Abstract Chronic pain affects a substantial fraction of the population, yet pharmacological management remains deeply inadequate. This failure likely reflects the focus on developing analgesics suppressing normal nociceptive signalling rather than correcting the pathological substrates distinguishing chronic from acute pain. Here we review how the identification of injury-induced downregulation of the potassium-chloride cotransporter KCC2 in spinal dorsal horn neurons represents a landmark. It first provided a mechanistic, long-term substrate for spinal inhibitory failure. This form of disinhibition had the potential to explain several cardinal symptoms of neuropathic pain; not just hyperalgesia, through spinal hyperexcitability, and tactile allodynia, through cross-talk between sensory modalities, but also spontaneous pain, through enabling spontaneous bursts of activity in spinal nociceptive output to emerge. A second landmark is that chloride dysregulation as a substrate of disinhibition yields non-linear, non-intuitive predictions of neural circuit behaviours that shed light on several features of chronic pain and its therapeutic challenges. One is paradoxical pro-excitatory actions of tapping into normally endogenous inhibitory neurotransmission, potentially explaining failures of benzodiazepines analgesia and of conditional pain modulation. Others include degradation of sensory processing, possibly explaining diffuse pain, and leaky plasticity, predisposing to catastrophic sensitization. In turn, mechanisms regulating KCC2 itself emerge as substrates of chronification, as well as substrates of opioid-induced maladaptive paradoxical hyperalgesia. Finally, divergent yet convergent signaling cascades underlying KCC2-downregulation reveal a form of pathway degeneracy across sexes with lessons for therapeutics. All-in-all, these findings position KCC2 as a key novel target, not just for analgesia, but also for disease modification.
Abstract Spontaneous pain is a highly prevalent and disabling consequence of neuropathic disorders, yet it remains mechanistically underdefined and therapeutically underserved. Historically, preclinical animal models and clinical trials have been overwhelmingly biased toward stimulus-evoked hypersensitivity, relegating spontaneous pain to a secondary manifestation. Emerging evidence now challenges this view. Converging data from pharmacology, neural recordings, and systems-level causal manipulations indicate that spontaneous and stimulus-evoked pain arise from substantially dissociable molecular, cellular, and circuit substrates. Injured-fiber–derived ectopic activity within specific sensory neuron subtypes serves as a dominant peripheral generator of spontaneous pain, whereas cellularly distinct, intact spared-fiber pathways mediate stimulus-evoked hypersensitivity. At spinal and supraspinal levels, spontaneous pain preferentially engages affective–salience networks during pain chronification and may ultimately become stabilized within higher-order circuitry—while remaining dynamically coupled to afferent input. This mechanistic delineation carries critical translational implications. Current diagnostic and treatment guidelines rarely differentiate symptom domains, and most therapies have been validated primarily using stimulus-evoked or overall pain intensity endpoints—potentially contributing to a mechanism–therapy mismatch and variable efficacy. We argue that spontaneous neuropathic pain should be defined as a separate symptom domain rather than considered as a spontaneous manifestation of evoked pain mechanisms. This recognition demands longitudinal, biomarker-informed phenotyping to capture its persistent and fluctuating nature, and thereby enable robust mechanistic dissection at peripheral, spinal, and cortical nodes. Reframing spontaneous neuropathic pain along these lines will provide a foundation for precision therapeutics that target defined cell types, specific molecular drivers, and maladaptive network states—enabling mechanism-based, symptom-aligned treatments.
Abstract Entrapment neuropathies are the most prevalent focal neuropathic pain conditions globally and impose a substantial individual and socioeconomic burden. Traditionally conceptualised as purely mechanical compression syndromes, this view is increasingly challenged by converging evidence from human tissue analyses, advanced neuroimaging, and deep clinical phenotyping. Entrapment neuropathies are now recognised as biologically dynamic disorders shaped to different extents by microvascular compromise, demyelination, axonal degeneration, immune dysregulation, neuroinflammation, central nervous system adaptations, and psychosocial influences. Varying combinations and dominance of biopsychosocial processes give rise to marked clinical heterogeneity even within the same diagnostic label. This mechanistic diversity helps explain common diagnostic discordances, including extraterritorial symptom spread, normal electrodiagnostic findings despite clinical symptoms indicative of entrapment neuropathies, and imaging–clinical presentation mismatch. It also challenges one-size-fits-all treatment approaches, which have largely failed in entrapment neuropathies. Uniquely, entrapment neuropathies provide a natural human model of focal nerve injury in the context of neuropathic pain. Surgical decompression allows integration of tissue-level biology with precise clinical phenotypes and offers time-locked insights into recovery. Lessons derived from this model extend beyond entrapment neuropathies and can inform broader understanding of neuropathic and nerve-related musculoskeletal pain conditions. Here, we synthesise contemporary mechanistic insights, examine how biological heterogeneity translates into distinct clinical phenotypes, and discuss potential implications for mechanism-informed management.
Abstract Equitable, high-value pain care remains out of reach for many populations worldwide, particularly for people living in low- and middle-income countries and cultural minority groups in high-income settings. Despite carrying a disproportionate burden of chronic pain, these populations remain underrepresented in high-quality pain research, underserved by existing health systems, and constrained by social, political, environmental, and commercial determinants of health. The lack of locally generated evidence forces clinicians and policymakers to rely on externally produced research that may not translate to local cultural, linguistic, or health-system contexts. This invited viewpoint synthesizes key contributors to pain inequity—including limited prioritization of chronic pain in low- and middle-income countries, underdeveloped rehabilitation capacity, poor access to essential treatments, commercial exploitation, and misalignment between culturally shaped pain beliefs and Western-derived assessment and treatment models. I highlight opportunities to strengthen equity in clinical care through improved education of health professionals and the public, culturally and linguistically responsive assessment, and contextually adapted self-management and treatment strategies. Equitable research requires standardized collection of sociodemographic variables, deliberate inclusion of underrepresented groups, and global partnerships that avoid colonizing practices. I propose principles for fair and impactful North–South collaborations focused on co-creation of research agendas, shared leadership, sustainable capacity building, and transparent governance. Advancing equitable global pain care and research will require collective action from clinicians, researchers, institutions, policymakers, journals, funders, and communities. A coordinated shift toward culturally grounded, contextually adaptable, and ethically collaborative approaches is essential to meaningfully reduce global pain disparities and ensure all individuals benefit from scientific progress.
Abstract Pain modulation is a fundamental survival mechanism that prioritises, shapes, and suppresses nociceptive inputs to optimise behaviour. Although acute pain signals potential or actual tissue damage, sustained pain can impair essential behaviours, necessitating modulatory circuits that dynamically regulate nociception according to context and motivational state. These systems are deeply conserved, embedded within primitive spinal and brainstem structures, and capable of powerful modulation independent of cortical input, although higher regions such as the prefrontal cortex can influence their function. Decades of work have sought to identify these core modulatory circuits to advance basic understanding and develop strategies for clinically meaningful hypoalgesia. More recently, dysfunction within these circuits has been implicated in chronic pain, driving efforts to characterise how their organisation and function change during persistent pain states. Although most mechanistic insights come from animal studies, human neuroimaging, particularly since the advent of functional magnetic resonance imaging, has begun to map their location and engagement during pain modulation. Early work focused on forebrain regions due to the limited spatial resolution of standard MRI, but ultra-high-field functional magnetic resonance imaging now enables mm 3 -scale investigation of brainstem nuclei. This review synthesises evidence from animal and human studies to outline the best-characterised modulatory pathway, consisting of projections from the midbrain periaqueductal gray to the rostral ventromedial medulla and onward to the dorsal horn/spinal trigeminal nucleus, and highlights recent work detailing its organization.
