Physiology of Pain

Physiology of pain—a narrative review on the pain pathway and its application in the pain management Shuang Liu1,2, Leigh Kelliher1 1Anaesthetic Department, Royal Surrey County Hospital, Guildford, UK; 2Anaesthetic Department, Royal Marsden Hospital, London, UK Contributions: (I) Conception and design: Both authors; (II) Administrative support: L Kelliher; (III) Provision of study materials: Both authors; (IV) Collection and assembly of data: S Liu; (V) Data analysis and interpretation: S Liu; (VI) Manuscript writing: Both authors; (VII) Final approval of manuscript: Both authors. Background and Objective: Pain is perhaps the commonest symptom for which patients seek medical care and represents a major socioeconomical burden on healthcare systems globally. Pain-related conditions were shown to be the leading causes of disability in 10–49 years old in a recent study on the global burden of disease [2019]. Despite a great deal of research into pain and analgesic strategies, the effective management of pain remains challenging. An appreciation system can be responsible for the activation of the pain pathway. Neuropathic pain is typically perceived as a burning or shooting pain and is often chronic and difficult to treat. Dorsal horn neurons and central sensitisation The grey matter of the spinal cord was divided into ten separate laminae by Rexed in 1952. Laminae I to VI are located within the dorsal horn and the majority of nociceptors synapse in laminae I, II and V where they form primary synapses with either interneurons or dorsal horn neurons. The majority of C fibres terminate in lamina II which is also known as substantia gelatinosa (SG). Dorsal horn neurons, so-termed because their nuclei are located in the dorsal horn of the spinal cord, are second-order sensory neurons that transmit nociception from the spinal cord to higher centres in brain. Clinically, chronic pain commonly occurs in the head, shoulders, lower back, and knees; it can be categorized into three primary types: nociceptive, neuropathic, and nociplastic [6]. Nociceptive pain arises from tissue damage or inflammation, neuropathic pain stems from nerve injury or dysfunction such as diabetic neuropathy, and nociplastic pain results from central nervous system sensitization without clear tissue or nerve damage such as chronic low back pain. However, due to its heterogeneous clinical presentations, chronic pain often resists accurate diagnosis and optimal management. Our review aims to bridge this gap by synthesizing current knowledge on the molecular pathways of chronic pain with the known mechanisms of exercise rehabilitation. By directly comparing the pathological molecular cascades of chronic pain with the corrective adaptations induced by exercise, we provide a robust biological rationale for its use and lay the groundwork for developing targeted, mechanism-based rehabilitation strategies. This integrated perspective is essential for moving beyond general exercise recommendations toward the development of more rational, targeted, and personalized exercise prescriptions for individuals with chronic pain. 2. Search Strategy Relevant studies were identified by searching academic databases, including PubMed, Web of Science, and Google Scholar, performed in July 2025. The search strategy was designed to be broad and inclusive, capturing literature on three core concepts: (1) chronic pain, (2) exercise-based intervention, and (3) the biological mechanisms. The search terms applied to all fields (title, abstract, and text word), combined using Boolean operators (AND, OR), are as follows: ‘chronic pain’ OR ‘nociceptive pain’ OR ‘neuropathic pain’ OR ‘nociplastic pain’ OR ‘central sensitization’ OR ‘peripheral sensitization’ OR ‘analgesia’ OR ‘ hypoalgesia’ AND ‘mechanism’ OR ‘molecular’ OR ‘cellular’ OR ‘pathway’ OR ‘neurobiology’ AND ‘training’ OR ‘exercise’ OR ‘physical activity’ OR ‘physical therapy’ OR ‘rehabilitation’ OR ‘exerciseinduced analgesia’ OR ‘exercise-induced hypoalgesia’. An additional search was carried out whereby we examined the references of the included articles. To be included, a study needed to meet the following criteria: (a) subjects: both human clinical studies and preclinical animal models were included to provide a broad, translational perspective on the topic; (b) pain condition: no restrictions were placed on the specific type of chronic pain; (c) intervention: all forms of exercise were considered; (d) publication type: original research articles and review articles were included; (e) language: the search was limited to original research written in English. Case reports, letters to the editor, conference abstracts, and non-peer-reviewed articles were not eligible for inclusion. 3. Classification and Mechanisms of Chronic Pain Chronic pain arises from complex and interrelated mechanisms that evolve following tissue injury, infection, or prolonged inflammation. Several classification systems for this condition have been proposed, often based on its etiology, anatomical location, or predominant underlying mechanisms. A common approach categorizes chronic pain into three major types based on its likely origin: nociceptive, neuropathic, or nociplastic pain. Alongside these three major types, the mixed pain phenotype is increasingly recognized by clinicians and researchers (Figure 1). While different pain classifications may have distinct initiating factors, the processes leading to pain stimulation or injection of morphine into the PAG produces profound analgesia and conversely, the suppression of the PAG is a major component in chronic pain states such as complex regional pain syndrome and is associated with further disease such as depression and anxiety (20,21). As a result, the role of receptors within the PAG in pain modulation has been the subject of a great deal of research, and the PAG is targeted in deep brain stimulation (DBS) therapy for the treatment of intractable pain (22). Figure 2 The PAG-RVM-spinal axis in the descending modulatory systems. STT, spinothalamic tract; PAG, periaqueductal grey; RVM, rostral ventromedial medulla. The activation of the PAG-RVM axis by collaterals from the ascending STTs forms part of negative feedback loop. The PAG is subject to complex modulation via the integration of multiple cortical higher functions such as prediction, anticipation, affect and emotions. It also incorporates the neuroendocrine axes and autonomic function in gauge the pain intensity from its hypothalamus and thalamus inputs. This model can guide us in the assessment of pain in individuals who cannot communicate, there have been trials of using additional parameters such as heart rate variability, fluctuation of skin conductance and pupil reflex to objectively assess pain (23). Figure 2. Molecular mechanisms of chronic pain. Peripheral ion channel regulation, pro-inflammatory mediator release, central neural plasticity changes, and glial cell activation all contribute to the establishment of chronic pain state. IL-6, interleukin-6; IL-1?, interleukin-1?; TNF-?, tumor necrosis factor-?; NGF, nerve growth factor; BDNF, brain-derived neurotrophic factor; NMDA, N-methyl-D-aspartate; SP, substance P; CGRP, calcitonin gene-related peptide. 3.1. Classification of Chronic Pain Nociceptive pain originates from direct non-neural tissue damage and inflammation. Clinically, it is categorized based on its origin, as somatic pain, arising from tissues such as skin, muscles, and bones, or visceral pain, which originates from internal organs [15]. In nociceptive pain, the release of inflammatory mediators leads to the activation and sensitization of peripheral nociceptors, resulting in the robust and direct transmission of pain signals to the central nervous system (CNS) [16]. The subsequent peripheral sensitization is characterized by the upregulation of ion channel activity and an altered profile of receptor expression, which together contribute to a persistent state of hyperexcitability. In contrast, neuropathic pain is primarily a consequence of nerve injury or disease. Following nerve damage, there is a dysregulation of ion channels—particularly sodium channels such as Nav1.7 and Nav1.8—become dysregulated, which leads to ectopic discharges and spontaneous neuronal firing [17]. This aberrant electrical activity is compounded by maladaptive plastic changes in the CNS, including the reorganization of synaptic connections and the activation of glial cells. These changes not only perpetuate the pain state but also render neuropathic pain notoriously resistant to conventional analgesics. Nociplastic pain, a concept that has gained recognition in recent years, is defined by the presence of altered central pain processing in the absence of obvious peripheral tissue or nerve damage [18]. The introduction of this term represents a critical advancement in this field, as it provides a distinct mechanistic descriptor for chronic pain syndromes, such as fibromyalgia, that were previously considered idiopathic [19]. Functional neuroimaging and electrophysiological studies have revealed that in brain regions integral to pain perception, such as the anterior cingulate cortex (ACC), insula, and prefrontal cortex, abnormal connectivity and dysregulated neurotransmitter activity occur in nociplastic pain states [20]. This results in the amplification of pain signals due to an imbalance between excitatory (glutamatergic) and inhibitory (GABAergic) neurotransmission, compounded by dysfunction of descending pain modulation pathways. In addition, genetic predisposition and psychological factors such as stress, anxiety, and depression can influence the development and maintenance of nociplastic pain [21]. In clinical practice, many patients do not present with a single, isolated type of pain but rather exhibit a complex interplay of these mechanisms. The concept of “mixed pain”, representing interactions and overlaps between different pain mechanisms, including nociceptive, neuropathic, and nociplastic components, is increasingly recognized, though its precise definition and diagnostic criteria are still evolving [22]. An initial nociceptive insult, typically resulting from tissue injury or inflammation, may serve as a trigger for peripheral sensitization. When such stimuli persist, they can eventually lead to nerve damage, thereby introducing neuropathic components. Simultaneously, the ongoing barrage of nociceptive input drives central sensitization, creating an environment in which the normally distinct pathways of pain processing begin to overlap. Over time, the convergence of peripheral and central mechanisms gives rise to a mixed pain phenotype, characterized by simultaneous alterations in peripheral ion channel function, maladaptive central plasticity, and impaired descending inhibitory controls. The recognition that chronic pain is not a uniform entity but rather a heterogeneous condition with overlapping molecular mechanisms has profound implications for both research and clinical practice, presenting a significant challenge that necessitates a fundamental shift from unimodal, mechanism-specific interventions towards more holistic, personalized treatment strategies capable of addressing the multifaceted nature of pain experience [23]. 3.2. Peripheral Mechanisms of Chronic Pain Peripheral tissue damage, persistent inflammation, and nerve injury triggers a cascade of biochemical events resulting from damage to tissues and surrounding cells, including cytokines such as interleukin-6 (IL-6), interleukin-1? (IL-1?) and tumor necrosis factor-? (TNF-?); chemokines; prostaglandins; bradykinin; neuropeptides; and neurotrophic factors such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) [24,25]. These mediators interact with receptors on the surface of peripheral nociceptors and are responsible for initiating intracellular signaling cascades [26], involving protein kinases such as protein kinase A, protein kinase C, and mitogen-activated protein kinases (MAPK) [27,28], which may result in the modulation of ion channels that are critical for pain transmission. Among these, transient receptor potential (TRP) channels (such as TRPV1 and TRPA1), voltage-gated sodium channels (notably Nav1.7 and Nav1.8), and various types of voltage-gated calcium channels on primary afferent neurons and their somata in the dorsal root ganglia (DRG) have been identified as key players in the process of chronic pain [29,30,31]. Recent evidence revealed that NGF plays a prominent role in this process, binding to its high-affinity receptor TrkA on nociceptors [32]. NGF-TrkA signaling activates downstream pathways (including MAPK) that are crucial for modulating the expression and function of ion channels and receptors, significantly contributing to sensitization [33]. These signaling cascades lead to a lower activation threshold, increased responsiveness, and spontaneous firing of nociceptors, a phenomenon known as peripheral sensitization [7]. Recent studies have demonstrated that selective modulation of TRPV1 and specific MAPK isoforms can significantly reduce nociceptor hyperexcitability, thereby highlighting promising therapeutic avenues [34,35]. However, peripheral sensitization is not merely a passive response to inflammation but is actively amplified by the nervous system through a process known as neurogenic inflammation [36]. A key peripheral driver of this is the axonal reflex (AR), a purely local mechanism. When peripheral C-fibers are activated by noxious stimulation, the resulting action potential travels not only orthodromically toward the spinal cord but also antidromically along collateral branches to trigger an AR, which leads to the release of neuropeptides, primarily substance P and calcitonin gene-related peptide (CGRP), directly at the site of injury [37]. Substance P increases vascular permeability, leading to plasma extravasation and edema (swelling), while CGRP, a potent vasodilator, causes an increase in local blood flow (redness/flare). Together, they initiate a localized inflammatory response, contributing to the “inflammatory soup” and further sensitizing nearby nerve endings. The peripheral environment also contains various non-neuronal cells that actively participate in peripheral sensitization and neuroinflammation. Beyond satellite glial cells in the DRG and macrophages which are noted in [38], mast cells, fibroblasts and Schwann cells release a spectrum of mediators, including cytokines, chemokines and growth factors (like NGF) after