NeuPainAud - The neural basis of chronic pain in alcohol use disorders

Alcohol is one of the most commonly used psychoactive substances worldwide. It has been documented as a source of enjoyment for a majority of users since the beginning of written history but is also the cause of disease and death for a significant minority of those who drink. Excessive alcohol use accounts for about 5% of global disease burden and close to 6% of all deaths. One of the main causes of progression into AUD is chronic pain, a widespread condition with extensive public health burden. The prevalence of AUD is increased in patients suffering from chronic pain, partly due to its analgesic properties which may be heightened among individuals with alcohol addiction. Maladaptive alcohol coping to alleviate pain not only facilitates the transition into AUD but also induces severe diseases due to alcohol-drug interactions (eg liver failure, gastric bleeding) with a tremendous impact on health and society. Pain can be a significant risk factor for relapse in those recovering from AUD, pointing to an urgent need to understand molecular mechanisms at pain-AUD intersection to identify i) contributing factors that predict the risk of AUD in response to chronic pain and ii) improve the treatment outcome. In here we will use a preclinical model to study the impact of chronic pain on continued alcohol use despite negative consequences (e.g compulsive alcohol) a key clinical feature of AUD. We will study the role of individual susceptibility and the influence of sex on the propensity to develop compulsive alcohol use during a condition of chronic pain. Our hypothesis is that activity of the central amygdala (CeA) neuronal ensembles expressing protein kinase d (PKCδ) is critically involved at the bases of the concurrent condition. In a susceptible minority, pathologically elevated PKCδ activity in CeA might represent a common neural substrate in chronic pain-induced compulsive drinking. Next, using in vivo calcium imaging and a novel PKCδ Cre transgenic rat line, we will detect neuronal dynamic changes specifically in PKCδ+ neurons in response to chronic inflammatory pain and alcohol use. Identifying the underpinning biological mechanisms holds a potential for discovery of long-term neuroadaptations and novel therapeutics in AUD patients with chronic pain. For instance, pathological PKCδ activation might be due to increased phosphorylation of Transient Receptor Potential Ankyrin 1 (TRPA1) channels which are key transducing channels in pain perception. Combining in vitro, ex vivo and in vivo approaches we will test PKCδ TRPA1 interaction and the therapeutic potential of TRPA1 antagonists in attenuating pain-induced alcohol consumption. Our results will critically advance the mechanistic understanding of the pain-AUD intersection and help to guide successful development of effective treatments in AUD patients with neuropathic pain.