Pain is a multidimensional phenomenon integrating biological, psychological, and social processes. It arises from complex neural interactions that transform nociceptive input into conscious experience, modulated by cognition, emotion, and context. Chronic pain reflects maladaptive neuroplasticity, autonomic imbalance, and predictive misinterpretation of threat. Modern pain science recognizes pain as an emergent inference rather than a direct injury signal. Effective management therefore requires mechanism-based, multidisciplinary strategies combining pharmacological, physical, psychological, and neuromodulatory interventions. Integrative, patient-centered rehabilitation grounded in neurobiological and psychosocial understanding offers the most promising path toward sustainable recovery and restored quality of life.
Pain Physiology: Neurophysiological Mechanisms, Pain Types, Autonomic Modulation, and Psychological Influences
by Tobias Giesen(a) | M.Sc. SEM, B.Sc. PT
(a) LB University, Institute for Sports Medicine and Physical Therapy (UK)
Abstract
Pain is a multidimensional phenomenon integrating biological, psychological, and social processes. It arises from complex neural interactions that transform nociceptive input into conscious experience, modulated by cognition, emotion, and context. Chronic pain reflects maladaptive neuroplasticity, autonomic imbalance, and predictive misinterpretation of threat. Modern pain science recognizes pain as an emergent inference rather than a direct injury signal. Effective management therefore requires mechanism-based, multidisciplinary strategies combining pharmacological, physical, psychological, and neuromodulatory interventions. Integrative, patient-centered rehabilitation grounded in neurobiological and PSYCHOSOCIAL UNDERSTANDING OFFERS THE MOST PROMISING PATH TOWARD SUSTAINABLE RECOVERY AND restored quality of life.
1. Introduction
Pain is not merely a sensory signal but a multidimensional, dynamic experience encompassing sensory- discriminative, affective-motivational, cognitive-evaluative, and sociocultural dimensions. It is simultaneously a biological warning system and a subjective psychological construct that serves to protect the organism from actual or potential harm. From an evolutionary perspective, pain is essential for survival—it alerts the organism to tissue injury, triggers avoidance behaviors, and facilitates healing through behavioral adaptation (Melzack, 1999; Butler & Moseley, 2016). However, when pain becomes chronic, disproportionate, or detached from its protective role, it transforms into a maladaptive state that impairs function, erodes mental health, and diminishes quality of life. Modern pain science views pain as an emergent phenomenon—arising from complex interactions between peripheral nociceptive processes, spinal integration, supraspinal modulation, and cognitive-affective interpretation within distributed brain networks (Garland, 2012; De Ridder et al., 2021). These processes are influenced by genetic predisposition, prior experience, emotional context, and social meaning. Accordingly, pain is not a linear consequence of nociceptor activation but a product of neural computations that infer threat and bodily integrity.
1.1 The Evolution of Pain Concepts
Historically, pain was understood within a biomedical framework, emphasizing tissue injury and linear sensory transmission. This mechanistic view, rooted in Cartesian dualism, conceptualized pain as a direct product of physical damage. By the mid-20th century, this view was challenged by Melzack and Wall’s Gate-Control Theory, which introduced the concept of dynamic modulation at the spinal level. According to this theory, sensory input from large-diameter afferents (Ap fibers) could inhibit pain transmission by “closing” neural gates in the dorsal horn. This paradigm shift marked the beginning of modern pain neuroscience, emphasizing modulation rather than mere transmission. Subsequent decades saw the emergence of the Neuromatrix Theory of Pain (Mel- zack, 1999), which proposed that pain arises from a distributed network of brain regions integrating sensory, cognitive, and emotional information. This theory recognized the brain as an active generator of the pain experience, rather than a passive recipient of peripheral signals. In parallel, the biopsychosocial model (Gatchel et al., 2007) reframed pain as the outcome of dynamic interactions among biological, psychological, and social variables—a model now foundational to contemporary clinical pain management.
1.2 Biological Foundations of Pain Perception
At the biological level, pain is initiated by nociceptors, specialized primary sensory neurons that detect noxious stimuli. These neurons, equipped with molecular transducers such as TRPV1, TRPA1, and ASIC ion channels, convert mechanical, thermal, and chemical insults into electrical impulses. These impulses are processed and amplified through a hierarchical network of spinal and supraspinal structures—including the dorsal horn, thalamus, somatosensory cortices, anterior cingulate cortex (ACC), insula, and prefrontal cortex (Willis, 1997; Woolf & Salter, 2000). At the molecular and cellular level, nociceptive signaling involves multiple receptor systems and inflammatory mediators—prostaglandins, bradykinin, cytokines, and chemokines—that sensitize nociceptor terminals, lowering their activation thresholds. Persistent activation leads to long-term potentiation of synaptic transmission in the spinal dorsal horn, a process termed central sensitization, which underlies chronic pain and hyperalgesia. At the systems level, pain engages both ascending excitatory pathways (e.g., spinothalamic and spinoreticular tracts) and descending inhibitory circuits originating in the periaqueductal gray (PAG) and rostral ventromedial medulla (RVM). The descending pathways utilize neurotransmitters such as serotonin, norepinephrine, and endogenous opioids to modulate dorsal horn excitability. Dysregulation of these pathways contributes to persistent pain syndromes, including fibromyalgia, neuropathic pain, and central sensitization disorders (Woolf, 2022).
1.3 Cognitive and Emotional Dimensions
Pain is deeply intertwined with cognition and emotion. Functional neuroimaging studies have identified overlapping activation in the ACC, insula, and prefrontal cortex—regions implicated in both pain processing and affective evaluation (De Ridder et al., 2021). These areas form a flexible and context-dependent network reflecting salience, prediction, and learning rather than pain itself (Kucyi & Davis, 2015). Pain perception is also modulated by expectation and attention. Anticipation of pain can amplify neural responses in sensory cortices, whereas distraction or positive expectation can attenuate them through prefrontal and anterior cingulate inhibition of subcortical structures. Such top-down modulation illustrates the predictive coding framework, in which pain represents the brain’s best inference about potential threat based on sensory input and prior experience (Friston, 2018; Tabor et al., 2017). Beyond biological substrates, social and environmental factors exert a profound influence on pain. Cultural norms shape how individuals express and interpret pain; social support and empathy can modulate endogenous opioid release and reduce perceived pain intensity. Conversely, social isolation, trauma, and chronic stress potentiate pain through sustained activation of the hypothalamic-pituitary-adrenal (HPA) axis and alterations in immune signaling. These insights underscore pain’s embeddedness within a biopsychosocial ecology, wherein context, meaning, and interpersonal dynamics are integral to the experience itself. Clinically, pain is both a symptom and a disease entity. While acute pain serves a protective biological purpose, chronic pain persists beyond tissue healing and involves neural plasticity that transforms pain into an independent pathology (Gilron, 2015). Chronic pain syndromes—ranging from osteoarthritis and neuropathic pain to complex regional pain syndrome (CRPS)—are among the leading causes of disability worldwide and impose substantial socioeconomic costs. Understanding pain as an integrated biopsychosocial process has revolutionized therapeutic approaches and underscores that effective treatment must address not only nociceptive input but also cognitive, emotional, and contextual dimensions influencing persistence and recovery.
2. Neurophysiological Mechanisms of Pain
Pain emerges from a multilevel neural process that transforms peripheral sensory events into conscious perceptual experiences. At its core, pain involves the detection of noxious stimuli, the transmission of encoded signals to the central nervous system, and the integration of this information with cognitive, emotional, and contextual cues. Nociceptors, the peripheral sensory neurons responsible for detecting potential tissue damage, represent the first stage in pain processing. These specialized neurons are primarily unmyelinated C-fibers and thinly myelinated AS-fibers whose free nerve endings are distributed throughout the skin, viscera, muscles, and connective tissue (McEntire, 2016). They transduce physical and chemical stimuli into electrical activity through specialized molecular receptors and ion channels embedded in their membranes. TRPV1 and TRPA1 act as polymodal sensors, while ASICs detect acidosis in ischemic or inflamed tissue, and P2X3 receptors respond to extracellular ATP released from damaged cells (Waxman et al., 2014). Voltage-gated sodium channels (Nav1.7, Nav1.8, Nav1.9) are essential for action potential generation and propagation; mutations in Nav1.7 cause congenital insensitivity to pain or paroxysmal extreme pain disorder, highlighting their central role. Activation of these channels allows sodium and calcium influx, depolarizing the nociceptor membrane. Once threshold is reached, action potentials conduct toward the spinal cord dorsal horn, where first-order neurons synapse with second- order projection neurons.
2.1 Peripheral Sensitization
Peripheral sensitization occurs when inflammatory mediators such as prostaglandins, bradykinin, cytokines, and serotonin reduce the activation threshold of nociceptors. These mediators act through G-protein-coupled receptors, increasing intracellular cyclic AMP and activating protein kinase cascades that phosphorylate ion channels and enhance excitability (Woolf & Salter, 2000). This biochemical plasticity explains primary hyperalgesia at the injury site and contributes to the transition from acute to chronic pain when inflammation persists. After entering the dorsal horn, nociceptive afferents primarily terminate in laminae I and II (the substantia gelatinosa). Here, neurotransmitters such as glutamate, substance P, and CGRP are released and act on postsynaptic receptors to propagate and modulate nociceptive signals (Willis, 1997). Glutamate acts on AMPA and NMDA receptors; persistent NMDA activation allows calcium influx, triggering intracellular cascades (e.g., CaMKII, CREB) that strengthen synaptic connections—the neural basis for central sensitization. Substance P binds NK1 receptors, sustaining slow excitatory potentials, and CGRP enhances glutamatergic transmission and contributes to neurogenic inflammation.
2.2 Glial Activation and Neuroinflammation
The dorsal horn is not purely neuronal; microglia and astrocytes actively participate in nociceptive signaling. Persistent peripheral input triggers glial activation, leading to the release of cytokines (e.g., TNF -a, IL-ip, IL-6) and BDNF. These molecules modulate neuronal excitability, disinhibit pain circuits, and maintain chronic sensitization (Gosselin et al., 2024). This neuroimmune interface links immune activation with neuronal plasticity and is pivotal in maintaining chronic pain. Second-order neurons project through multiple ascending tracts: the spinothalamic tract transmits pain and temperature to the thalamus and then to S1 and S2; the spinoreticular tract mediates arousal and attention; and the spinomesencephalic tract terminates in the PAG, linking ascending nociceptive input with descending modulation. Contemporary neuroimaging challenges the notion of a single pain center; instead, pain engages a distributed “pain connectome” encompassing thalamus, insula, ACC, prefrontal cortex, amygdala, and PAG (De Ridder et al., 2021; Kucyi et al., 2023). Each node contributes uniquely: the thalamus integrates sensory input; the insula processes interoceptive awareness and intensity; the ACC encodes emotional salience and motivation; the PFC governs attention and expectation-based modulation; and limbic structures link pain with fear, stress, and memory. Chronic pain is associated with functional reorganization within these regions, including increased connectivity between limbic and default mode networks (Kuner & Flor, 2024), contributing to persistence even after peripheral injury resolves.
2.3 Central Sensitization and Pain Plasticity
Chronic pain often results from maladaptive neuroplastic changes within the CNS, collectively termed central sensitization. This phenomenon involves increased excitability of dorsal horn neurons (via NMDA receptor activation and reduced GABAergic inhibition), enhanced synaptic efficacy through long-term potentiation-like mechanisms, receptive field expansion, spontaneous neuronal firing, and recruitment of normally nonnociceptive Ap afferents into pain pathways. At the molecular level, altered gene expression and glial-derived neuromodulators sustain persistent hyperalgesia and allodynia (Woolf & Salter, 2000). Descending control systems exert both inhibitory and facilitatory influences over spinal nociceptive processing. The PAG and RVM form the core of this network, sending projections that release serotonin, norepinephrine, and endogenous opioids to modulate spinal excitability (Woolf, 2022). Under normal circumstances, the system balances inhibition and facilitation; chronic stress, depression, or sleep deprivation can shift the balance toward facilitation, amplifying pain. Conversely, placebo analgesia, expectation, and mindfulness-based interventions enhance descending inhibition via prefrontal-PAG connectivity and endogenous opioid release (Eippert et al., 2022). The dynamic interplay between bottom-up input and top-down modulation illustrates that pain is not a passive consequence of injury but an actively constructed percept shaped by prediction, emotion, and context.
3. Types of Pain: Mechanistic, Neurobiological, and Clinical Perspectives
Pain is not uniform but reflects multiple pathophysiological mechanisms. Classification by etiology and neurobiology is crucial for diagnosis and management. Nociceptive pain arises from activation of intact nociceptor pathways due to tissue damage and serves a protective role tightly linked to inflammation or mechanical injury (Armstrong, 2023). Tissue injury triggers inflammatory mediators that sensitize nociceptors by lowering thresholds and increasing firing frequency. Somatic nociceptive pain originates from skin, muscles, bones, or joints and is typically well localized; visceral pain arises from internal organs, is diffuse and poorly localized, and may be referred due to convergence of afferents on common dorsal horn neurons. In nociceptive pain, cortical activation concentrates in S1/S2, insula, and ACC, and resolves as peripheral input subsides. Clinically, nociceptive pain responds to NSAIDs, acetaminophen, and short-term opioids in select cases; targeting inflammatory mediators remains foundational, though psychosocial stressors can amplify nociception via descending facilitation (Azevedo, 2025).
3.1 Neuropathic Pain
Neuropathic pain results from lesions or diseases affecting the somatosensory nervous system (Leone, 2024). It reflects maladaptive reorganization wherein injury-induced hyperexcitability persists beyond tissue repair. Peripheral nerve damage leads to ectopic discharges, sodium channel upregulation (Nav1.3, Nav1.7, Nav1.8), and potassium channel downregulation, producing spontaneous firing. Non-injured adjacent fibers may sprout, expanding receptive fields and spreading pain. Centrally, sustained input induces dorsal horn reorganization, loss of inhibitory interneurons, and increased NMDA receptor expression; microglial activation sustains hyperexcitability (Gosselin et al., 2024). Clinically, neuropathic pain is burning, shooting, electric, or tingling, with allo- dynia, hyperalgesia, paresthesia, and temporal summation. Causes include diabetic neuropathy, postherpetic neuralgia, trigeminal neuralgia, spinal cord injury, and multiple sclerosis. Glial cytokines (IL-ip, TNF-a) and BDNF alter chloride homeostasis via KCC2 downregulation, converting GABAergic inhibition into excitation (Coull et al., 2003). Neuroimaging reveals increased connectivity among somatosensory cortex, insula, and PFC and decreased gray matter in prefrontal and insular cortices (Kuner & Flor, 2024). Management requires gabapentinoids, SNRIs, TCAs, topical lidocaine or capsaicin, and in refractory cases neuromodulation or microglial-targeted strategies.
3.2 Nociplastic Pain
Nociplastic pain, introduced by the IASP, describes pain arising from altered nociception without clear tissue damage or neural lesion (Kaplan et al., 2024). It captures disorders previously labeled as central sensitivity syndromes, including fibromyalgia, chronic fatigue syndrome, temporomandibular disorder, and irritable bowel syndrome. Mechanisms include central sensitization with NMDA-dependent plasticity, impaired descending inhibition (reduced serotonergic/noradrenergic tone), altered functional connectivity (hyperconnectivity between insula, ACC, and default mode network), and autonomic dysregulation with reduced HRV and HPA-axis hyperactivity (Azevedo, 2025). Small fiber neuropathy and local immune activation may contribute in some patients. Clinically, widespread pain, fatigue, sleep disturbance, cognitive dysfunction, and affective comorbidity are common, often disproportionate to objective findings. Management emphasizes multimodal, interdisciplinary strategies: CBT and mindfulness, graded exercise, pain neuroscience education, SNRIs or gabapentinoids, low- dose naltrexone, and non-invasive brain stimulation to restore inhibitory tone and adaptive neural patterns.
3.3 Mixed Pain and Transitional States
Clinical reality often involves mixed mechanisms, such as chronic low back pain with radiculopathy or postoperative pain evolving into central sensitization. Transitional processes illustrate a continuum model where overlapping mechanisms interact over time (Woolf, 2022). Recognizing mixed mechanisms is critical because each component responds differently to therapies. Assessment tools like painDETECT, DN4, and the Central Sensitization Inventory help identify predominant pathways and tailor treatment. From a systems neuroscience standpoint, pain typology reflects progressive plasticity and maladaptation across hierarchical levels: nociceptive pain as appropriate biological alarm, neuropathic pain as hyperexcitability from structural lesion, and nociplastic pain as emergent dysfunction of network regulation and prediction. This evolution mirrors a shift from bottom-up to top-down dominance in processing, where cognitive, emotional, and homeostatic dysregulation perpetuate chro- nicity even in the absence of peripheral injury (Friston, 2018; Kaplan et al., 2024). Future classification will likely be biomarker-informed, incorporating molecular signatures, neuroimaging markers, and psychophysiological indices.
3.4 Temporal and Autonomic Patterns of Pain
Pain evolves dynamically across time and physiological systems and should be understood as a temporal and systemic process involving continuous interaction between neural, immune, endocrine, and psychological domains. The transition from acute to chronic pain reflects a shift from adaptive warning to maladaptive hypersensitivity maintained by central and autonomic dysregulation (Poisbeau, 2025; Gilron, 2015). Acute pain arises in response to noxious stimuli and serves to protect by signaling damage, initiating avoidance, and activating repair. It involves activation of nociceptors by local mediators, short-lived sensitization, and sympathetic recruitment for fight-or-flight responses. In the subacute phase (four weeks to three months), partial resolution of inflammation coexists with persistent nociceptive signaling. Persistent afferent activity can induce central sensitization; psychological factors like fear and catastrophizing interact with physiology to promote pain memory formation (De Ridder et al., 2021). Interventions targeting biological repair and cognitive-emotional reframing are critical to prevent chronification. Chronic pain, extending beyond three months, is increasingly recognized as a disease, involving structural and functional reorganization, central sensitization, maladaptive cortical plasticity, persistent neuroimmune activation, and neuroendocrine imbalance. It coexists with sleep disturbance, fatigue, anxiety, depression, and cognitive dysfunction and contributes to disability and reduced quality of life (Gatchel et al., 2007).
Chronification is driven by peripheral factors (ongoing inflammation, nerve injury, ischemia, metabolic dysfunction, silent nociceptor activation), central factors (LTP-like changes, NMDA receptor activity, loss of inhibitory control, network hyperconnectivity), and psychological/behavioral factors (fear, avoidance, maladaptive cognitions, chronic stress with cortisol dysregulation). The autonomic nervous system is pivotal in modulating physiological and perceptual aspects of pain. Acute sympathetic activation is adaptive but persistent arousal increases muscle tone and ischemia, sensitizes nociceptors via p-adrenergic signaling, and reduces parasympathetic recovery, creating allostatic load (Azevedo, 2025). Parasympathetic regulation via the vagus exerts anti-inflammatory and restorative effects; enhanced vagal tone through diaphragmatic breathing, mindfulness, yoga, and vagus nerve stimulation increases HRV and reduces limbic activation. Chronic pain exhibits autonomic imbalance with low HRV, impaired baroreceptor sensitivity, and altered cortisol rhythms; low HRV reflects diminished prefrontal inhibition of limbic-autonomic centers and contributes to dysregulation (Thayer & Lane, 2009). Neuroendocrine-immune crosstalk involving the HPA axis and sympathoadrenal system further shapes pain; acute stress temporarily suppresses inflammation, while chronic stress dysregulates cortisol and impairs neuroplasticity and hippocampal function (De Ridder et al., 2021). Glial activation bridges immune and neural processes, releasing cytokines and BDNF that potentiate central sensitization. Emotional states modulate pain; anxiety, depression, and anger amplify it via limbic activation and impaired descending inhibition, while positive affect and social support engage endogenous opioids and cannabinoids to enhance resilience. Chronic activation of the limbic- autonomic-HPA triad yields hypervigilance, poor sleep, and immune suppression; psychophysiological interventions such as HRV biofeedback and stress-inoculation training are therefore integral to multidisciplinary programs (Azevedo, 2025).
4. Clinical Implications and Mechanism-Based Management
The complexity of pain demands a multidimensional therapeutic framework grounded in mechanisms and context. Clinicians must recognize pain as a dynamic systems disorder emerging from interactions between peripheral nociception, central processing, autonomic regulation, and psychosocial modulation. A mechanism-based approach aligns treatment with pathophysiology: nociceptive pain targets inflammation and tissue injury; neuropathic pain targets hyperexcitability and ectopic discharges; nociplastic pain targets central sensitization and impaired inhibition; and mixed pain requires multimodal strategies. Pharmacological therapy for nociceptive pain focuses on reducing sensitization and inflammation with NSAIDs, acetaminophen, and corticosteroids, reserving opioids for short-term acute or cancer pain. Multimodal analgesia achieves synergy with fewer side effects (Gilron, 2015). Neuropathic pain requires gabapentinoids, SNRIs, TCAs, and topical agents; emerging therapies include sodium channel subtype blockers and microglial modulators (Leone, 2024). Nociplastic pain may benefit from SNRIs, gabapentinoids, low-dose naltrexone, ketamine in refractory cases, and cannabinoids, but pharmacotherapy should be embedded within biopsychosocial rehabilitation (Kuner & Flor, 2024).
Movement-based therapies are central. Graded exercise and graded exposure counter fear-avoidance and deconditioning, induce endogenous analgesia, increase anti-inflammatory cytokines, and restore cortical inhibition; dosing must respect sensitivity thresholds, especially in nociplastic conditions. Manual and somatic therapies reduce mechanical nociception, enhance proprioception, and stimulate descending inhibition; importantly, therapeutic alliance and touch context activate oxytocinergic and parasympathetic pathways that modulate perception (Azevedo, 2025). Neurodynamic techniques improve neural mobility and reduce mechanical allodynia, while sensorimotor retraining re-maps cortical representations in conditions like CRPS and phantom limb pain (Moseley & Butler, 2017). Psychological therapies are indispensable. CBT reduces catastrophizing and kinesiophobia and improves function; ACT increases psychological flexibility and values-based engagement; mindfulnessbased interventions reduce limbic hyperactivity and enhance prefrontal control, with imaging evidence of amygdala downregulation (Azevedo, 2025).
Neuromodulatory and emerging interventions target circuitry directly. TENS applies Gate-Control principles to inhibit spinal nociception. Spinal cord stimulation and dorsal root ganglion stimulation provide durable relief in refractory neuropathic pain by modulating ascending and descending pathways. Non-invasive brain stimulation (rTMS, tDCS) can restore cortical inhibition and alter maladaptive connectivity (De Ridder et al., 2021). Vagus nerve stimulation leverages parasympathetic modulation to reduce inflammation and autonomic imbalance; early trials demonstrate benefits in fibromyalgia and post-COVID syndromes (Azevedo, 2025). Education and therapeutic alliance are foundational. Pain neuroscience education reframes pain as a protective output rather than a direct index of tissue damage; combined with active rehabilitation, it reduces fear, catastrophizing, and disability (Moseley & Butler, 2017). The therapeutic alliance, characterized by empathy and shared decision-making, activates cortical networks associated with analgesia and enhances neuroplastic recovery (Tracey, 2023).
Multidisciplinary rehabilitation remains the gold standard for complex chronic pain. Programs integrate comprehensive assessment across biological, psychological, and social domains; goal-oriented rehabilitation prioritizing function; education, pacing, and self-management; and ongoing outcome evaluation using validated measures. Systematic reviews show significant improvements in function, return to work, and quality of life compared to unimodal therapy (Brode et al., 2024; Frisk et al., 2023). Future directions emphasize precision and integration: biomarker development (neuroimaging, inflammatory, genetic), digital health and wearable sensors for individualized phenotyping, neuro-immune modulation targeting microglial and cytokine cascades, and psychophysiological rehabilitation using biofeedback and virtual reality to retrain perception. Such innovations will refine diagnosis and enable mechanistic rehabilitation that dynamically adapts to neurobiological states.
5. Discussion
Pain represents one of the most intricate phenomena of biology and consciousness—a multidimensional, plastic, and contextually modulated process that transcends physiology. Far from being a mere symptom, pain is an emergent neuropsychological state arising from continuous interaction between nociceptive input, neural network processing, and psychosocial interpretation. Its perception is shaped by molecular signaling, cortical integration, emotional valence, cognitive expectation, and social context. Evolutionarily, pain is protective, but dysregulation transforms it into a maladaptive disease state underpinned by plastic changes, autonomic imbalance, and psychological amplification. Modern theories—from Gate-Control and Neuromatrix to Predictive Coding and the Biopsychosocial paradigm—reframe pain as an actively constructed protective inference. Clinically, effective management must modulate peripheral inputs and reshape central predictions, emotional learning, and behavioral context. Mechanism-based management emphasizes multimodal, interdisciplinary approaches tailored to neurobiological and psychosocial profiles. Pharmacological treatments address nociceptive and neuropathic mechanisms; exercise and physical therapies restore sensorimotor function and neurochemical balance; cognitive and mindfulness interventions recalibrate maladaptive predictions and affect; and neuromodula- tory techniques target cortical and spinal circuits. Education enables patients to reconceptualize pain as an alterable output of the nervous system. The future lies in precision rehabilitation integrating biomarkers, psychophysiology, and digital monitoring to guide individualized treatment. Advances in neuroimaging, computational modeling, and bioelectronic medicine promise to bridge molecular pathology and subjective experience, enabling therapies that are mechanistically grounded and personally meaningful. Ultimately, understanding pain requires empathic interpretation alongside biological knowledge, uniting the scientific with the humanistic to restore agency, embodiment, and quality of life. In this integrated view, pain becomes not merely a signal to silence, but a message to understand, reinterpret, and transform.
In further considering the multidimensional architecture of pain, it is instructive to synthesize how learning, memory, and prediction intersect with autonomic and immune regulation to stabilize or destabilize the pain phenotype across time. Pain memories are not simple recordings of nociceptive input; they are reconstructed narratives encoded across hippocampal-prefrontal-amygdalar networks that assign meaning and guide future predictions. When a person repeatedly encounters contexts in which pain was threatening, the brain comes to infer danger at lower thresholds, biasing perception toward protective responses even in the absence of ongoing tissue damage. This inferential bias is reinforced by bodily states—reduced heart rate variability, poor sleep, chronic stress—that provide interoceptive evidence consistent with threat. In this sense, bodily dysregulation becomes both a consequence and a cause of persistent pain, closing a feedback loop that must be interrupted on multiple levels if recovery is to occur.
Mechanistically, the recalibration of such loops depends on generating reliable prediction errors in safe contexts so that prior beliefs about threat can be updated. Graded exposure, paced activity, and sensorimotor retraining do precisely this: they confront the nervous system with outcomes that contradict catastrophic predictions (“movement will worsen damage,” “load will be intolerable”) and therefore drive learning toward safety. The therapeutic alliance operates as a contextual amplifier of this learning signal; trust, empathy, and clear explanations increase the precision assigned to new information and reduce defensive arousal, allowing adaptive plasticity to proceed. Education, in turn, reduces ambiguity and unpredictability—two of the most powerful drivers of defensive bias—by giving patients a coherent model of why pain persists and what levers can change it.
From a systems-design perspective, effective pain rehabilitation resembles control of a complex dynamical system with multiple feedback loops and time delays. Interventions that act only on single nodes—purely pharmacological or purely psychological—often fail because they ignore cross-couplings that reconstitute the original state. By contrast, coordinated interventions (exercise plus education plus stress regulation plus targeted pharmacology) shift the system across a critical threshold, after which self-stabilizing processes (improved sleep, increased activity, reduced fear, enhanced parasympathetic tone) reinforce one another. This explains why modest improvements in several domains can yield disproportionate functional gains: the system has moved into a basin of attraction aligned with recovery, not with chronicity.
The ethical dimension of pain care is not incidental. Because pain is inseparable from meaning, clinicians become participants in the patient’s predictive ecology. Language that emphasizes tissue damage may inadvertently strengthen maladaptive priors, whereas language that emphasizes adaptability, plasticity, and safety can foster resilience without denying suffering. Precision rehabilitation therefore includes precision communication— calibrating explanations to the individual’s beliefs, culture, and goals. This humanistic precision is as critical as algorithmic precision driven by biomarkers, because in the end it is the person’s brain that must author new predictions about the body.
Finally, future research should pursue integrative biomarkers that respect the layered nature of pain. Composite indices that combine neural connectivity metrics, inflammatory profiles, autonomic signatures (HRV), and psychometric measures may better track mechanism than any single variable. Such indices could guide adaptive treatment sequencing: start with autonomic regulation when HRV is low and sleep is poor; prioritize graded exposure when fear and avoidance dominate; deploy neuromodulation when cortical inhibition markers are diminished; and use anti-inflammatory or glial-modulating strategies when cytokine profiles are elevated. In clini cal practice, this would translate to learning health systems that iteratively test, measure, and update treatment plans in partnership with patients—a practical instantiation of predictive coding applied to care itself.
6. Conclusion
Pain is a multidimensional, dynamic, and plastic phenomenon that arises from the complex interplay of peripheral nociceptors, spinal circuits, supraspinal modulation, autonomic regulation, and psychosocial influences. A thorough understanding of nociceptive, neuropathic, and nociplastic pain mechanisms, temporal pain patterns, and neurophysiological modulation is essential for developing effective, individualized treatment strategies. The integration of neurobiological insights with theoretical frameworks such as Gate-Control, Neuromatrix, and biopsychosocial models enables clinicians to adopt comprehensive approaches that optimize patient outcomes and improve quality of life.
About the Author:
Tobias Giesen is a physiotherapist specialized in musculoskeletal physiotherapy. After his Bachelor's degree in Physiotherapy, he studied for a Master of Science in Sport and Exercise Medicine at a British faculty and completed it successfully. His particular interests lie in medical neuroscience, pain medicine, and manual therapy.
References
(1) Armstrong, S. A. (2023). Physiology, Nociception. StatPearls. Retrieved from https://www.ncbi.nlm.nih.gov/books/NBK551562/
(2) Azevedo, N. (2025). Pain and the autonomic nervous system: The role of non-invasive neuromodulation. Frontiers in Pain Research. https://doi.org/10.3389/fpain.2025.1410808
(3) De Ridder, D., Vanneste, S., & Freeman, W. (2021). The anatomy of pain and suffering in the brain and its implications for treatment. Neuroscience & Biobehavioral Reviews, 123, 1-13. https://doi.org/10.1016/j.neubiorev.2021.01.015
(4) Garland, E. L. (2012). Pain processing in the human nervous system. Frontiers in Psychology, 3, 1-11. https://doi.org/10.3389/fpsyg.2012.00111
(5) Giniatullin, R. (2020). Ion channels of nociception. Frontiers in Pharmacology, 11, 580. https://doi.org/10.3389/fphar.2020.00580
(6) Gilron, I. (2015). Chronic pain: mechanisms, diagnosis, and treatment. CMAJ, 187 (10), 751-758. https://doi.org/10.1503/cmaj.150356
(7) Gorczyca, R. (2013). Psychological aspects of pain perception. PubMed. https://pubmed.ncbi.nlm.nih.gov/25000837/
(8) Kaplan, C. M., Kelleher, E., Irani, A., Schrepf, A., & Clauw, D. J. (2024). Deciphering nociplastic pain: clinical features, risk factors, and potential mechanisms. Nature Reviews Neurology. https://doi.org/10.1038/s41582- 024-00966-8
(9) Leone, M. (2024). Neuropathic pain mechanisms and management. Lancet Neurology, 23 (2), 155-168. https://doi.org/10.1016/S1474-4422(23)00390-5
(10) McEntire, D. M. (2016). Pain transduction: a pharmacologic perspective. Frontiers in Pharmacology, 7, 57. https://doi.org/10.3389/fphar.2016.00057
(11) McGrath, P. A. (1994). Psychological aspects of pain perception. PubMed. https://pubmed.ncbi.nlm.nih.gov/7702468/
(12) Melzack, R. (1999). Pain—an overview. Acta Anaesthesiologica Scandinavica, 43 (9), 880-884. https://doi.org/10.1034/j.1399-6576.1999.430903.x
(13) Melzack, R., & Wall, P. D. (1965). Pain mechanisms: a new theory. Science, 150 (3699), 971-979. https://doi.org/10.1126/science.150.3699.971
(14) Poisbeau, P. (2025). Neurophysiology of acute and chronic pain: from genes to circuits. BJA Education. https://doi.org/10.1016/j.bjaed.2025.04.001
(15) Verywell Health. (2014). Acute and subacute pain. Retrieved from https://www.verywellhealth.com/acute-and- subacute-2615141
(16) Willis, W. D. (1997). Neuroanatomy of the pain system and of the pathways that modulate pain. Journal of Clinical Neurophysiology, 14 (1), 2-31. https://doi.org/10.1097/00004691-199701000-00002
(17) Woolf, C. J. (2022). Pain modulation in the spinal cord. Acta Anaesthesiologica Scandinavica, 66 (6), 673684. https://doi.org/10.1111/aas.14110
(18) Gatchel, R. J., Peng, Y. B., Peters, M. L., Fuchs, P. N., & Turk, D. C. (2007). The biopsychosocial approach to chronic pain: scientific advances and future directions. Psychological Bulletin, 133 (4), 581-624. https://doi.org/10.1037/0033-2909.133.4.581
[...]
Buy now
- Quote paper
- Tobias Giesen (Author), 2025, Pain Physiology. Neurophysiological Mechanisms, Pain Types, Autonomic Modulation, and Psychological Influences, Munich, GRIN Verlag, https://www.grin.com/document/1665603
