The Role of Melanocortin Plasticity in Pain-Related Outcomes After Alcohol Exposure

Abstract

The global COVID-19 pandemic has shone a light on the rates and dangers of alcohol misuse in adults and adolescents in the US and globally. Alcohol exposure during adolescence causes persistent molecular, cellular, and behavioral changes that increase the risk of alcohol use disorder (AUD) into adulthood. It is established that alcohol abuse in adulthood increases the likelihood of pain hypersensitivity and the genesis of chronic pain, and humans report drinking alcohol to relieve pain symptoms. However, the longitudinal effects of alcohol exposure on pain and the underlying CNS signaling that mediates it are understudied. Specific brain regions mediate pain effects, alcohol effects, and pain-alcohol interactions, and neural signaling in those brain regions is modulated by neuropeptides. The CNS melanocortin system is sensitive to alcohol and modulates pain sensitivity, but this system is understudied in the context of pain-alcohol interactions. In this review, we focus on the role of melanocortin signaling in brain regions sensitive to alcohol and pain, in particular the amygdala. We also discuss interactions of melanocortins with other peptide systems, including the opioid system, as potential mediators of pain-alcohol interactions. Therapeutic strategies that target the melanocortin system may mitigate the negative consequences of alcohol misuse during adolescence and/or adulthood, including effects on pain-related outcomes.

Keywords: MC4R; alcohol; melanocortin; opioids; pain.

Figure 1

Cleavage of precursor protein pro-opiomelanocortin (POMC). Pro-hormone convertase 1/3 (PC1/3) cleaves POMC into pro-adrenocorticotropic hormone (Pro-ACTH) and β-lipotropin. PC 1/3 further processes pro-ACTH into ACTH where proconvertase 2 (PC 2) then sequentially cleaves ACTH to ACTH (1–17) and corticotropin-like intermediate peptide (CLIP). From there, carboxypeptidase E cleaves the basic amino acid residues of ACTH (1–17) allowing amidation by peptidyl α-ami-dating monooxygenase (PAM) to form des-acetyl-α-MSH (DA-α-MSH), where then n-acetyltransferase (NAT) acetylates DA-α-MSH into the mature α-MSH. PC2 also cleaves the N-terminal portion of POMC fragement/pro-γ-melanocyte stimulating hormone (MSH) into γ-MSH. Finally, β-lipotropin is processed into the endogenous opioid β-endorphin and γ-lipotrophin.

Figure 2

Schematic summary of the evidence-based and hypothetical effects of pain and alcohol withdrawal on melanocortin signaling within the central nervous system, and of the effects of altered melanocortin signaling on pain-related behaviors. Pre-clinical evidence suggests that pain and alcohol withdrawal [see (98, 105)] are associated with increased melanocortin tone through increases in α-MSH and/or POMC in brain regions implicated in pain and substance abuse, including the amygdala. MC4R couples to all three major G-coupled protein pathways, however activation of PKA and the mitogen activated protein kinase (MAPK) ERK1/2 are associated preclinically with pain-states (145, 146), and antagonism of MC4R reduces pain-related outcomes and results in decreases in ERK1/2 activation (72). The molecular mechanisms underlying MC4R drug effects on alcohol intake remain unclear.