RESUMEN
ABSTRACT: Preclinical and clinical work has demonstrated altered plasticity and activity in the nucleus accumbens (NAc) under chronic pain states, highlighting critical therapeutic avenues for the management of chronic pain conditions. In this study, we demonstrate that myocyte enhancer factor 2C (MEF2C), a master regulator of neuronal activity and plasticity, is repressed in NAc neurons after prolonged spared nerve injury (SNI). Viral-mediated overexpression of Mef2c in NAc neurons partially ameliorated sensory hypersensitivity and emotional behaviors in mice with SNI, while also altering transcriptional pathways associated with synaptic signaling. Mef2c overexpression also reversed SNI-induced potentiation of phasic dopamine release and neuronal hyperexcitability in the NAc. Transcriptional changes induced by Mef2c overexpression were different than those observed after desipramine treatment, suggesting a mechanism of action different from antidepressants. Overall, we show that interventions in MEF2C-regulated mechanisms in the NAc are sufficient to disrupt the maintenance of chronic pain states, providing potential new treatment avenues for neuropathic pain.
RESUMEN
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. 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. 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. 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 with controls. With phasic stimulation, aCIE rats also showed greater dopamine release compared with AIR-exposed rats. Inhibition of dopamine transmission targeted in the NAc shell reversed the aCIE-associated facilitation of mechanical allodynia in both sexes. These data suggest that aCIE exposure exacerbates pain sensitivity during withdrawal in an accumbal dopamine-dependent manner.
RESUMEN
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.