Adolescent Alcohol Exposure Produces Sex-Specific Long-term Hyperalgesia via Changes in Central Amygdala Circuit Function

BACKGROUND Exposure to alcohol during adolescence produces many effects that last well into adulthood. Acute alcohol is analgesic and people living with pain report drinking alcohol to reduce pain, but chronic alcohol produces increases in pain sensitivity. METHODS Here, we tested the acute and lasting effects of chronic intermittent adolescent alcohol exposure (AIE) on pain-related behavioral and brain changes in male and female rats. We also tested the long-term effects of AIE on synaptic transmission in midbrain (vlPAG)-projecting central amygdala (CeA) neurons, using patch clamp electrophysiology. Finally, we used circuit-based approaches (DREADDs) to test the role of vlPAG-projecting CeA neurons in mediating AIE effects on pain-related outcomes. RESULTS We report that AIE produces long-lasting hyperalgesia in males but not females. Similarly, AIE led to a reduction in synaptic strength of medial central amygdala (CeM) cells that project to the ventrolateral periaqueductal gray (vlPAG) in males but not females. Challenge with an acute painful stimulus (i.e., formalin) in adulthood produced expected increases in pain reactivity, and this effect was exaggerated in male rats with a history of AIE. Finally, we show that CeA-vlPAG circuit activation rescues AIE-induced hypersensitivity in male rats. Our findings are the first to show long-lasting sex-dependent effects of adolescent alcohol exposure on pain-related behaviors and brain circuits in adult animals. CONCLUSIONS This work has implications for understanding the long-term effects of underage alcohol drinking on pain-related behaviors in humans.