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Pain warns of actual or impending tissue damage. We use this information to safely navigate our environment and detect early signs of disease or injury.

Physicians cannot objectively measure patient pain and suffering. Where pain is due to inflammatory, musculoskeletal, or peripheral nerve injury causes, conventional imaging (e.g., CT and MRI scans) cannot confirm patient complaints. Negative test results can frustrate physicians and physical therapists and cause them to conclude that the pain complaints are psychological.

When medical staff distrust their patients, this undermines the therapeutic alliance and results in unnecessary diagnostic testing, poor compliance, and poor clinical outcomes. When physicians and nurses know their patients, they will learn whose pain complaints are attempts to obtain opioids or exaggerated by anxiety and depression and whose reports are credible. Graphic © Romariolen/Shutterstock.com.






Listen to a mini-lecture on an Overview of Pain © BioSource Software LLC. Graphic © Barks/Shutterstock.com.

Computer-related disorder (CRD) is a common workplace pain syndrome that may not appear on traditional imaging but can be detected using a one- or two-channel electromyograph.

BCIA Blueprint Coverage

This unit addresses Chronic neuromuscular pain (IV-C) and Specific CNS structures (VI-A).




This unit covers Pain Perception, Pain Models, Pain Dimensions, and How Chronic Pain Affects the Nervous System.

Please click on the podcast icon below to hear a full-length lecture.

Pain Perception

Free nerve endings are the body's primary nociceptors (pain receptors).


Listen to a mini-lecture on Nociceptors © BioSource Software LLC. Graphic © Designua/Shutterstock.com.



There are three main kinds of nociceptors: mechanoreceptors (mechanical stress and tissue damage), chemoreceptors (chemical messengers), and thermoreceptors (temperature extremes). Nociceptors may be unimodal (respond to only one stimulus) or polymodal (respond to multiple stimuli).

Na_v1.7 and 1.8 Sodium Channels

Two sodium channels, Na_v1.7 and Na_v1.8, are particularly important in pain signaling. Na_v1.7 acts as a "fuse," amplifying small depolarizations in sensory neurons, while Na_v1.8 serves as a "firecracker," generating the majority of the electrical current needed for neurons to fire an action potential. Dysfunction in these channels can lead to extreme pain or, conversely, an inability to feel pain. Sodium channel graphic © Juan Gaertner/Shutterstock.com.



The FDA approved suzetrigine, a selective Na_v1.8 inhibitor, in 2025 as Journavx (jor-na-vix) for treating moderate to severe acute pain.

Afferent Axons

Four main types of afferent axons conduct information crucial to pain perception: A-alpha, A-beta, A-delta, and C-fibers. Primary afferent neurons within dorsal root ganglia (DRG) synapse with spinal cord dorsal horn neurons. Pain afferent graphic © Blamb/shutterstock.com.

A-delta fibers transmit the first pain signal and largely determine pain sensations. C-fibers convey the second pain signal and influence emotional and motivational responses to pain. A-beta fibers rapidly conduct light touch and are theorized to close Melzack and Wall's pain gate (Taylor, 2021).

Listen to a mini-lecture on Afferent Pain Fibers © BioSource Software LLC.

Trigger Point Mechanisms

Trigger points are hyperirritable regions of taut bands of skeletal muscle in the muscle belly or associated fascia (connective tissue). Graphic © Naeblys/Shutterstock.com.





Listen to a mini-lecture on Trigger Points © BioSource Software LLC.

Pressure on trigger points is painful. Trigger points can produce referred (remote) pain and tenderness, motor dysfunction, and autonomic changes. Trigger points cannot be detected using SEMG electrodes but can be identified using needle EMG electrodes and palpation (examination by feeling or pressing with the hand). Graphic © Alila Medical MediaShutterstock.com.

Pain Pathways

There is a complex dynamic interaction between ascending pathways that distribute pain information to the brain and descending pathways that modulate (facilitate or inhibit) incoming pain signals.


Listen to a mini-lecture on Pain Pathways © BioSource Software LLC.

In theory, disruption of the balance between the ascending and descending pathways can result in functional and structural changes in the central nervous system that produce chronic pain.

Ascending Pathways

The dorsal-column medial-lemniscus and anterolateral systems are the two major ascending somatosensory pathways. Both systems transmit information from peripheral receptors to the brain over a three-neuron pathway that includes a primary afferent axon, a secondary projection neuron, and a tertiary neuron whose cell body lies in the thalamus. Pain pathway graphic © Blamb/shutterstock.com.

Caption: Pain information conducted by Ad and C-fibers travels to the brain via the anterolateral system. These afferents cross the midline and ascend the spinal cord before distributing information to brainstem sites, the thalamus, and cortical areas, including SI, the cingulate cortex, and the insula.

Interneurons in these ascending pathways receive and modulate messages from nociceptors. A single interneuron may communicate with thousands of other interneurons via excitatory and inhibitory synapses. Chronic pain can modify these complex interneuron networks through repeated stimulation that sensitizes them to innocuous stimuli. This is mainly a problem when localized inflammation does not remit. In wind-up, a patient may continue to experience pain after an injury has healed because interneurons continue to activate each other in the absence of peripheral pain signals (Sherman, 2004).

Dorsal-Column Medial-Lemniscus System

The dorsal-column medial-lemniscus system distributes touch (fine tactile and vibratory) and proprioceptive (joint and limb position) information to the somatosensory cortex. Most sensory neurons that contribute to this system have very small receptive fields that allow precise spatial localization and project to the spinal cord using large-diameter myelinated Aβ fibers. Visceral (large internal) organs provide pain information via C-fibers that enter the spinal cord and synapse on dorsal horn neurons.

Anterolateral System

The anterolateral system (ALS) distributes pain and temperature information to the somatosensory cortex and other brain regions. Dorsal horn axon synapses with various brain neurons allow these areas to facilitate or inhibit pain (Advokat et al., 2022).

The anterolateral system comprises the spinothalamic, spinoreticular, spinomesencephalic, and spinohypothalamic tracts. It receives information about the face from the three branches of the trigeminal nerve.

The spinothalamic tract distributes sensory information regarding pain. The spinoreticular tract conveys motivational and emotional information, including suffering.

Trigeminal Nerve

The trigeminal nerve projects pain and temperature information concerning the face to the same thalamic nuclei targeted by the spinothalamic and spinoreticular tracts.

Descending Pathways

Several descending systems modulate (increase or decrease) the transmission of pain information. The cerebral cortex modulates pain transmission via projections to the thalamus and reticular formation. The locus coeruleus more directly modulates pain transmission by its projections to the spinal cord's dorsal horn, the site of ascending pain signals.

Periaqueductal gray (PAG) axons form excitatory synapses on neurons located in the nucleus raphe magnus (NRM) and the nucleus reticularis paragigantocellularis (NRPG) in the medulla. The NRM and NRPG are part of the reticular formation. Their axons enter the spinal cord and synapse on interneurons in the dorsal horn.

Ranney (2001) identified five bidirectional loops between the reticular formation and the spinal cord (spinoreticular and reticulospinal) on each side of the body. These loops transmit information in both directions and can facilitate or inhibit pain transmission. They connect the spinal cord to the dorsolateral pons, medulla, and hypothalamus. Stimulation of these loops can affect pain transmission from hours to days.

Tricyclic antidepressants increase descending pathways' serotonin and norepinephrine, gating ascending pain signals (Advokat et al., 2022). Most NRM neurons excite spinal cord interneurons by releasing serotonin. These interneurons, in turn, inhibit C-fibers by releasing enkephalin, which binds to their terminal buttons and reduces their release of transmitter. This inhibition involves a process called presynaptic inhibition.

NRPG neurons excite spinal cord interneurons by releasing norepinephrine. These interneurons inhibit neurons that project through a non-opioid polysynaptic pathway to the thalamus.

PAG neurons are influenced by diverse projections, including the ascending spinomesencephalic tract of the ALS and descending axons from the cerebral cortex, thalamus, and hypothalamus. Mu (μ) opioid receptors on PAG neurons allow both opioids that are released synaptically, extra-synaptically via volume transmission and through drug administration to influence their activity (Kingsley, 2000).

Endocannabinoids, which are related to THC from marijuana, can block the transmission of pain signals from the periphery to the dorsal horn of the spinal cord (Kalat, 2019).

Gating Pain

Melzack and Wall (1965) were the first investigators to explain why people respond differently under different circumstances to identically painful stimuli. Their Gate-Control Theory of Pain represented an early pattern theory of how we react to and controls response to painful stimuli.


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Melzack and Wall conceptualized pain as a cutaneous (skin) sensation that arises from somatosensory signals converging on spinal cord dorsal horn neurons that communicate with an adjustable pattern detector in the thalamus and cortices.

Caption: Ron Melzack

The Gate-Control Theory was the first model to propose cognitive-emotional mediation of pain and interaction between ascending and descending pathways. Their theory replaced the simplistic one-way model where pain signals ascend from the spinal cord to the brain.

In the Gate-Control Theory of Pain, C-fibers carry information about pain to neurons in the substantia gelatinosa, located in the spinal cord's dorsal horn.

The illustration below © 2003 Josephine Wilson.


From the substantia gelatinosa, information about pain is relayed to the brainstem and then to the cerebral cortex, where pain is consciously experienced. Gatchel (2005) believes that the pain "gate" is opened by pain-centered thoughts and negative thinking; negative feelings like anger, helplessness, hopelessness, sadness, and stress; and behaviors like inactivity, insufficient sleep, poor diet, and smoking.

Axons from the periaqueductal gray (PAG) and the periventricular gray areas release pain-inhibiting neurotransmitters in the substantia gelatinosa to "close the gate." Aβ fibers that carry tactile information and coping behaviors can "close the gate" to stop pain information from reaching the brain (Gatchel, 2005).

One significant advancement is the integration of synaptic plasticity mechanisms into the original framework. Recent studies have highlighted the roles of NMDA receptor-mediated synaptic plasticity and intrinsic neuronal plasticity in modulating pain pathways. These findings suggest that changes in synaptic strength and neuronal excitability can influence the gating mechanism, thereby affecting pain perception. Such plastic changes can lead to persistent pain states, as the nervous system becomes sensitized to nociceptive inputs.

Furthermore, the original Gate Control Theory has been refined to account for the influence of descending pathways from the brain that can modulate the gating mechanism in the spinal cord. These descending controls can either amplify or dampen pain signals, providing a neurophysiological basis for the role of psychological factors such as attention, emotion, and expectation in pain perception. This understanding has led to therapeutic approaches that target these descending pathways to manage pain more effectively.

Pain receptors use substance P to signal tissue damage and pain to the central nervous system. Substance P is released by small-diameter, unmyelinated C-fibers in the substantia gelatinosa and excites neurons whose axons carry information about pain to the brain. However, centers in the cerebrum and brain stem project axons down to the substantia gelatinosa. These axons can release endorphins and non-opiate transmitters like norepinephrine and serotonin to produce analgesia (the absence of pain) by inhibiting C-fiber release of substance P in the substantia gelatinosa via presynaptic inhibition (Wilson, 2003).

The stress response can produce analgesia that is not reversed by the opioid-blocker naloxone. ACTH, corticosterone, and neurotensin can reduce pain without releasing opioids.

Treatments for pain appear to activate the endorphin, non-opiate pain-inhibitory systems, or both. These treatments include drugs, counterirritation, acupuncture, transcutaneous electrical nerve stimulation (TENS), and hypnosis.

Neural Plasticity and Phantom Limb Pain

The topographical map of the primary somatosensory cortex is plastic and can be reorganized. The topographical organization of the primary somatosensory cortex is altered following the amputation of a limb. The ability of the primary somatosensory cortex to reorganize may contribute to the experience of chronic pain, especially a type of chronic pain known as phantom limb pain.

In phantom limb pain, a person who has had a limb amputated continues to feel pain in the missing limb long after it has been amputated. The severity of phantom limb pain is directly related to the extent of the reorganization of the somatosensory cortex, with more pain associated with more extensive cortical reorganization (Wilson, 2003).

Pain as a Homeostatic Emotion

Craig (2003) proposed, in contrast to pattern theorists like Melzack and Wall, that pain is a unique homeostatic emotion concerned with preserving the body. He challenged the Gate-Control Theory of Pain by observing that neither somatosensory cortical damage nor stimulation alters pain. Chronic pain can be reduced by stimulating the somatosensory thalamus. In primates, pain is a feeling produced by separate sensory channels that directly project via a central homeostatic afferent pathway from the thalamus to the cortex. These thalamocortical projections help us construct an image of the body's current physiological state (sensation) and directly activate the limbic motor cortex (affective motivation).

A sensation is generated by the interoceptive and anterior insular cortex, "the feeling self." Affective motivation is produced by the anterior cingulate cortex (ACC), the "behavioral agent." Thus, pain consists of a specific sensation and affective motivation to initiate autonomic and motor responses to a condition that threatens body integrity.

Pain Perception

Pain perception has sensory-discriminative, motivational-affective, and cognitive-evaluative dimensions.


Listen to a mini-lecture on Pain Perception © BioSource Software LLC.

The sensory-discriminative component of pain perception, which determines what the pain feels like (dull aching or sharp), is processed in the secondary somatosensory cortex.

The motivational-affective component, which determines emotional or physical pain's unpleasantness, is processed in the anterior cingulate cortex of the frontal lobe.

Finally, the cognitive-evaluative component, which determines what the pain means (GI distress or angina), is processed in the prefrontal cortex and the insula (Wilson, 2003).

Check out Christopher deCharms' TED Talk, A Look Inside the Brain in Real Time.

Eisenberger, Lieberman, and Williams (2003) used a functional MRI (fMRI) to study the brains of subjects who believed that two companions playing an online baseball simulation suddenly dropped them from the game. Their emotional distress activated the anterior cingulate cortex, which evaluates the unpleasantness of both emotional and physical pain. The more distress subjects feel, the greater the activity in anterior cingulate cortex. Participants taking Tylenol reported fewer hurt feelings than those taking a placebo, and there was less activation of the anterior cingulate.

Our perception of pain is greatly influenced by expectancy. Watch Joshua W. Pate's Mysterious Science of Pain.

Since pain is a complex perception, clinicians cannot objectively measure a patient's pain. In the absence of evidence of traumatic injury, this can lead to family members' and caregivers' mistaken belief that the pain is imaginary or exaggerated. Patients can subjectively rate their pain from 0 to 10 using analog scales. Graphic © EgudinKa/Shutterstock.com.

Pain Models

The biopsychosocial and dynamic pain connectome models are two influential pain models.



Listen to a mini-lecture on Pain Models © BioSource Software LLC. Graphic © Image Point Fr/Shutterstock.com.

Biopsychosocial Model

The biopsychosocial model proposes that the interplay of physical pathology, psychological processes, and social and economic factors determines each patient's unique pain experience, pain behavior, and physical disability. In Gatchel's (2005) view, "the biopsychosocial model is now viewed as the most heuristic approach; it appropriately conceptualizes pain as a complex and dynamic interaction among physiologic, psychologic, and social factors that often results in, or at least maintains, pain" (p. 23).

The Fear-Avoidance Model

The fear-avoidance model (FAM) is a psychological framework that explains how individuals develop chronic pain through maladaptive responses to pain-related fear. Originally proposed by Lethem et al. (1983) and later refined by Vlaeyen and Linton (2000), the model describes a cycle in which individuals who interpret pain as threatening may engage in avoidance behaviors, leading to physical deconditioning, increased disability, and heightened pain sensitivity. In contrast, those who view pain as non-threatening are more likely to maintain normal activity levels and recover.

FAM expands the biopsychosocial model by providing a mechanistic explanation for the psychological and behavioral aspects of pain chronification. While the biopsychosocial model broadly integrates biological, psychological, and social influences on pain, FAM offers a specific pathway through which cognitive and emotional factors contribute to long-term pain outcomes. It emphasizes the role of catastrophic thinking, fear of movement (kinesiophobia), and avoidance behaviors as key determinants of pain persistence, highlighting how pain-related distress can drive neural plasticity and reinforce the chronic pain experience (Vlaeyen & Linton, 2012).

Recent developments in pain neuroscience have further refined FAM by incorporating insights from predictive coding and network-based models of pain. Functional neuroimaging studies suggest that fear-avoidance behaviors are linked to hyperactivity in the amygdala, anterior insula, and prefrontal cortex, which regulate pain-related fear and learning (Meulders, 2019). Additionally, emerging evidence shows that persistent avoidance behaviors can disrupt the dynamic interactions of the default mode network and salience network, reinforcing pain expectations and emotional distress (Kucyi & Davis, 2015).

In clinical applications, FAM has led to targeted interventions such as graded exposure therapy and cognitive-behavioral therapy (CBT), which aim to reduce fear-avoidance cycles by gradually reintroducing feared movements and modifying maladaptive beliefs about pain. These approaches have been shown to improve functional outcomes in patients with chronic musculoskeletal pain (Vlaeyen et al., 2016).

By integrating cognitive-affective mechanisms into the broader biopsychosocial framework, the fear-avoidance model has enhanced our understanding of chronic pain and informed more effective interventions. It underscores the importance of addressing psychological factors in pain management, shifting the focus from purely biomedical approaches to holistic, interdisciplinary treatments.

Dynamic Pain Connectome Model

The dynamic pain connectome model offers a comprehensive perspective on how pain is processed in the brain, emphasizing the fluid and interconnected nature of neural networks involved in pain perception (Kucyi & Davis, 2015). Traditional models often focused on static representations of specific brain regions associated with pain. In contrast, the dynamic pain connectome model posits that pain perception arises from the continuous and dynamic interactions among multiple brain networks, which fluctuate over time and across different contexts.

Central to this model is the understanding that spontaneous fluctuations in brain activity significantly influence pain experiences. Research indicates that even in the absence of external stimuli, the brain exhibits intrinsic activity patterns that can modulate the perception of pain. These spontaneous neural activities suggest that the brain's resting-state networks play a crucial role in how pain is experienced and processed.

The model also highlights the involvement of large-scale brain networks beyond traditional pain pathways. Notably, the salience network, which detects and filters salient stimuli, and the default mode network, associated with self-referential thoughts and mind-wandering, are integral to pain processing (Menon & Uddin, 2010). The dynamic interplay between these networks and classical nociceptive pathways underscores the complexity of pain perception and its modulation by cognitive and emotional factors.

Caption: Brain networks: One atlas with seven networks. Seven brain networks derived from resting-state fMRI data were adapted from Schaefer et al. (2018).

Empirical studies have provided evidence supporting the dynamic pain connectome model. For instance, research has demonstrated that fluctuations in functional connectivity within and between these networks correlate with variations in pain intensity and perception. These findings suggest that pain is not solely a result of static neural activations but is profoundly influenced by the temporal dynamics of brain network interactions.

In summary, the dynamic pain connectome model advances our understanding of pain by framing it as an emergent property of dynamic and context-dependent brain network interactions. This perspective opens new avenues for research and potential therapeutic interventions targeting the modulation of these network dynamics to alleviate pain.

Pain Dimensions

Acute versus chronic pain and respondent versus operant pain are two critical pain dimensions.


Listen to a mini-lecture on Pain Dimensions © BioSource Software LLC. Graphic © sirtravelalot/Shutterstock.com.

Acute Versus Chronic Pain

Acute pain is pain associated with tissue damage, involves brief, intense, unpleasant sensations, warns of potential injury, and may produce transient anxiety. The pain experience is easily recognized and localized. Healing and treatment are effective about 90% of the time.

Chronic pain is pain not caused by cancer that has persisted for at least 3 months and has not responded to medical treatment (Advokat et al., 2022). Although other authors (e.g., Taylor, 2021) cite 6 months, injury healing is often complete, and opioids manage non-cancer pain less effectively within three months.

Nonsteroidal anti-inflammatory drugs (e.g., ibuprofen) provide better non-cancer pain control than opioid analgesics when pain becomes chronic.

There is a weak relationship between physical findings and pain severity. Chronic pain disrupts patients' daily activities. They may become preoccupied with their pain, increase health care utilization (testing, treatment, and medication), and present with anger, depression, and frustration. Check out Elliot Krane's TED Talk, The Mystery of Chronic Pain.

Episodic or recurrent pain is pain that has recurred for more than 3 months. Like acute pain, these episodes are brief. However, these episodes often produce psychological distress (like chronic pain), and patients may present with anxiety, depression, helplessness, and stress. While pain medication may reduce pain severity, it usually does not prevent recurrent episodes. Prolonged episodes of low back or headache pain may resemble chronic pain syndromes in symptoms, psychological distress, and degree of incapacitation (Gatchel, 2005).

Respondent Versus Operant Pain

Respondent pain is pain due to an identifiable stimulus, like a dental drill. This pain does not require previous learning. Operant pain results from prior reinforcement of pain behaviors by the environment (secondary gain).

How Chronic Pain Affects the Nervous System

Chronic pain damages spinal cord neurons and the brain.


Listen to a mini-lecture on Chronic Pain Effects © BioSource Software LLC. Graphic © EgudinKa/Shutterstock.com.

How Chronic Pain Affects Spinal Cord Neurons

Unremitting pain in patients diagnosed with arthritis, cancer, diabetes, and nerve trauma lowers their spinal cord neurons' firing threshold. Weak somatosensory stimulation, like a light touch, causes spinal cord neuron firing and body-wide pain (Melton, 2004). Graphic © James Steidl/Shutterstock.com.

Chronic Pain Damages the Brain

Chronic pain can produce brain atrophy and impair judgment. Apkarian used magnetic imaging to compare the prefrontal cortex's overall volume and gray matter density of chronic low back pain patients and healthy volunteers. The low back pain patients showed 1.3 mm³ more dorsolateral prefrontal cortex shrinkage a year than usual. Their shrinkage was comparable to 10-20 years of normal aging (Apkarian et al., 2004).

Next, he compared decision-making on the Iowa Gambling Test by 26 patients who had suffered low back pain for at least one year and 29 normal volunteers. He excluded severely depressed or anxious individuals from this study to minimize confounding. In the Iowa Gambling Test, participants select cards from decks that differ in maximum cash rewards and penalties. While normal participants developed card selection strategies that won money, low back pain patients randomly selected their cards and made 40% fewer successful decisions. The performance of low back pain patients was inversely correlated with their self-reported suffering. Despite their decision-making deficits, they showed no global cognitive impairment.

Apkarian found similar results with chronic Complex Regional Pain Syndrome (CRPS), also called reflex sympathetic dystrophy or causalgia, which may follow arm or leg injury (Melton, 2004).

The Red Hair Gene and Anesthesia

Red hair is linked to a reduced response to anesthetics due to a genetic mutation in the melanocortin 1 receptor (MC1R) gene, which is responsible for the production of pheomelanin, the pigment that gives red hair its color (Mogil et al., 2005). However, MC1R also interacts with the body's pain modulation pathways, leading to altered pain sensitivity and a higher requirement for anesthetic drugs.

Research has shown that individuals with natural red hair often require about 20% more inhaled anesthetic agents like desflurane and sevoflurane to achieve the same level of sedation as those without the MC1R mutation. Local anesthetics, such as lidocaine, are also reported to be less effective in red-haired individuals, necessitating higher doses for the same numbing effect.

One proposed mechanism involves MC1R's influence on the endogenous pain system. The mutation appears to enhance pain sensitivity, making red-haired individuals more resistant to standard anesthetic doses. Additionally, MC1R is thought to interact with the body's endorphin and opioid system, which may explain why some red-haired individuals have an altered response to opioid-based painkillers. This genetic variation creates a unique challenge for anesthesiologists and dentists, as failure to account for increased anesthetic needs can result in inadequate pain management during surgical or dental procedures.

While the effect is not uniform across all red-haired individuals, the trend has been well-documented in anesthesiology research. The clinical implications are significant, as medical professionals must be aware of the potential need for higher anesthetic doses in these patients. Understanding this genetic influence helps tailor anesthesia protocols to ensure effective sedation and pain relief.

Glossary

A-alpha (Aα) fibers: large-diameter myelinated fibers that rapidly conduct (80-120 meters per second) muscle length, contraction force, and light touch stimuli via the dorsal-column medial-lemniscal and anterolateral systems.

A-beta (Aβ) fibers: large-diameter myelinated fibers that rapidly conduct (35-75 meters per second) light touch stimuli via the dorsal-column medial-lemniscal and anterolateral systems.

A-delta (Aδ) fibers: small-diameter myelinated fibers found in skin and mucous membranes strongly influence the sensory-discriminative component of pain. They rapidly conduct (5-30 meters per second) pain signals from unimodal mechanoreceptors via the anterolateral system to the thalamus and somatosensory cortex.

acute pain: pain associated with tissue damage, involves brief, intense, unpleasant sensations, warns of potential injury, and may produce transient anxiety.

allodynia: neuropathic pain syndrome where nonpainful stimuli, like light touch, elicit severe pain.

angina pectoris: chest pain due to insufficient perfusion of the heart with blood.

anion: negative ion, for example, chloride (Cl^-).

anterior cingulate cortex (ACC): a frontal division that mediates executive functions and generates affective motivation to initiate autonomic and motor responses to a condition that threatens body integrity; final site for physical and psychological pain integration.

anterolateral system (ALS): also called the spinothalamic system, the ALS is a somatosensory pathway that distributes most pain information to the brain.

arteriovenous anastomoses (AVAs): junctions of two or more vessels that supply the same region, directly shunt blood from arterioles to venules, and help to regulate temperature.

ascending pain pathways: the dorsal-column medial-lemniscus system and anterolateral system transmit information from peripheral receptors to the brain over a three-neuron pathway that includes a primary afferent axon, a secondary projection neuron, and a tertiary neuron whose cell body lies in the thalamus.

BDNF: brain-derived neurotrophic factor, which reverses pain inhibition by neurons that release GABA and glycine in lamina I of the spinal cord, where several pain pathways begin.

biopsychosocial model: Engel’s perspective that the complex interplay of psychological, biological, and sociological factors results in health or illness.

bradykinin: a peptide that binds to nociceptors and increases their firing rate, worsening pain.

C-fiber: slowly-adapting small unmyelinated axon that slowly transmits pain information.

cerebral cortex: the layer of gray matter that covers the cerebral hemispheres. The cerebral cortex consists of gray matter and white matter.

chronic pain: pain not due to cancer that has persisted for at least 3 months and has not responded to medical treatment.

cognitive-evaluative component: the meaning of pain is processed in the prefrontal cortex and the insula.

Complex Regional Pain Syndrome (CRPS): a chronic progressive disease involving severe pain, swelling, and skin lesions. The International Association for the Study of Pain divides CRPS into Type I, including Reflex Sympathetic Dystrophy (RSD) when nerve damage is absent, and Type II, causalgia, when nerve damage is present.

cortisol: glucocorticoid produced by the adrenal cortex helps convert fat and protein to glucose and reduces inflammation.

default mode network: a system including the medial prefrontal and posterior cingulate cortex, which is active during rest and self-referential thinking. It influences pain perception by integrating expectations, memories, and cognitive appraisals

descending pathways: pain-modulating systems that descend from the brain to the dorsal horn of the spinal cord.

diathesis-stress model: the view that stressors interact with our inherited or acquired biological vulnerabilities, called diatheses, to produce medical and psychological symptoms.

dorsal-column medial-lemniscal system: a somatosensory pathway that distributes touch information through the dorsal columns to the brain.

dorsal columns: part of the dorsal-column medial-lemniscus system. These columns are located toward each half of the spinal cord's back and innervated by sensory neurons that leave the dorsal root.

dorsal root: the upper sensory root of a spinal nerve.

dorsal root ganglion (DRG): cell body cluster in the dorsal root of a spinal nerve.

dynamic pain connectome model: pain is produced by fluctuating interactions between brain networks rather than isolated nociceptive regions. It emphasizes dynamic functional connectivity, involving sensory, cognitive, and affective processes.

endocannabinoid: a molecule related to THC that reduces the firing of afferent fibers that transmit pain information to the spinal cord.

endorphin: an endogenous opioid polypeptide secreted by the pituitary gland and hypothalamus and released synaptically by neurons.

episodic (recurrent) pain: pain that has recurred for more than 3 months. Like acute pain, these episodes are brief. However, these episodes often produce psychological distress (like chronic pain), and patients may present with anxiety, depression, helplessness, and stress.

fascia: soft tissue element of connective tissue.

fear-avoidance model: a framework explaining chronic pain development through pain-related fear, catastrophic thinking, avoidance behaviors, and physical deconditioning, reinforcing pain persistence.

first pain signal: the sensation of sharp, brief pain carried by Aβ fibers that warns that damage has occurred.

free nerve ending: axon that projects to the skin without a specialized accessory structure and detects pain and temperature information.

Gate-Control Theory of Pain: model that proposes cognitive-emotional mediation of pain and interaction between ascending and descending pathways to modulate pain perception.

Gevirtz’s mediational model of muscle pain: the perspective that lack of assertiveness and resultant worry each trigger sympathetic activation. Increased sympathetic efferent signals to muscle spindles and overexertion can produce a spasm in the muscle spindle's intrafusal fibers, increasing muscle spindle capsule pressure and causing myofascial pain.

histamine: a biogenic amine that produces swelling and binds to nociceptors and increases their firing rate, worsening pain.

hypothalamic-pituitary-adrenal (HPA) axis: hormonal cascade that starts with signals from the amygdala to the hypothalamus and ultimately targets the adrenal glands, releasing the hormones CRH, ACTH (corticotropin), and cortisol.

insula: also called the insular cortex, is a structure deep within the lateral sulcus. The anterior aspect is a limbic-associated cortex and generates a sensation and conscious emotional experience about the body’s current state.

interoceptive and anterior insular cortex: structure deep within the lateral sulcus. The anterior aspect is a limbic-associated cortex and generates a sensation and conscious emotional experience about the body’s current state.

locus coeruleus: noradrenergic branch of the ascending reticular activating system, responsible for vigilance. Subnormal norepinephrine transmission may contribute to ADHD.

medial lemniscus pathway: brainstem pathway that distributes sensory information from the gracile and cuneate nuclei to the thalamus.

microglia: a glial immune cell that removes dead or injured cells and releases BDNF (brain-derived neurotrophic factor).

motivational-affective component: the unpleasantness of a painful stimulus is processed in the anterior cingulate cortex of the frontal lobe.

mu (μ) receptor: an opioid receptor that strongly binds enkephalins and beta-endorphins but weakly binds dynorphins. Morphine and codeine bind to this receptor.

muscle spindle: receptors that detect muscle length, tension, and pressure.

naloxone: opiate antagonist that does not reverse analgesia due to stress.

Na_v1.7: a sodium channel that acts as a "fuse," amplifying small nerve signals but not triggering full action potentials.

Na_v1.8: aa sodium channel that functions as a "firecracker," generating most of the electrical current needed for neuronal firing.

nerve growth factor (NGF): a protein that regulates neuron growth in spinal and sympathetic ganglia and probably plays a role in nociception.

nociceptor: receptor that detects stimuli that damage tissue or threaten tissue injury.

nucleus raphe magnus: serotonergic neurons that participate in the endogenous opiate system and inhibit pain in the spinal cord. These neurons excite spinal cord interneurons by releasing serotonin. The interneurons, in turn, inhibit C-fibers by releasing enkephalin, which binds to their terminal buttons and reduces their release of transmitter. This process is called presynaptic inhibition.

nucleus reticularis paragigantocellularis (NRPG): neurons that excite spinal cord interneurons by releasing norepinephrine. These interneurons inhibit neurons that project through a non-opioid polysynaptic pathway to the thalamus.

operant pain: pain that results from previous reinforcement of pain behaviors by the environment (secondary gain).

palpation: examination by feeling or pressing with the hand.

periaqueductal gray (PAG): a midbrain region whose axons form excitatory synapses on neurons located in the nucleus raphe magnus (NRM) and the nucleus reticularis paragigantocellularis (NRPG) in the medulla. The PAG plays a role in the descending modulation of pain and control of defensive behavior.

phantom limb pain: chronic pain syndrome in which a patient perceives that an amputated or missing limb is still intact.

polymodal nociceptor: nociceptor that responds to several stimuli.

prefrontal cortex: the most anterior frontal lobe division subdivided into dorsolateral, medial, orbitofrontal, and anterior cingulate regions responsible for executive functions like attention and planning.

presynaptic inhibition: a modulatory process where a neuron decreases neurotransmitter release by reducing calcium ion entry.

primary hyperalgesia: supersensitivity to stimulation that affects joints, muscles, or skin that have suffered damage or inflammation.

prostaglandin: lipid hormone that promotes swelling.

referred pain: pain perceived at a distance from the site of injury. For example, angina pectoris.

respondent pain: pain due to an identifiable stimulus, like a dental drill. This pain does not require previous learning.

salience network: a systemincluding the anterior insula and dorsal anterior cingulate cortex, detects and prioritizes relevant stimuli. It modulates pain by directing attention and integrating sensory and emotional responses.

second pain signal: the sensation of dull, aching pain carried by C-fibers reminds the body to protect itself against further injury.

secondary hyperalgesia: supersensitivity to stimulation that affects the tissue surrounding joints, muscles, or skin that have suffered damage or inflammation.

secondary somatosensory cortex (SII): a cortical region that receives direct projections from SI and creates a superimposed map of both sides of the body.

sensory-discriminative component: the subjective feeling of pain (dull aching or sharp) is processed in the secondary somatosensory cortex.

spinohypothalamic tract: a pathway that bypasses the reticular formation and projects to the hypothalamus, amygdaloid complex, nucleus accumbens, and septum. This tract may contribute to our autonomic, neuroendocrine, and emotional responses to noxious stimuli.

spinomesencephalic tract: a pathway that travels with the spinotectal tract and targets the periaqueductal gray (PAG), locus coeruleus, and tectum. This tract may convey information concerning motivational and emotional responses to pain.

spinoreticular tract: also called the paleospinothalamic tract. This pathway targets the reticular formation and then the thalamic parafascicular nuclei and intralaminar nuclei. Axons from these thalamic nuclei project to the anterior cingulate, amygdala, and hypothalamus. This tract may contribute to arousal and convey information about our emotional response to pain, including suffering.

spinothalamic tract: also called the neospinothalamic tract. This pathway targets the thalamus's ventral posterior nucleus (VPN), like the dorsal-column medial-lemniscus system. VPN neurons project to corresponding somatosensory cortical region. This tract may convey information about pain and temperature.

substance P: tachykinin neuropeptide functions as a neurotransmitter and neuromodulator that plays a role in transmitting peripheral pain signals to the CNS.

substantia gelatinosa: C-fibers transmit pain information to neurons in the spinal cord's dorsal horn that is relayed to the brainstem, thalamus, and cerebral cortex.

suzetrigine (Journavx): a Nav1.8 inhibitor approved for treating moderate to severe acute pain without opioid-related side effects.

substantia gelatinosa: C-fibers transmit pain information to neurons in the spinal cord's dorsal horn that is relayed to the brainstem, thalamus, and cerebral cortex.

synaptic plasticity mechanisms: Processes that modify synaptic strength and efficiency in response to activity, including long-term potentiation (LTP) and long-term depression (LTD), influencing learning, memory, and pain modulation.

trigeminal nerve: 5th cranial nerve that projects pain and temperature information concerning the face to the same thalamic nuclei targeted by the spinothalamic and spinoreticular tracts. This cranial nerve also controls biting, chewing, and swallowing.

trigger points: hyperirritable regions of taut bands of skeletal muscle in the muscle belly or associated fascia.

unimodal nociceptor: nociceptor that responds to only one stimulus.

ventral posterior nucleus (VPN) of the thalamus: nucleus that integrates somatosensory information from the opposite side of the face via the trigeminal nerve. The majority of VPN axons target the primary somatosensory cortex (SI), while a minority target the secondary somatosensory cortex (SII) or the posterior parietal cortex.

Wickramasekera’s Illness Behavior Syndrome: The patient assumes a role reinforced by a healthcare system that treats chronic pain as if it were acute. This role consists of five components: dramatizing complaints, progressive impairment, drug misuse, progressive dependency, and reduced income.

wind-up: pain after an injury has healed because interneurons continue to activate each other in the absence of peripheral pain signals.

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Assignment

Now that you have completed this unit, explain why treating chronic pain as if it acute can be debilitating. What is the clinical relevance of descending pain-modulating pathways?

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