8/8 NADIA U01 Long-Term Effects of Adolescent Alcohol on Pain

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Adolescent alcohol use leads to persistent neural adaptations and behavioral dysregulation that increase the risk of developing alcohol use disorder (AUD). Acute alcohol reduces pain, and chronic pain (e.g., hyperalgesia) can promote alcohol drinking through negative reinforcing analgesic effects. Paradoxically, chronic alcohol produces hyperalgesia or worsen pre-existing pain states. Recently, we reported that medial central amygdala (CeA) projections to a midbrain region called the periaqueductal gray (vlPAG) are critical for mediating hyperalgesia in chronically alcohol exposed adult male rats. This chronic alcohol weakens synaptic connectivity between medial CeA and vlPAG in adult male rats, photostimulation of the CeA-vlPAG circuit rescues hyperalgesia in alcohol-dependent adult rats, and photoinhibition of this circuit produces hyperalgesia in naïve rats. Our lab and others find that antagonism of corticotropin-releasing factor type-1 receptors (CRFR1) in CeA reduces hyperalgesia associated with alcohol withdrawal, nicotine withdrawal and traumatic stress in adult rats. Our overarching hypotheses are that chronic intermittent alcohol exposure in adolescent rats (AIE) produces persist long-term effects on polymodal (i.e., mechanical and thermal) hyperalgesia that is mediated by weakened CeA-vlPAG connectivity and increased CRFR1 signaling in CeA. The CRFR1 signaling gating of CeA-vlPAG function is important for mediating AIE-induced hyperalgesia. We include preliminary data showing that 1) AIE produces rapid and long-lasting thermal and mechanical hyperalgesia during adolescence and that this effect persists into adulthood (Fig. 1), 2) AIE reduces synaptic drive and excitatory/inhibitory ratio on vlPAG-projecting medial CeA neurons in adulthood (Fig. 3), 3) CRFR1 is expressed on vlPAG projecting cells (Fig. 2), and 4) validation data for a CRFR1:cre rat for CRFR1+ cell type- specific modulation of CeA outputs (Fig. 4). Because we also propose to challenge rats with a short-lasting inflammatory pain challenge in adulthood, we have also piloted dose-response effects of carrageenan on nociception in adult Wistar rats. Here, we propose aims that will test the hypotheses that AIE produces hyperalgesia during adolescence that persists into adulthood (Specific Aim 1), that AIE reduces synaptic drive and excitatory/inhibitory balance of synaptic transmission onto vlPAG-projecting CeA neurons via a CRFR1- dependent (Specific Aim 2), and that pharmacological, circuit-based, and epigenetic modulation of CRFR1+ PAG- projecting CeA neurons will rescue AIE-induced hyperalgesia and CeA-vlPAG circuit plasticity (Specific Aim 3). Importantly, we propose specific collaborations with Research Component 6 (PI:Chandler) and 5 (PI: Crews) along with the Epigenetics Core (PI: Pandey) of the NADIA consortium. This proposal focuses on testing adolescent alcohol effects on pain-related outcomes and aligns with the overall goal of the NADIA consortium to examine the effects of adolescent alcohol exposure on the adult organism.