Targeting IL-6 as a novel therapeutic approach for alcohol abstinence - related mechanical allodynia.

Alcohol use disorder (AUD) is defined by the emergence of negative affective symptoms during withdrawal. Neuroinflammation is a key contributor to AUD, and it is well known to play an essential role in the pathogenesis of pain states. The chronic-intermittent ethanol two-bottle choice (CIE-2BC) paradigm is well-established to generate alcohol-dependent (Dep) and non-dependent (Non-Dep) mice. Our recent work demonstrated that the CIE-2BC model promotes mechanical allodynia in Dep mice, with these mice developing mechanical allodynia during withdrawal. In this study, we examined the role of interleukin-6 (IL-6) in the development of mechanical allodynia by adapting the CIE-2BC mouse model and employing the von Frey test, in situ hybridization (RNAscope), and Multiplex protein analysis of the spinal cord, examining changes in this target including an array of cytokines associated with IL-6 signaling. CIE-2BC escalated alcohol drinking and enhanced mechanical allodynia in Dep versus Non-Dep mice, with Dep females displaying greater alcohol intake. Dep mice displayed increased IL-6 protein in the spinal cord while males additionally had increased Il6+ cell expression versus Non-Dep controls. Systemic treatment of an IL-6 receptor antibody (IL-6R Ab) did not decrease mechanical allodynia during abstinence. Collectively, these data suggest that alcohol exerts sex-dependent effects on spinal IL-6 levels. However, in our study, blocking IL-6 signaling did not reduce alcohol-associated pain sensitivity in a mouse model of comorbid pain and alcohol dependence.