Central Amygdala Circuits Mediate Hyperalgesia in Alcohol-Dependent Rats

Alcohol withdrawal symptoms contribute to excessive alcohol drinking and relapse in alcohol-dependent individuals. Among these symptoms, alcohol withdrawal promotes hyperalgesia, but the neurological underpinnings of this phenomenon are not known. Chronic alcohol exposure alters cell signaling in the central nucleus of the amygdala (CeA), and the CeA is implicated in mediating alcohol dependence-related behaviors. The CeA projects to the periaqueductal gray (PAG), a region critical for descending pain modulation, and may have a role in alcohol withdrawal hyperalgesia. Here, we tested the roles of (1) CeA projections to PAG, (2) CeA melanocortin signaling, and (3) PAG μ-opioid receptor signaling in mediating thermal nociception and alcohol withdrawal hyperalgesia in male Wistar rats. Our results demonstrate that alcohol dependence reduces GABAergic signaling from CeA terminals onto PAG neurons and alters the CeA melanocortin system, that CeA-PAG projections and CeA melanocortin signaling mediate alcohol withdrawal hyperalgesia, and that μ-opioid receptors in PAG filter CeA effects on thermal nociception.

SIGNIFICANCE STATEMENT Hyperalgesia is commonly seen in individuals with alcohol use disorder during periods of withdrawal, but the neurological underpinnings behind this phenomenon are not completely understood. Here, we tested whether alcohol dependence exerts its influence on pain modulation via effects on the limbic system. Using behavioral, optogenetic, electrophysiological, and molecular biological approaches, we demonstrate that central nucleus of the amygdala (CeA) projections to periaqueductal gray mediate thermal hyperalgesia in alcohol-dependent and alcohol-naive rats. Using pharmacological approaches, we show that melanocortin receptor-4 signaling in CeA alters alcohol withdrawal hyperalgesia, but this effect is not mediated directly at synaptic inputs onto periaqueductal gray-projecting CeA neurons. Overall, our findings support a role for limbic influence over the descending pain pathway and identify a potential therapeutic target for treating hyperalgesia in individuals with alcohol use disorder .