Pain warns of actual or impending tissue damage. We use this information to safely navigate within our environment and detect early signs of disease. Patients, like Type 1 diabetics, who exhibit peripheral neuropathy, may be unaware of infection or traumatic injury to their extremities due to the breakdown of pain perception.

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

Students completing this unit will be able to discuss:

  1. Chronic neuromuscular pain
    A. Ascending and descending pain pathways
    B. Gate control theory
    C. Trigger point mechanisms
  2. Specific central nervous system structures and neurotransmitter pathways subserving pain

Free nerve endings are the body’s primary nociceptors (pain receptors). 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 several stimuli, like C-fibers).

Sherman (2004) estimates that almost 50% of nociceptors located in joints and, possibly, the skin are "silent." These unmyelinated C-fibers only react to stimuli like limb movement and touch when there is local inflammation. Their activation increases pain two-fold.

Painful stimuli often damage tissue, which causes the release of substance P, bradykinin, histamine, and prostaglandin. Nociceptors release the peptide substance P through their many axonal branches in nearby skin. Substance P produces capillary swelling and histamine release from mast cells, sensitizing other nociceptors located at the injury site. Bradykinin, histamine, and prostaglandin bind to nociceptors and increase their firing rate, increasing pain. Histamine and the prostaglandins also produce swelling (Wilson, 2003).

Tissue injury can increase sensitivity to normal stimulation like light touch. The nervous system can increase pain by lowering the pain threshold, increasing pain severity, or generating spontaneous pain. This supersensitivity is called primary hyperalgesia, when it affects joints, muscles, or skin that have suffered damage or inflammation, and secondary hyperalgesia, when it affects surrounding tissue (Bear, Connors, & Paradiso, 2007).

Four main types of afferent axons conduct information crucial to pain perception: A-alpha, A-beta, A-delta, and C-fibers.

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

A-beta (Aβ) fibers
are large-diameter myelinated fibers that rapidly conduct (35-75 m/s) light touch stimuli via the dorsal-column medial-lemniscal and anterolateral systems.

A-delta (Aδ) fibers
are small-diameter myelinated fibers found in skin and mucous membranes that strongly influence the sensory-discriminative component of pain. They rapidly conduct (5-30 m/s) pain signals from unimodal mechanoreceptors via the anterolateral system to the thalamus and somatosensory cortex shown below. Aδ fibers carry the first pain signal that warns that damage has occurred. This sensation is described as sharp, brief pain.


are small-diameter unmyelinated fibers located in deep tissue and skin that strongly influence the affective and motivational components of pain. These fibers slowly conduct (1 m/s) pain signals from polymodal chemoreceptors and thermoreceptors to the hypothalamus, thalamus, and cortex. C-fibers carry the second pain signal that reminds the body to protect itself against further injury. This sensation is described as dull, aching pain.

Afferent fibers from the nociceptors in the skin and viscera (large internal organs) converge and interact in the spinal cord. Cross-talk between these axons produces referred pain like angina, in which visceral pain due to insufficient oxygen to the heart muscle is mainly experienced in the upper chest, but sometimes the back, arms, lower jaw, neck, or shoulders (Bear, Connors, & Paradiso, 2007; Heuther & McCance, 2004).

The combined firing of A-δ and C-fibers results in double pain, where a patient experiences two peaks, sharp, brief pain and dull, aching pain (Taylor, 2006).

Axons that carry nociceptive information release glutamate during mild pain and release both glutamate and substance P during more intense pain (Kalat, 2004).

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. 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.

The dorsal-column medial-lemniscus system and anterolateral system 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.

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 inoccuous stimuli. This is particularly 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).

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.

Sensory neurons enter the spinal cord through the dorsal root, ascend in the dorsal columns on the same side, and synapse with dorsal column nuclei in the medulla. Axons from dorsal column nuclei cross over to the opposite side and ascend via the medial lemniscus to the ventral posterior nucleus (VPN) of the thalamus. The VPN also integrates somatosensory information from the 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.

The anterolateral system (ALS) distributes pain and temperature information to the somatosensory cortex and other brain regions. The main afferent axons that comprise the ALS are small-diameter Aδ and C-fibers. Since the sensory neurons that contribute to this system have large receptive fields, spatial localization is imprecise. The majority of these sensory neurons synapse within the spinal cord and most of their second-order neurons cross over and ascend via the contralateral anterolateral spinal cord. A minority of these neurons do not cross over and, instead, ascend on the same side.

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

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

The spinoreticular tract (also called the paleospinothalamic tract) 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.

The spinomesencephalic tract 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.

The spinohypothalamic tract 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.

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

The thalamic nuclei targeted by these tracts, in turn, project pain and temperature information to SI, SII, the posterior parietal cortex, and other brain regions (Kingsley, 2000; Pinel, 2006).


Several descending systems modulate the transmission of pain information. Ranney (2001) speculates that there are 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 either facilitate or inhibit pain transmission. These loops connect the spinal cord to the dorsolateral pons, medulla, and hypothalamus. Stimulation of these loops can affect pain transmission from hours to days.

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 dorsal horn of the spinal cord.

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.

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, a process called presynaptic inhibition.

NRPG neurons excite spinal cord interneurons by releasing norepinephrine. These interneurons inhibit neurons that project to the thalamus through a polysynaptic pathway that does not release opioids.

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) receptors on PAG neurons allow both opioids that are released synaptically, extra-synaptically through volume transmission, and through drug administration to influence their activity (Kingsley, 2000).

Melzack and Wall (1965)
were the first investigators to explain why people respond in different ways under different circumstances to identically painful stimuli. Their Gate-Control Theory of Pain represented an early pattern theory of how we respond to and control our response to painful stimuli. They conceptualized pain as a type of cutaneous (skin) sensation that arises from somatosensory signals converging on dorsal horn neurons (in the spinal cord) that communicate with an adjustable pattern detector in the thalamus and cortices.

This was the first model to propose cognitive-emotional mediation of pain and an interaction between ascending and descending pathways, instead of the simplistic one-way model where pain signals simply 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, which is located in the dorsal horn of the spinal cord and extends into the medulla. From the substantia gelatinosa, information about pain is relayed to the brain stem, 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).

Pain receptors use a neurochemical known as substance P to signal the presence of 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 nonopiate 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 the release of opioids.

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

Craig (2003) proposed, in contrast to pattern theorists like Melzack and Wall, that pain is a unique homeostatic emotion concerned with the preservation of the body. He challenged the Gate-Control Theory of Pain by observing that neither somatosensory cortical damage nor stimulation alters pain, that chronic pain can be reduced by stimulation of the somatosensory thalamus, and that 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 create an image of the body's current physiological state (sensation) and directly activate the limbic motor cortex (affective motivation). Specifically, 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 both a specific sensation and affective motivation to initiate autonomic and motor responses to a condition that threatens body integrity.

Pain perception has sensory-discriminative, motivational-affective, and cognitive-evaluative dimensions. 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 the pain's unpleasantness, is processed in the anterior cingulate cortex of the frontal lobe. 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).

Eisenberger, Lieberman, and Williams (2003) used a functional MRI (fMRI) to study the brains of subjects who believed that two companions playing an on-line baseball simulation suddenly dropped them from the game. Their emotional distress activated the anterior cingulate cortex, which evaluates the unpleasantness of physical 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 that has persisted for at least 6 months (longer than the 2-4 months usually required for healing) and has not responded to medical treatment. 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.

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

Pain behaviors persist after injury has healed. The patient assumes a role that is reinforced by a health care system that treats chronic pain as if it were acute. Wickram's Illness Behavior Syndrome (1988) consists of five components:

  1. dramatization of complaints
  2. progressive impairment, which often results in low levels of physical activity and damaging posture, muscle shortening, and inflammation
  3. drug misuse
  4. progressive dependency
  5. reduced income

The topographical map of the primary somatosensory cortex is quite plastic and can be reorganized. The topographical organization of the primary somatosensory cortex is altered following 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 greater cortical reorganization (Wilson, 2003).

Melzack's (1992) neuromatrix model of phantom limb pain proposes that a widely-distributed neural network responds to sensory stimulation and generates a signal that the body is intact and one's own. When there are no sensory signals from the periphery, this neurosignature produces the false perception that the patient still has a limb (even after amputation). Almost 70 percent of amputees report phantom burning, cramping, or shooting pain as part of their body although the limb is missing.

The neuromatrix consists of three neural systems: the sensory pathway from the thalamus to the somatosensory cortex, emotional and motivational pathways from the brain stem reticular formation to the limbic system, and cortical regions that recognize the self and process sensory input found mainly in the parietal lobe. Phantoms in patients born without limbs suggest that the neuromatrix may be mostly prewired. Experience may modify the connections which resemble Hebb's cell assemblies.

Sensory signals entering the brain pass through all three systems in parallel, they share their analysis, and send an integrated evaluation to other brain regions. (The site where this output becomes completely conscious is unknown.) This output includes an evaluation of the sensory information and a neurosignature (message that the signals come from our own body).

The neuromatrix model hypothesizes that peripheral sensory stimulation or CNS processes can generate specific patterns of neural network firing that create a multidimensional pain experience. The neuromatrix develops through an interplay of genetics, sensory experience, and learning. This is a diathesis-stress model of pain. A person's vulnerability to pain (diathesis) interacts with acute stressors to trigger neural network firing patterns that we experience as pain. Pain, in turn, can become a powerful chronic stressor (Gatchel, 2005).

Injury that threatens homeostasis is stressful and can activate Selye's hypothalamic-pituitary-adrenal (HPA) axis, releasing cortisol. Prolonged cortisol release can metabolize new muscle protein and inhibit calcium replacement in bones, resulting in joint and muscle pain (Gatchel, 2005).

This model explains common complaints of burning and cramping in the phantom limb. When the neuromatrix loses sensory input from a limb, this may produce high levels of neuromatrix firing (like thalamic bursting) which may produce perceptions of burning. Failure of a limb to move in response to neuromatrix commands may result in more intense neuromatrix firing which may be perceived as cramping or shooting pain.

This phenomenon extends to phantom seeing and phantom hearing. Patients with cataracts or damage to visual processing circuitry report highly detailed visual perceptions (15 percent of patients who suffer partial or complete vision loss report visual phantoms). Deaf patients often report noises (tinnitus) which range from loud, unpleasant sounds (like whistling or clanging) to music or voices. In all these cases, loss of normal sensory input increases neuromatrix activity which the brain transforms into perceptions.

Phantom limbs, seeing, and hearing demonstrate that the brain constructs perceptions in the absence of sensory inputs. (The brain does more than detect and evaluate stimuli.) Second, phantoms show that the brain is prewired to perceive the body and limbs. Melzack concludes: "the brain generates the experience of the body. Sensory inputs merely modulate that experience; they do not directly cause it" (p. 126).


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).

Unremitting pain in patients diagnosed with arthritis, cancer, diabetes, and nerve trauma lowers the firing threshold of their spinal cord neurons. Now, weak somatosensory stimulation, like a light touch, causes spinal cord neuron firing and body-wide pain (Melton, 2004).

Chronic pain may structurally reroute neuronal connections in the dorsal horn of the spinal cord. Alterations in the expression of genes like c-fos and c-jun in second-order neurons may change enzyme and neuropeptide (e.g., nerve growth factor) release and modify synapses with sensory neurons carrying pain information. Both structural reorganization of the dorsal horn and volume transmission (extrasynaptic release) of neurotransmitters may contribute to the spread of pain beyond the site of injury (Ranney, 2001).

Coull and colleagues (2005) propose that damage to sensory neurons activates microglia (glial immune cells). These microglia release 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. BDNF alters the distribution of anions (mainly Cl-) in sensory neurons that transmit pain information. When GABA and glycine bind to receptors on these affected neurons, they depolarize them and amplify pain transmission. This results in allodynia, a neuropathic pain syndrome where nonpainful stimuli, like light touch, elicit severe pain.

Chronic pain can produce brain atrophy and impair judgment. Apkariana used magnetic imaging to compare the overall volume and gray matter density of the prefrontal cortex of chronic low back pain patients and normal volunteers. The low back pain patients showed significantly greater cortical atrophy.

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, subjects are allowed to select cards from decks that differ in maximum cash rewards and penalties. While normal subjects developed card selection strategies that won money, low back pain patients randomly selected their cards and made 40% fewer successful decisions. The low back pain patients' performance was inversely correlated with their self-reported suffering. Despite their decision-making deficits, they showed no global cognitive impairment.

Apkariana 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).

Trigger points are hyperirritable regions of taut bands of skeletal muscle in the muscle belly or associated fascia (connective tissue). 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).

Hubbard and Gevirtz have proposed that sympathetically-mediated muscle spindle spasm may be the major local mechanism in myofascial pain. An important implication of this theory is that muscle spindles may be activated by stress and anxiety.

Muscle spindles
detect muscle length, tension, and pressure. They are activated by the sympathetic branch of the autonomic nervous system when epinephrine binds to α-1 adrenergic receptors. They are activated by the sympathetic branch of the autonomic nervous system when epinephrine binds to α-1 adrenergic receptors. Inserted EMG electrodes reveal muscle spasm in the affected muscle fiber, shown by elevated inserted EMG amplitudes, while nearby fibers in the same muscle are electrically silent. Consistent with this model, intrafusal muscle spasm is terminated by α-1 adrenergic antagonists like phentolamine and phenoxybenzamine, but not curare. Gevirtz (2003) contends that intrafusal muscle spasm accounts for most of the variance in chronic pain, whereas neurological factors that influence afferent pain pathways account for a minority of the variance in chronic pain.   



Gevirtz's (2003) mediational model of muscle pain proposes 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 intrafusal fibers of the muscle spindle, increasing muscle spindle capsule pressure and causing myofascial pain.



Now that you have completed this module, 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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