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Pain Physiology
Neurobiology of Pain
The experience of pain involves a series of complex neurophysiologic processes,
collectively termed nociception, with four distinct components: transduction,
transmission, modulation, and perception. Transduction is the process by which a
noxious stimulus (e.g., heat, cold, mechanical distortion) is converted to an electrical
impulse in sensory nerve endings. Transmission is the conduction of these electrical
impulses to the CNS with the major connections for these nerves being in the dorsal
horn of the spinal cord and thalamus with projections to the cingulate, insular, and
somatosensory cortices. Modulation of pain is the process of altering pain
transmission. It is likely that both inhibitory and excitatory mechanisms modulate pain
(nociceptive) impulse transmission in the PNS and CNS. Pain perception is thought to
be mediated through the thalamus acting as the central relay station for incoming pain
signals and the primary somatosensory cortex serving for discrimination of specific
sensory experiences.1 Pain may occur in the absence of the occurrence of these four
steps. For example, pain from trigeminal neuralgia occurs in the absence of
transduction of a chemical stimulus at a nociceptor reflecting axonal discharges
initiated at the site of a compressed or demyelinated nerve. Modulation of pain
impulses may not occur if specific nervous system tracts are injured. For example,
phantom limb pain occurs in the absence of nociception or nociceptors (pain
receptors).
Sensitization of Nociceptors
Sensitization of nociceptors refers to the increased responsiveness of peripheral
neurons responsible for pain transmission to heat, cold, mechanical, or chemical
stimulation. Sensitization of nociceptors frequently occurs and is attributable to the
release of inflammatory mediators and adaptation of signaling pathways in primary
sensory neurons induced by noxious stimuli. In the majority of cases of acute
inflammation, the process naturally resolves as tissues heal and peripheral
sensitization diminishes and nociceptors return to their original resting threshold.
Chronic pain, however, occurs if the conditions associated with inflammation do not
resolve, resulting in sensitization of peripheral and central pain signaling pathway and
increased pain sensations to normally painful stimuli (hyperalgesia) and the
perception of pain sensations in response to normally nonpainful stimuli (allodynia).
Numerous endogenous chemicals, neurotransmitters, peptides (such as substance
P, calcitonin generelated peptide or CGRP, bradykinin), eicosanoids and related
lipids (prostaglandins, thromboxanes, leukotrienes, endocannabinoids), neurotrophins,
cytokines, and chemokines, as well as extracellular proteases and protons,
significantly contribute to the process of nociception and neuronal sensitization during
peripheral inflammation and nerve injury.4 Most of these mediators are not
constitutively stored but rather are synthesized de novo at the site of injury. The
agents contribute to pain via two principal mechanisms. Some of these agents (e.g.,
bradykinin, protons, prostaglandin E2, purines, and cytokines) can directly activate
nociceptors and/or induce the sensitization of the nociceptor response to painful
stimuli, whereas others (e.g., serotonin, histamine, arachidonic acid metabolites, and
cytokines) may activate the inflammatory cells, which in turn release cytokines,
thereby leading to sensitization. The variety of chemical mediators released during
inflammation can potentiate nociceptor responses (Fig. 6-1).
A variety of receptors and ion channels have been identified on dorsal root
ganglion neurons and on peripheral terminals of nociceptive afferent fibers. These
receptors, including purinergic,5metabotropic glutamatergic, tachykinin,6 TRPV1
receptor and neurotrophic receptors, and ion channels (e.g., Nav1.8) in primary
sensory neurons may also undergo significant adaptation after noxious stimuli,
significantly lowering the firing thresholds of nociceptors and critically contributing
to the induction and maintenance of neuronal sensitization, which manifest as
allodynia and hyperalgesia.7
Interneurons make up the great majority of the neuronal population throughout the
dorsal horn. Many dorsal horn interneurons have axons that remain in the same lamina
as the cell body, and they also give rise to axons that extend into other laminae.
Interneurons in the dorsal horn can be divided into two main functional types:
inhibitory cells, which use GABA and/or glycine as their principal transmitter, and
excitatory glutamatergic cells. Interneurons in dorsal horn are important for
integration and modulation of incoming nociceptive information.
Projection neurons with axons that project to the brain are present in relatively
large numbers in lamina I and are scattered through the deeper part of the dorsal horn
(laminae III to VI) and the ventral horn. Both the lamina I and the laminae III and IV
projection neurons that express the NK1 receptor are heavily innervated by substance
Pcontaining primary afferents. Those in lamina I, together with some of the
projection cells in deeper laminae, have axons that cross the midline and ascend to a
variety of supraspinal targets including the thalamus, the midbrain PAG, lateral
parabrachial area of the pons, and various parts of the medullary reticular formation.
Two types of descending monoaminergic (serotoninergic and norepinephrinergic)
axons project from the brain throughout the dorsal horn, mostly terminating in
laminae I and II, and are involved in descending pain modulation. Serotoninergic
axons in the spinal cord originate in the medullary raphe nuclei, whereas those that
contain norepinephrine are derived from cells in the locus ceruleus and adjacent areas
of the pons.
Gate Theory
The gate control theory of pain was first proposed by Ronald Melzack and Patrick
Wall in 1965 to illustrate the neuronal network underlying pain modulation (a
neurologic gate) in the spinal dorsal horn. According to this theory, painful
information is projected to the supraspinal brain regions if the gate is open, whereas
painful stimulus is not felt if the gate is closed by the simultaneous inhibitory
impulses (Fig. 6-4). Here is a commonly used example to describe how this neuronal
network modulates pain transmission. Usually, rubbing the skin of painful area seems
to somehow relieve the pain associated with a bumped elbow. In this case, rubbing the
skin activates large-diameter myelinated afferents (A), which are faster than A
fibers or C fibers conveying painful information. These A fibers deliver information
about pressure and touch to the dorsal horn and override some of the pain messages
(closes the gate) carried by the Ad and C fibers by activating the inhibitory
interneurons in the dorsal horn. This hypothesis provided a practical theoretical basis
for some approaches such as massage, transcutaneous nerve stimulation, and
acupuncture to effectively treat pain in clinical patients.
Psychobiology of Pain
Unpleasant emotional experiences are an intrinsic and undesirable feature of painful
experiences for the patients. Discomfort, fear of pain, and anxiety are the most
common psychological responses observed in the patients with pain, although other
adverse emotional responses, including depression, anger, disgust and guilt are not
unusual in these patients.
Affective qualities of pain are transmitted and processed via the same pathways as
those for the painful sensory transmission. Peripheral nociceptive information is
delivered through spinoreticular pathways to diencephalic and telencephalic
structures, including the medial thalamus, hypothalamus, amygdala, and limbic
cortex. Central sensitization and adaptation of synaptic plasticity occur in these brain
regions and contribute to the induction and maintenance of the emotional distress that
often accompanies pain.11
Intrinsic interactions occur between the sensory and affective components of pain.
Although the affective qualities of the painful experience vary from individual to
individual, most patients experiencing acute or chronic pain display substantial
emotional, behavioral, or social abnormalities. While these affective symptoms may
gradually wane, a substantial proportion of patients with chronic pain experience
debilitating depression, anxiety, cognitive deficits such as memory impairment, and
other negative psychological components of pain. Similarly, emerging evidence
suggests that severe emotional distress can trigger new pain or exacerbate ongoing
pain in the patients with previous painful experiences.
Visceral Pain
While somatic pain is easily localized and characterized by distinct sensations,
visceral pain is diffuse and poorly localized, typically referred to somatic sites (e.g.,
muscle and skin), and it is usually associated with stronger emotional and autonomic
reactions. Visceral pain is often produced by stimuli different from those adequate for
activation of somatic nociceptors. These features may be attributable to dual nerve
innervation and the unique structure of visceral receptive endings.
Among all tissues in the body, the viscera are unique in that each organ receives
innervation from two sets of nerves, either vagal and spinal nerves or pelvic and
spinal nerves, and the visceral afferent innervation is sparse relative to somatic
innervation. Spinal visceral afferent fibers have their cell bodies in dorsal root ganglia
(DRG) and terminate in the spinal dorsal horn. The central termination of visceral
afferents synapse spinal neurons in laminae I, II, V, and X over several segments and
deliver the visceral sensory information through the contralateral spinothalamic tract
or ipsilateral dorsal column to supraspinal brain sites. These spinal neurons also
receive convergent input from somatic and other visceral structures, providing the
structural basis for referred pain; for example, the left-sided jaw and arm pain that
accompany myocardial ischemia are mediated by convergence of visceral and somatic
sensory fields. Another nervous structure conveying pain information from organs in
the thoracic and abdominal cavities is the vagus nerve, which has cell bodies in the
nodose ganglion and central terminals in the nucleus tractus solitarii. The vagus
afferent innervation plays an important role in the prominent autonomic and
emotional reactions in visceral diseases associated with pain (Fig. 6-7). The majority
of visceral afferent fibers are thinly myelinated A fibers or unmyelinated C fibers
with unencapsulated free nerve endings, with a small number of A fibers associated
with Pacinian corpuscles in the mesentery. Best characterized mechanosensitive
endings in the viscera are the intraganglionic laminar endings (IGLEs) and
intramuscular arrays associated with vagal afferent fibers that innervate the stomach.
Most of these visceral sensory neurons contain substance P and/or CGRP, and they
also express the high-affinity nerve growth factor receptor TrkA. These biomarkers
significantly increase and the nociceptors become sensitized during visceral
inflammation. Unlike noxious stimuli to induce somatic pain, many damaging stimuli
(cutting, burning, clamping) produce no pain when applied to visceral structures.
Activation of visceral nociceptors is generally induced by ischemia, stretching of
ligamentous attachments, spasm of smooth muscles, or distension of hollow structures
such as the gallbladder, common bile duct, or ureter. These stimuli occur in many
visceral pathologic processes, and the pain they induce may serve a survival function
by promoting immobility.
Complex Regional Pain Syndromes
The International Association for the Study of Pain (IASP) Classification of Chronic
Pain defines complex regional pain syndrome (CRPS) as a variety of painful
conditions following injury which appears regionally having a distal predominance of
abnormal findings, exceeding in both magnitude and duration the expected clinical
course of the inciting event often resulting in significant impairment of motor
function, and showing variable progression over time. These chronic pain syndromes
have different clinical features including spontaneous pain, allodynia, hyperalgesia,
edema, autonomic abnormalities, active and passive movement disorders, and trophic
changes of skin and subcutaneous tissues. Two types of CRPS, type I (reflex
sympathetic dystrophy) and type II (causalgia), by the presence of a major identifiable
nerve injury in the CRPS II and the absence of a major nerve injury in CRPS I. CRPS
I develops more often than CRPS II, and females are more often affected than males
(2:1 to 4:1). The incidence of CRPS I is 1% to 2% after fractures, 12% after brain
lesions, and 5% after myocardial infarction, and the incidence of CRPS II in
peripheral nerve injury varies from 2% to 14% in different series, with a mean around
4%.
The following IASP clinical criteria are applied to diagnose the CRPS. CRPS type
I: (a) type I is a syndrome that develops after an initiating noxious event; (b)
spontaneous pain or allodynia/hyperalgesia occurs, is not limited to the territory of a
single peripheral nerve, and is disproportionate to the inciting event; (c) there is or has
been evidence of edema, skin blood flow abnormality, or abnormal sudomotor activity
in the region of the pain since the inciting event; and (d) this diagnosis is excluded by
the existence of conditions that would otherwise account for the degree of pain and
dysfunction. CRPS type II: (a) type II is a syndrome that develops after nerve injury;
spontaneous pain or allodynia/hyperalgesia occurs and is not necessarily limited to the
territory of the injured nerve; (b) there is or has been evidence of edema, skin blood
flow abnormality, or abnormal sudomotor activity in the region of the pain since the
inciting event; and (c) this diagnosis is excluded by the existence of conditions that
would otherwise account for the degree of pain and dysfunction.
The mechanism underlying the pathogenesis of CRPS remains unclear, although it
is recognized that CRPS is a neurologic disease including the autonomic, sensory, and
motor systems as well as cortical areas involved in the processing of cognitive and
affective information, and the inflammatory component appears to be particularly
important in the acute phase of the disease. Effective, evidence-based treatment
regimens for CRPS are lacking.