Chronic Pain and Comorbidities: Molecular Mechanisms, Circuit Dysregulation, and Translational Opportunities

Chronic pain rarely occurs in isolation. Instead, it emerges as part of a broader constellation of symptoms that span affective, cognitive, metabolic, and physiological domains. Anxiety and depression, disrupted feeding behavior, altered sleep architecture, fatigue, cognitive impairment, and heightened vulnerability to opioid misuse are among the most prevalent and debilitating comorbidities. These co-occurring conditions significantly worsen quality of life, increase disease burden, and complicate treatment strategies. Yet the molecular and circuit-level mechanisms that link chronic pain to these comorbid states remain incompletely understood.Across the central and peripheral nervous systems, chronic pain drives widespread neuroadaptations in stress circuits, reward pathways, limbic processing centers, and homeostatic regulators. Aberrant activity in nociceptive afferents interacts with neuromodulatory systems controlling emotion, sleep, feeding, and motivation. In parallel, chronic inflammation, glial activation, synaptic remodeling, and maladaptive gene expression contribute to persistent dysregulation. Advances in electrophysiology, imaging, single-cell omics, and molecular genetics are now enabling more refined mapping of these interactions, revealing shared biological signatures between chronic pain and its comorbidities.This Research Topic aims to consolidate emerging research on how chronic pain engages, disrupts, or co-opts molecular pathways across multiple physiological systems, and how these interactions drive the onset and persistence of comorbid conditions. By integrating findings from preclinical models, human-derived systems, and clinical studies, the collection seeks to identify mechanistic nodes that may be leveraged for therapeutic intervention.We invite contributions that investigate the behavioral, physiological, neurobiological, and molecular mechanisms underlying comorbidities associated with chronic pain, including but not limited to:• Mechanisms linking nociceptive signaling with limbic circuits, stress pathways, monoaminergic systems, neuroimmune activation, and maladaptive plasticity underlying mood and anxiety disorders.• Pain-related changes in reward circuits, hypothalamic signaling, metabolic hormones, dopaminergic modulation, and nutrient-driven neuroplasticity influencing feeding behavior.• Interactions between chronic pain, sleep–wake regulation, orexinergic and brainstem arousal pathways, sleep architecture, and reciprocal influences on pain sensitivity and chronification.• Neuroadaptations in reward pathways, receptor-level changes, opioid-induced hyperalgesia, and molecular substrates that increase risk of misuse or impede cessation.• Neuroinflammatory, synaptic, and neuromodulatory processes contributing to widespread functional decline across cognitive and motivational domains.• Genomic, transcriptomic, proteomic, and metabolomic profiling of pain–comorbidity interactions; identification of convergent pathways and therapeutic targets.• Molecular interventions, neuromodulatory strategies, or pharmacological approaches targeting shared mechanisms between chronic pain and its comorbid conditions.Submissions should advance our understanding of mechanisms and modulators of pain and comorbidity through molecular, cellular, circuit-level, or translational lenses. Topic editors: Spring Valdivia, Thomas M. Kinfe, Fernando Kasanetz Source: https://www.frontiersin.org/research-topics/76340/chronic-pain-and-comorbidities-molecular-mechanisms-circuit-dysregulation-and-translational-opportunities