The dynorphin (DYN)/kappa opioid receptor (KOR) system has increasingly been investigated as a possible pharmacotherapeutic target for alcohol use disorder, but findings on the direction of its effects have been mixed. Activation of KORs by DYN has been shown to elicit dysphoric effects, and the DYN/KOR system has canonically been considered particularly important in driving alcohol intake through negative reinforcement in dependent states. However, this review also highlights its activity in opposing the positive reinforcement that drives alcohol intake at earlier stages. Both DYN and KORs are concentrated in the extended amygdala, a set of interconnected regions that includes the bed nucleus of the stria terminalis, central nucleus of the amygdala, and nucleus accumbens shell. This review focuses on the role of the DYN/KOR system in the extended amygdala in ethanol use. It begins by examining the effects of ethanol on the expression of DYN/KOR in the extended amygdala, expression of DYN/KOR in alcohol‐preferring and alcohol‐avoiding animals, and the effects of knocking out DYN/KOR genes on ethanol intake. Then, it examines the effects on ethanol use in both dependent and nondependent states from systemic pharmacological manipulations of DYN/KOR and from specific manipulation of this system in regions of the extended amygdala. We propose that greater expression and binding of DYN/KOR, by reducing the positive reinforcement that drives early stages of intake, initially acts to prevent the escalation of ethanol drinking. However, prolonged, binge‐like, or intermittent ethanol intake enhances levels of DYN/KOR in the extended amygdala such that the system ultimately facilitates the negative reinforcement that drives later stages of ethanol drinking. This review highlights the potential of the DYN/KOR system as a target that can affect different outcomes across different stages of ethanol drinking and the development of alcohol use disorder.
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.
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