The Physiology of Pain: Nociception and the Pain Pathways from a Chiropractic Perspective

This article details the complex physiological processes of pain, including nociception and the ascending and descending neural pathways. It examines how chiropractic care can modulate these systems to alleviate pain and improve function.

ThatCarHitMe.com Editorial
Oct 26, 2026
5 min read

Pain physiology is the study of the neural mechanisms by which noxious stimuli are detected, transmitted, and processed by the nervous system. A sophisticated understanding of this process is fundamental to the modern, evidence-based practice of chiropractic, as many manual therapies are hypothesized to produce their analgesic effects by modulating these specific neurophysiological pathways. Research has demonstrated that spinal manipulation activates large-diameter mechanoreceptive afferents in paraspinal tissues, including muscle spindle and Golgi tendon organ afferents 1. This afferent barrage is believed to influence pain perception at the spinal cord and supraspinal levels. While a 2017 systematic review by Coronado et al. noted methodological heterogeneity in studies, it concluded that spinal manipulative therapy may modulate central sensitization, a key component of chronic pain states 2. Therefore, a detailed knowledge of nociception and pain processing provides a scientific rationale for the clinical application of chiropractic care in managing musculoskeletal pain conditions.

This article outlines the physiological journey of a pain signal, from peripheral tissue to the brain and back. It begins with peripheral nociception, the process by which specialized sensory neurons, or nociceptors, detect potentially damaging stimuli. These include fast-conducting, myelinated A-delta (Aδ) fibers, which signal initial, sharp pain 3, and unmyelinated C-fibers. The article details peripheral sensitization, where inflammatory mediators such as bradykinin bind to nociceptor receptors, activating protein kinase A (PKA) and protein kinase C (PKC) cascades 4. These kinases phosphorylate ion channels like TRPV1, lowering their activation threshold and amplifying pain signals 5. The genetic basis of pain is illustrated by the Nav1.7 voltage-gated sodium channel, encoded by the SCN9A gene; loss-of-function mutations in this gene lead to congenital insensitivity to pain, demonstrating the channel's required role in initiating action potentials in nociceptors 6, 7.

From the periphery, the article examines central processing within the spinal cord dorsal horn. It explains central sensitization, a state of neuronal hyperexcitability that contributes to chronic pain. This includes the phenomenon of 'wind-up', a frequency-dependent increase in dorsal horn neuron excitability first described by Clifford Woolf 8. The underlying mechanism involves glutamate release from C-fibers, which, upon sustained input, removes the magnesium block on NMDA receptors, allowing calcium influx and initiating long-lasting changes in neuronal function 9. The article then traces the ascending pain pathways, contrasting the lateral spinothalamic tract, which conveys sensory-discriminative information on pain location and intensity to the thalamus 10, with the spinoreticular tract, which projects to the brainstem and limbic system to mediate the affective-motivational aspects of pain 11.

Finally, the discussion moves to supraspinal processing and modulation. It describes the network of brain regions involved in the pain experience, often termed the 'pain matrix', which includes the somatosensory cortices, insula, and anterior cingulate cortex (ACC) 12. The ACC and insula are particularly associated with processing the emotional unpleasantness of pain 13. The article concludes by detailing the descending pain modulatory system, a powerful endogenous analgesic network. This system originates in the periaqueductal gray (PAG) of the midbrain and projects to the rostral ventromedial medulla (RVM) 14. Neurons from the RVM descend to the dorsal horn, where they release neurotransmitters like serotonin (5-HT) and norepinephrine (NE) to inhibit nociceptive transmission, in part by activating local inhibitory interneurons 15, 16. This descending control is a key target for therapeutic interventions aimed at pain relief.

Definition and overview of pain and nociception

The experience of pain is a complex and subjective phenomenon, formally defined by the International Association for the Study of Pain (IASP) as "an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage." It is critical to distinguish this personal experience from nociception, which is the objective neurophysiological process of encoding and processing noxious stimuli. Nociception represents the afferent activity produced in the peripheral and central nervous systems by stimuli that have the potential to damage tissue. While nociception can and often does lead to the sensation of pain, it can also occur without a conscious perception of pain. This foundational process is initiated by a specialized class of primary afferent neurons known as nociceptors, which are equipped to detect thermal, mechanical, and chemical threats to tissue integrity.

Nociceptors are categorized based on the properties of their axons. The primary afferent neurons responsible for the initial sensation of pain are the thinly myelinated A-delta (Aδ) fibers 3. These fibers conduct nerve impulses at relatively fast velocities, typically between 5 and 30 meters per second, a property conferred by their myelin sheath. This rapid transmission is responsible for the sensation of "first pain," which is characteristically sharp, well-localized, and immediate, serving as a rapid warning signal of injury 3. In contrast, the unmyelinated and slower-conducting C-fibers are responsible for "second pain," a more delayed, diffuse, and enduring sensation often described as burning, throbbing, or aching.

The process of converting a noxious stimulus into an electrical signal, known as transduction, occurs at the peripheral terminals of nociceptors. In the context of tissue injury and inflammation, this process is significantly modulated. Damaged cells release a host of inflammatory mediators, including bradykinin, which binds to G-protein coupled receptors located on the nociceptor's membrane 4. This binding event triggers intracellular second messenger cascades that involve protein kinase A (PKA) and protein kinase C (PKC) 4. These kinases then phosphorylate serine and threonine residues on the intracellular domains of key ion channels, such as the Transient Receptor Potential Vanilloid 1 (TRPV1) channel 5. This phosphorylation lowers the channel's activation threshold, making the nociceptor more responsive to subsequent thermal or chemical stimuli, a phenomenon known as peripheral sensitization.

Once the generator potential created by ion influx through channels like TRPV1 is sufficient, a full action potential must be generated for the signal to propagate along the axon to the central nervous system. This critical step depends on voltage-gated sodium channels. The Nav1.7 sodium channel, encoded by the SCN9A gene, is highly expressed in nociceptive primary sensory neurons where it acts as a threshold channel 7. It amplifies the small depolarizations from generator potentials, driving the membrane to the threshold required for firing an action potential 7. The essential function of this specific channel is starkly illustrated by the rare genetic disorder known as congenital insensitivity to pain (CIP). Individuals with loss-of-function mutations in the SCN9A gene cannot generate action potentials in their nociceptors and are consequently unable to feel any physical pain, despite having otherwise normal sensory and cognitive function 6, 17.

Historical perspectives on pain in chiropractic

The chiropractic profession's initial conceptualization of pain was rooted in the vitalistic and mechanistic principles articulated by its founder, Daniel David Palmer, in the late 19th and early 20th centuries. In his foundational 1910 text, The Chiropractor, Palmer posited that a misaligned vertebra, termed a "subluxation," could physically impinge on a spinal nerve. Within this framework, pain was not viewed as a complex sensory and emotional experience, but rather as a direct symptom of nerve interference. This mechanical obstruction was believed to interrupt the flow of a metaphysical life force, or "Innate Intelligence," from the brain to the body's tissues, thereby causing a state of "dis-ease" which included pain as a primary manifestation 18,. The therapeutic solution was correspondingly direct: a specific spinal adjustment was intended to correct the misalignment, remove the nerve pressure, restore the flow of Innate Intelligence, and consequently alleviate the pain.

This "bone-on-nerve" doctrine, while anatomically and physiologically simplistic, provided a powerful and distinct identity for the nascent profession. For much of the 20th century, this model served as the central explanatory framework for chiropractic's approach to health and disease. Its tenets were propagated through the Palmer family's leadership 18 and became deeply embedded in the profession's culture and education, as documented in various regional histories from Texas 19 to Wisconsin. The focus remained largely on the structural fault, with pain being a direct, almost digital, signal of neural compromise that could be "switched off" by correcting the subluxation. This structural-deterministic view of pain persisted for decades, often placing the profession at odds with the evolving understanding of pain in mainstream medicine and neuroscience 20.

A significant paradigm shift began in the latter half of the 20th century, as chiropractic educators and researchers started to integrate developments from contemporary neuroscience. The Gate Control Theory of pain, proposed by Melzack and Wall in 1965, was particularly influential in providing a new, more scientifically plausible mechanism for the analgesic effects of spinal manipulation 21. This theory offered an alternative to the nerve impingement model, suggesting that the therapeutic effect of an adjustment was not due to removing a physical blockage. Instead, the intense, rapid sensory input from the manipulation was thought to activate large-diameter, non-nociceptive A-beta fibers. This afferent barrage could then inhibit the transmission of signals from small-diameter nociceptive fibers at the level of the spinal cord's dorsal horn, effectively "closing the gate" to pain. This conceptual evolution began to appear in educational materials, with chiropractic technique textbooks from the period starting to incorporate these rudimentary neurophysiological principles alongside traditional structural explanations. The focus began to subtly shift from correcting a static misalignment to providing a dynamic neuro-modulatory input. This transition marked the beginning of the profession's move from a peripheral, structural explanation of pain toward a more central, neuro-functional understanding.

The neurobiology of pain pathways

The complex experience of pain begins with peripheral nociception, the detection of noxious stimuli by specialized primary sensory neurons. These nociceptors are equipped with transducer proteins, such as the transient receptor potential vanilloid 1 (TRPV1) channel, a polymodal detector that opens in response to noxious heat (above 42°C), acidic conditions, or capsaicin, allowing an influx of calcium that initiates a neural signal 22. Following tissue injury, this system becomes sensitized. Inflammatory mediators like bradykinin are released and bind to G-protein coupled receptors on the nociceptor membrane 4. This binding activates second messenger systems involving protein kinase A (PKA) and protein kinase C (PKC) 423. PKA and PKC phosphorylate the intracellular domains of the TRPV1 channel, which lowers its activation threshold and heightens its sensitivity, a process known as peripheral sensitization 524. The subsequent generation of an action potential relies heavily on voltage-gated sodium channels, particularly Nav1.7. This channel, encoded by the SCN9A gene, is highly expressed in nociceptive neurons where it amplifies receptor potentials 7. The definitive role of Nav1.7 is demonstrated by the rare condition of congenital insensitivity to pain (CIP), which results from loss-of-function mutations in the SCN9A gene, rendering individuals unable to feel pain 617.

Once an action potential is generated, the signal travels along primary afferent fibers to the spinal cord's dorsal horn. Fast, sharp, and well-localized pain is transmitted by myelinated A-delta (Aδ) fibers 3, while sustained, burning pain is carried by unmyelinated C-fibers. Repetitive C-fiber stimulation can lead to central sensitization, a state of neuronal hyperexcitability within the central nervous system. A key manifestation of this is "wind-up," a frequency-dependent increase in the excitability of dorsal horn neurons, first detailed by Clifford Woolf 8. This process begins with glutamate release from C-fibers activating AMPA receptors on second-order neurons 9. With persistent input, the magnesium block on NMDA receptors is removed, permitting a significant influx of calcium that triggers intracellular cascades and produces long-lasting hyperexcitability 925. From the dorsal horn, signals ascend to the brain via distinct pathways. The lateral spinothalamic tract transmits sensory-discriminative information (location, intensity) with high somatotopic precision to the ventral posterolateral (VPL) nucleus of the thalamus 1026. In contrast, the spinoreticular tract projects to the brainstem reticular formation and limbic system, mediating the affective-motivational and arousal components of pain 11. These ascending signals activate a distributed network of brain regions often called the "pain matrix," which includes the somatosensory cortices, thalamus, prefrontal cortex, anterior cingulate cortex (ACC), and insula 12. The ACC and insula are particularly associated with processing the emotional unpleasantness and suffering related to the pain experience 13.

The central nervous system is not a passive recipient of pain signals; it actively modulates them through descending pathways. This top-down regulation originates primarily in the midbrain periaqueductal gray (PAG), which projects to the rostral ventromedial medulla (RVM) in the brainstem 1427. The RVM acts as a critical relay, sending projections via the dorsolateral funiculus of the spinal cord to terminate in the dorsal horn 15. Here, these descending neurons modulate the activity of nociceptive transmission neurons, in part by synapsing on and activating local enkephalinergic interneurons that inhibit incoming signals from primary afferents 1528. The descending fibers from the RVM exert their influence by releasing monoamine neurotransmitters, including serotonin (5-HT) and norepinephrine (NE) 16. These neurotransmitters have complex effects, but they frequently produce pre- and post-synaptic inhibition of nociceptive signaling in the dorsal horn, effectively dampening the pain signal before it ascends to the brain 1629.

Mechanistic theories of manual therapy

The clinical effects of manual therapy are underpinned by several neurophysiological theories that explain how mechanical inputs can modulate the perception of pain. Two foundational models are the Gate Control Theory and the phenomenon of Diffuse Noxious Inhibitory Controls (DNIC). These theories propose that manual interventions modify nociceptive processing at the level of the spinal cord dorsal horn and through the engagement of descending pain inhibitory systems.

The Gate Control Theory, first proposed by psychologist Ronald Melzack and anatomist Patrick Wall in 1965, posits a neurological "gate" within the substantia gelatinosa of the spinal dorsal horn 21. According to this model, nociceptive signals transmitted by small-diameter, slow-conducting A-delta (Aδ) and C-fibers compete with signals from large-diameter, fast-conducting A-beta (Aβ) fibers which convey non-painful sensations like touch and pressure. Both fiber types converge on projection neurons, or transmission (T) cells, that relay signals to the brain, as well as on local inhibitory interneurons 21. The theory stipulates that activity in the large Aβ fibers preferentially stimulates these inhibitory interneurons, which in turn release neurotransmitters that hyperpolarize the T-cells. This presynaptic and postsynaptic inhibition effectively "closes the gate," reducing the transmission of nociceptive signals from the small fibers to the brain. From a chiropractic perspective, this theory provides a direct rationale for the analgesic effects of spinal manipulation. Research by Joel G. Pickar has shown that the mechanical forces of a spinal adjustment activate large-diameter mechanoreceptive afferents, including Type Ia muscle spindle afferents and Type Ib Golgi tendon organ afferents, in the paraspinal muscles 1. This barrage of large-fiber input is hypothesized to close the spinal gate, thereby reducing the perception of pain originating from the stimulated segment.

A second major theory involves the activation of endogenous analgesic systems through a mechanism known as Diffuse Noxious Inhibitory Controls (DNIC), a 'pain-inhibits-pain' phenomenon described by Daniel Le Bars and his colleagues 30. DNIC is a systemic response where a noxious stimulus applied to one part of the body inhibits nociceptive responses throughout the rest of the body. Unlike the segmentally organized Gate Control Theory, DNIC is mediated by a supraspinal loop that involves brainstem structures, including the subnucleus reticularis dorsalis 30. The therapeutic force of a spinal manipulation, particularly a high-velocity, low-amplitude thrust, may be intense enough to serve as the conditioning noxious stimulus that triggers this widespread inhibitory effect. This supraspinal loop is part of the larger descending pain modulation network originating in the midbrain periaqueductal gray (PAG) and relaying through the rostral ventromedial medulla (RVM) 1427. A 2011 functional MRI study by Gay et al. provided evidence for this link, demonstrating that cervical spine manipulation produced increased metabolic activity in the PAG 31. This suggests that manual therapy can directly engage the brainstem centers responsible for initiating top-down pain inhibition. Furthermore, manual therapy may also influence the state of central sensitization, a condition of nervous system hyperexcitability implicated in chronic pain 8. A 2017 systematic review by Coronado et al., while noting methodological limitations across studies, concluded that spinal manipulative therapy may modulate central sensitization processes 2.

Research on the physiological effects of spinal manipulation

The clinical effects of spinal manipulative therapy (SMT), a core intervention in chiropractic care, are underpinned by a growing body of research into its specific neurophysiological mechanisms. The application of a high-velocity, low-amplitude thrust, as detailed in chiropractic technique manuals, initiates a cascade of events from peripheral receptors to central processing centers. A primary mechanism involves the robust activation of large-diameter, myelinated afferent nerve fibers. Research by neurophysiologist Joel G. Pickar demonstrated that the forces applied during SMT are sufficient to excite mechanoreceptors in the deep paraspinal tissues, including Type Ia muscle spindle afferents and Type Ib Golgi tendon organ afferents 1. This barrage of non-nociceptive input is hypothesized to inhibit the transmission of pain signals at the level of the dorsal horn, a concept central to the Gate Control Theory proposed by Melzack and Wall in 1965 21. According to this model, the activation of these large fibers stimulates inhibitory interneurons in the substantia gelatinosa, effectively "closing the gate" on incoming signals from small-diameter nociceptive A-delta and C-fibers 21.

Beyond the spinal cord, SMT appears to influence supraspinal centers involved in pain processing and modulation. One significant area of investigation is SMT's effect on central sensitization, a state of nervous system hyperexcitability characterized by phenomena like 'wind-up' and implicated in the transition to chronic pain 89. While a 2017 systematic review by Coronado et al. highlighted methodological inconsistencies that prevented a definitive conclusion on effect size, it did find evidence suggesting that SMT may modulate central sensitization processes, potentially by reducing the temporal summation of pain 2. This central modulation may be driven by SMT's influence on descending pain-inhibitory pathways. These pathways originate in brainstem regions such as the midbrain periaqueductal gray (PAG) and project to the rostral ventromedial medulla (RVM), which in turn sends inhibitory signals down to the dorsal horn 141527. A key functional MRI study in 2011 by Gay et al. provided evidence for this link, showing that cervical spine manipulation produced an immediate increase in glucose metabolism in the PAG, indicating heightened activity 31. The same study also observed decreased activity in areas like the dorsolateral prefrontal cortex, suggesting a complex pattern of brain activity modulation following the intervention 31.

In addition to neural pathways, SMT may also exert influence over the biochemical environment related to pain and inflammation. Studies led by Teodorczyk-Injeyan investigated the systemic effects of SMT on inflammatory biomarkers. In a cohort of asymptomatic subjects, a single session of SMT was found to attenuate the in-vitro production of the pro-inflammatory cytokines TNF-α and IL-1β by monocytes challenged with lipopolysaccharide 32. This finding points toward a potential anti-inflammatory or immunomodulatory effect of the therapy. The research also noted, however, that the same intervention did not produce a significant change in circulating levels of the neuropeptide substance P within the two-hour observation window post-treatment 32. Collectively, these findings suggest that SMT induces a multi-system response, combining peripheral afferent stimulation, modulation of central sensitization, activation of descending pain control centers, and attenuation of key inflammatory mediators.

Clinical applications in chiropractic care

An understanding of contemporary pain physiology directly informs chiropractic clinical practice, from patient assessment to the rationale for manual therapies. During the initial patient evaluation, a chiropractor can differentiate the probable neurophysiological drivers of pain based on the patient's report. For instance, a description of sharp, well-localized pain points toward the activation of myelinated A-delta (Aδ) fibers 3, whereas a report of dull, burning, or poorly localized aching is characteristic of C-fiber nociception. Physical examination may reveal signs of peripheral sensitization, such as allodynia or hyperalgesia, which are underpinned by mechanisms like the phosphorylation of TRPV1 channels by protein kinase C (PKC) and protein kinase A (PKA) in response to inflammatory mediators 4, 5, 24. This process lowers the activation threshold of nociceptors, making them more responsive to stimuli. The clinical importance of specific ion channels is underscored by conditions like congenital insensitivity to pain, which results from loss-of-function mutations in the SCN9A gene encoding the Nav1.7 sodium channel, a channel essential for initiating action potentials in nociceptive neurons 6, 7, 17.

In cases of chronic or widespread pain, chiropractors assess for clinical indicators of central sensitization. This state of nervous system hyperexcitability involves phenomena such as 'wind-up', the frequency-dependent amplification of pain signals in the dorsal horn, as first described by Clifford Woolf 8. The underlying mechanism involves glutamate-mediated activation of NMDA receptors following repetitive C-fiber input, leading to a lasting increase in neuronal excitability 9, 25. The presence of central sensitization helps explain why a patient's pain experience may seem disproportionate to the degree of peripheral tissue injury.

The primary therapeutic intervention in chiropractic, spinal manipulative therapy (SMT), is theorized to modulate pain through multiple neurophysiological pathways. At the spinal cord level, the application of a high-velocity, low-amplitude thrust, a core component of chiropractic technique, is thought to engage the Gate Control Theory proposed by Ronald Melzack and Patrick Wall in 1965 21. Research by Joel G. Pickar has shown that spinal manipulation activates large-diameter, myelinated afferents such as Type Ia muscle spindle and Type Ib Golgi tendon organ afferents in paraspinal tissues 1. According to the theory, this robust, non-nociceptive input activates inhibitory interneurons in the dorsal horn, which in turn reduces the transmission of signals from A-delta and C-fibers to second-order transmission cells 21. This mechanism may also contribute to the modulation of central sensitization, although a 2017 systematic review by Coronado et al. noted that while SMT appears to influence processes like temporal summation, methodological heterogeneity in studies has prevented a definitive conclusion on the effect size 2.

Beyond the spinal cord, SMT appears to engage descending, or top-down, pain modulatory systems. A 2011 fMRI study by Gay et al. demonstrated that cervical spine manipulation led to increased metabolic activity in the periaqueductal gray (PAG) 31, a key midbrain structure that initiates descending pain control 14, 27. The PAG projects to the rostral ventromedial medulla (RVM) in the brainstem, which sends descending fibers down the dorsolateral funiculus 15. These pathways release inhibitory neurotransmitters like serotonin and norepinephrine in the dorsal horn, suppressing the activity of nociceptive neurons both pre- and post-synaptically 16, 28, 29. This provides a supraspinal mechanism for the analgesic effects of SMT. This neurophysiological framework allows chiropractors to explain pain not as a simple indicator of tissue damage but as a complex output of the nervous system, influenced by ascending signals, descending modulation, and central processing within the 'pain matrix' of the brain 12.

Significance, limitations, and future directions

The neurophysiological model of pain provides an evidence-based framework for understanding the mechanisms of spinal manipulative therapy (SMT). This model moves beyond a purely biomechanical view, positing that SMT's therapeutic effects are mediated, in part, through the modulation of the nervous system. Research by Joel G. Pickar demonstrated that spinal manipulation generates a barrage of afferent signals from the paraspinal tissues by activating large-diameter mechanoreceptors, such as muscle spindle and Golgi tendon organ afferents 1. This afferent input is hypothesized to modulate pain at the spinal cord level, consistent with the Gate Control Theory proposed by Melzack and Wall 21, where non-nociceptive input inhibits the transmission of pain signals in the dorsal horn. Furthermore, evidence suggests SMT engages supraspinal descending pain inhibitory systems. A 2011 fMRI study by Gay et al. found that cervical manipulation increased metabolic activity in the periaqueductal gray (PAG) 31, the primary control center for descending pain modulation 14. SMT may also influence the inflammatory milieu; studies by Teodorczyk-Injeyan et al. showed that SMT could downregulate the production of pro-inflammatory cytokines like TNF-α and IL-1β in asymptomatic subjects 32.

Despite this promising model, the supporting research is characterized by significant limitations and heterogeneity. A 2017 systematic review by Coronado et al., examining the effect of SMT on central sensitization, found the included studies were too methodologically diverse and limited to allow for a meta-analysis or to calculate a specific effect size for SMT on temporal summation 2. While the review noted that SMT may modulate central sensitization, it underscored the need for more rigorous and standardized research protocols 2. This challenge is reflected in specific experimental findings. For instance, while Teodorczyk-Injeyan and colleagues observed changes in inflammatory cytokines post-SMT, they did not find a significant change in circulating substance P levels within the two-hour observation period, highlighting the complexity of the biological response and the need for further investigation into timing and mechanisms 32.

Future research may benefit from incorporating more contemporary models of brain function, such as the predictive coding framework developed by neuroscientist Karl Friston 33. This model proposes that the brain is not a passive recipient of sensory information but actively generates predictions about the causes of its sensory inputs. Chronic pain, from this perspective, can be conceptualized as a persistent and maladaptive "prediction error," where there is a mismatch between the brain’s expectation of pain and the actual sensory signals from the body 33. Within this framework, SMT can be viewed as a form of powerful, structured somatosensory input that challenges and potentially updates the brain's faulty predictive model of the body. By providing a novel, salient, and non-threatening sensory experience, manipulation may help to recalibrate the aberrant processing that maintains the chronic pain state. This conceptual shift provides a new rationale for investigating SMT's effects on brain network dynamics, sensory processing, and the subjective experience of pain.

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