Changes in pain processing after adolescent… (F31AA032982) – Project Grant to The Research Foundation For…

Abstract: The nucleus accumbens (NAC) shell receives dopamine (DA) projections from the ventral tegmental area (VTA) and serotonin (5HT) projections from dorsal raphe nucleus (DRN), together highlighting the integrative monoamine control within this region. Chronic ethanol exposure during adolescence poses a significant threat to a critical period in 5HT and DA circuitry development as alcohol exposure during this time disrupts development of the NAC shell, further promoting maladaptations in behaviors such as reward seeking, arousal, and pain perception. For example, adolescent chronic intermittent ethanol (acie) exposure in rodents augments tactile sensitivity and hyperalgesia in response to inflammation during protracted withdrawal. To date, little is known about the underlying neurobiological mechanisms driving these changes. Interestingly, recent literature has identified both hyperfunctional dopamine in the NAC shell and hypofunctional 5HT in the DRN in models of acie-associated increases in tactile sensitivity. However, acie exposure- and persistent pain-associated neuroplasticity in DA and 5HT have yet to be investigated. Our overarching hypothesis that both acie- and inflammatory pain-exposure will dysregulate typical DA and 5HT development, but the combined effect of acie and inflammatory pain will synergistically potentiate DA and suppress 5HT function, ultimately disrupting the typical DA and 5HT balance in the NAC shell. This dysregulation will in turn augment perceptual pain sensitivity. In order to test this hypothesis, in aim 1, we will use EX vivo fast scan cyclic voltammetry (fscv) to measure changes in DA and 5HT release and uptake kinetics in the NAC shell in rats with and without acie exposure, and with and without inflammatory pain experience. We predict that rats with both acie and pain exposure will exhibit the greatest DA and the lowest 5HT release and the respective uptake kinetics. In aim 2 we will employ cell-type specific chemogenetic approaches to excite or inhibit DA (VTA→NAC shell) or 5HT (DRN→NAC shell) projections in rats with inflammatory pain and a history of acie, and age-matched controls (no acie exposure history and no inflammatory pain). Using chemogenetic viruses with distinct activating ligands, we will use a within subject design to inhibit and excite the same projection on separate days and measure the resulting changes in mechanical pain sensitivity with VON frey testing. We predict that both inhibiting DA and exciting 5HT will at least partially alleviate acie associated exacerbation of mechanical allodynia. By identifying projection-specific contributions to pain modulation and quantifying the shift in ratio of DA and 5HT within the NAC shell, we will identify how monoaminergic imbalance contributes to acie-associated heightened pain sensitivity, ultimately elucidating non-opioidergic therapeutic targets for persistent pain management in individuals with history of chronic alcohol use. Together with my research plan and a comprehensive training plan developed under the guidance of a strong mentoring team, i will advance both technically and professionally, making substantive progress towards my goal of becoming an independent academic scientist.

Changes in pain processing after adolescent alcohol exposure

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