Chronic pain often accompanies neuropsychiatric conditions, impacting patient well-being, and worsening prognosis. The gut-brain axis, autonomic nervous system and alterations in some brain areas have emerged as crucial in pain chronification. Studies in rodents and humans reveal significant neuroadaptations within the mesocorticolimbic system fostering the emerge of negative affective states and cognitive deficits that promote maladaptive behaviours, such as compulsive alcohol consumption, and predicting pain chronification. Pilot research indicates sex-dependent glial alterations induced by pain within the mesocorticolimbic system potentially linking inflammation, glutamate neurotransmission, and behavioural changes. Interestingly, all these brain alterations are connected to gut by means of vagal afferences. Our hypothesis suggests that chronic pain disrupts vmPFC-NAc function via glial alterations, affecting cognitive and emotional behaviours, with sex-specific effects on alcohol consumption. Chronic pain (inflammatory, nociplastic and/or central sensitization) disrupts the gut-brain axis through the vagal pathway, exacerbated by alcohol consumption. This imbalance intensifies vmPFC-NAc alterations, perpetuating pain and its comorbidities. Understanding these brain-body mechanisms could identify chronic pain patient phenotypes as potential biomarkers, providing targeted psychological and gut microbiota interventions for pain management and associated comorbidities.