Adolescent ethanol exposure promotes mechanical allodynia and alters dopamine transmission in the nucleus accumbens shell

Abstract

Excessive alcohol consumption in adolescence can disrupt neural development and may augment pain perception. Recent studies have shown that the nucleus accumbens (NAc) shell is involved in mediating pain sensitivity after peripheral inflammation in rodent models of chronic pain and alcohol use disorder (AUD). Interestingly, there have been very few studies examining the impact of chronic ethanol exposure during adolescence on pain sensitivity in adulthood. Therefore, in this project we investigated the impact of adolescent chronic intermittent ethanol (aCIE) exposure on mechanical allodynia and thermal hyperalgesia. Furthermore, given the involvement of the NAc shell in pain processing and chronic ethanol mediated changes, we measured changes in accumbal dopamine kinetics during protracted withdrawal. We found that both male and female aCIE rats show mechanical allodynia during withdrawal; however, only male rats exhibit thermal hyperalgesia during protracted withdrawal. Furthermore, male and female aCIE rats show greater evoked tonic dopamine release, maximal rate of dopamine reuptake, and dopamine affinity to the dopamine transporter in the NAc shell compared to controls. With phasic stimulation, aCIE rats also showed greater dopamine release compared to air exposed rats. These data suggest that aCIE exposure exacerbates pain sensitivity during withdrawal. Furthermore, based on prior literature, it is possible that the increased pain sensitivity may be driven, at least in part, by augmented dopamine kinetics in the NAc shell observed in the current study.

Adolescent alcohol exposure promotes mechanical allodynia and alters synaptic function at inputs from the basolateral amygdala to the prelimbic cortex

“…In this study, mechanical and thermal sensitivity were assessed from adolescence to early adulthood using the electronic Von Frey and Hargreaves tests. Mechanical sensitivity was heightened in both male and female rats exposed to AIE, consistent with previous findings in rodents [18][19][20][21] . While AIE induced significant mechanical hypersensitivity, thermal sensitivity remained unchanged.…”

“…Emerging evidence from preclinical rodent models indicates that AIE exposure induces long-lasting hyperalgesia [18][19][20][21] . While changes within extended amygdala circuitry contribute to altered nociception in AIE exposed animals [19][20][21] , the impact on prefrontal nociceptive circuits remains unexplored.…”

“…Emerging evidence from preclinical rodent models indicates that AIE exposure induces long-lasting hyperalgesia [18][19][20][21] . While changes within extended amygdala circuitry contribute to altered nociception in AIE exposed animals [19][20][21] , the impact on prefrontal nociceptive circuits remains unexplored. This study investigated the e ects of AIE exposure and carrageenan-induced inflammatory paw pain on synaptic function and intrinsic excitability within a BLA-PrL-vlPAG circuit involved in modulating the descending pain pathway.…”

“…This dynamic extends to adolescents where untreated pain correlates with earlier initiation of alcohol use 14 , and alcohol consumption is associated with heightened ongoing and future pain [15][16][17] . Recent preclinical studies in rodents further indicate that adolescent intermittent ethanol (AIE) exposure induces persistent hyperalgesia spanning into adulthood [18][19][20][21] . Given the association between pain and AUD, understanding the impact of adolescent alcohol use on nociceptive circuits is crucial for improving AUD treatments.…”

Nucleus accumbens shell cholinergic interneurons potently drive binge alcohol drinking: A commentary on Sharma et al., 2024

“…In addition, there are no sex differences in changes in NAcSh cholinergic markers in response to adolescent alcohol exposure (Hauser et al., 2021), or in ventral tegmental area GABA projections onto NAcSh CINs (Al‐Hasani et al., 2021). There are also no sex differences in how adolescent alcohol increases pain and NAcSh signaling (Kelley et al., 2023), or in stress response activation of NAcSh neurons (Clark et al., 2023). Thus, one possibility is that multiple drivers of motivated behavior converge in NAcSh, but that mechanisms that promote higher female alcohol drinking, and often greater punishment‐resistant drinking (Radke et al., 2021), are downstream of NAcSh.…”