption delayed recovery from tactile hypersensitivity induced by a transient nerve injury. We postulate that the observed AIH is driven by maladaptive changes in neural processing that establish a vulnerability to chronic pain. The goal of this exploratory project is to investigate the spinal mechanisms of AIH. In a preliminary experiment, we found that AIH is attenuated by intrathecal administration of gabazine, an antagonist of gamma-aminobutyric acid (GABA) type A receptors (GABAAr). This observation suggests that chronic alcohol consumption leads to maladaptive changes that disrupt spinal inhibitory signaling – a mechanism implicated in hypersensitivity across a broad spectrum of rodent pain models, including neuropathic pain and morphine-induced hyperalgesia. Moreover, the chloride transporter KCC2 has been identified as a key contributor to this mechanism and a druggable chronic pain management target. Based on our preliminary data, we hypothesize that chronic alcohol consumption leads to tactile hypersensitivity through dysregulation of spinal inhibitory signaling. In Aim 1, we will determine whether chronic alcohol consumption leads to excitatory actions of the normally inhibitory neurotransmitters GABA and glycine (Gly) using behavioral testing and patch clamp electrophysiology. In Aim 2, we will identify mechanisms of dysregulated spinal inhibition following chronic alcohol consumption. We will combine targeted analysis of the contribution of KCC2 to AIH and a global approach using single-nucleus RNAseq and quantitative phosphoproteomic analyses of the effects of alcohol in the dorsal horn, which will identify potential signaling pathways contributing to altered KCC2 function and additional potential spinal mechanisms underlying AIH. Impact: Increased mechanistic understanding of the spinal effects of chronic alcohol consumption will inform efforts to identify pain management strategies tailored to AUD.