This article provides an integrated review of the basic anatomy and physiology of the pain processing pathways. The transmission and parcellation of noxious stimuli from the peripheral nervous system to the central nervous system is discussed. In addition, the inhibitory and excitatory systems that regulate pain along with the consequences of dysfunction are considered.
Key points
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Pain signals are transmitted along Aδ and C nociceptive nerve fibers to the central nervous system.
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Most peripheral nerve fibers will synapse in the Rexed lamina and then ascend in the contralateral spinothalamic tract before terminating in the ventral posterior nuclei and central nuclei of the thalamus.
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The receptive fields of the thalamus may reorganize following injury.
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The primary and secondary somatosensory cortex receive the bulk of direct projections from the thalamus; the insula, orbitofrontal cortex, dorsolateral prefrontal cortex, amygdala and cingulate are additional early relay sites important in pain processing.
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The rostral ventromedial medulla, the dorsolateral pontomesencephalic tegmentum, and the periaquaductal gray region are important structures in the descending regulation of noxious stimuli at the dorsal horn.
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The neuromatrix theory of pain incorporates the gate control theory of pain that focused on pain regulation at the spinal cord with more recent evidence that expands the role of the cortex.
Introduction
The pain pathways form a complex, dynamic, sensory, cognitive, and behavioral system that evolved to detect, integrate, and coordinate a protective response to incoming noxious stimuli that threatens tissue injury or organism survival. This defense system includes both the primitive spinal reflexes that are the only protection for simple organisms all the way up to the complex emotional responses humans consciously and subconsciously experience as pain. The mental representation of pain is stored as both short-term and long-term memory and serves as an early warning avoidance system for future threats. When severe, mental anguish may be projected with a physical complaint or symptom. Although many of the basic structures of the pain pathways have been defined, a more complete understanding of the interactions that would enable the development of targeted therapies remains elusive.
Peripheral sensory system and mechanisms of sensitization
The location, intensity, and temporal pattern of noxious stimuli are transduced into a recognizable signal through unmyelinated nociceptors at the terminal end of sensory neurons. Through physical deformation or molecular binding, membrane permeability and, consequently, the membrane potential fluctuate. If depolarization reaches a critical threshold, an action potential is propagated along the length of a sensory nerve toward the spinal cord.
Most sensory receptors respond to a single stimulus modality. Nociceptors, designed to detect tissue injury, are excited by three noxious stimuli: mechanical, thermal, and chemical. Mechanical stimuli deform the receptor to augment receptor ion permeability, whereas chemicals such as bradykinin, serotonin, histamine, potassium ions, acids, acetylcholine, and proteolytic enzymes bind directly to receptors to influence membrane permeability. Prostaglandins and substance P (SP) do not directly activate pain receptors but indirectly influence membrane permeability.
Nociceptive receptors sit at the ends of pseudounipolar sensory neurons with cell bodies in the dorsal root, trigeminal, or nodose ganglia ( Fig. 1 ). Pain receptors are unencapsulated free nerve endings. Sensory nerve fibers range from 0.5 to 20 μm in diameter and can conduct impulses at speeds ranging from 0.5 to 120 m/sec. Larger diameter neurons conduct information at a faster speed. Nerve fibers are divided up into two main categories: type A, which are medium to large diameter myelinated neurons, and type C, small diameter unmyelinated neurons. Pain transmission is divided into two categories, fast and slow. A-delta fibers detect and transmit pain quickly. These fibers are relatively small (1–6 m), thinly myelinated neurons that can conduct at speeds of 6 to 30 m/sec. C fibers are small (<1.5 m) and unmyelinated, conducting pain at 0.5 to 2 m/sec. A-beta are large (6–12 m) myelinated fibers that are high speed (30–70 m/sec). They have encapsulated receptors and transmit information about touch, pressure, and vibration. Most A-delta fibers are associated with thermo or mechanoreceptors. C fibers can be associated with polymodal receptors, suggesting a role in monitoring the overall tissue condition.
Innocuous stimuli may elicit excitation of neurons in the peripheral nociceptive system following repeated injury or inflammation. These pathologic changes contribute to phenomena such as sensitization, allodynia, or hyperalgesia. In peripheral sensitization, neurons fire at a lower threshold and have greater response magnitude to a given stimuli, may fire spontaneously, or may even have altered receptive field areas. This occurs via inflammatory mediators, including bradykinin, prostaglandins, serotonin, tumor necrosis factor alpha, and histamine. After integration in the brainstem, descending pronociceptive and antinociceptive pathways contribute to peripheral sensitization. When the function of these pathways becomes abnormal, chronic pain may occur.
The expression of molecules, including GABA, histamine, serotonin, and opiate receptors in nociceptive neurons, may be modulated by inflammation or injury. Near the receptor there is a high concentration of sodium channels. Increased channel expression can alter sensitivity of nerve endings to noxious stimuli by modulating integration of stimuli and threshold potential for action potential generation. Increased sodium channel expression has been reported after nerve injury and may contribute to hyperexcitability and associated abnormal sensation. C fibers have long response times and are slow to adapt. Because of this, they show summation of response to noxious stimuli in the presence of tissue injury, perhaps contributing to sensitization and hyperalgesia.
Inflammation results in an upregulation of SP, including in A-beta fibers. In this setting, A fibers may play a role in central sensitivity, perhaps contributing to hypersensitivity. A-beta fibers terminate in lamina III of the spinal cord where SP receptors are present. They may contribute to ongoing activation of SP expressing nociceptive neurons in chronic pain states.
Dorsal root ganglia
Sensory neuron cell bodies are located in the dorsal root ganglia (DRG). DRG neurons are classically pseudounipolar; one process extends into the peripheral nerve and the other process extends centrally, transmitting information through the dorsal root into the spinal cord. Each DRG contains thousands of unique sensory neuron cell bodies that are capable of encoding and then transmitting specific information gathered from external stimuli. Cells in the DRG are subclassified into peptidergic neurons and nonpeptidergic neurons. Peptidergic neurons contain peptides such as SP, calcitonin gene–related peptide (CGRP), and somatostatin. Each DRG neuron is surrounded by glial cell cytoplasm. The surface of the DRG neuron cell bodies are covered with perikaryal projections that are invested in the surrounding glial cytoplasm, increasing the surface area.
The soma of DRG neurons synthesizes and transports the substances needed for neuron functioning to the far reaches of the axon terminals, including receptors, ion channels, as well as molecules essential for synaptic transmission. The most common neurotransmitter that is synthesized by DRG cells is glutamate; however, many DRG cells also express SP, which facilitates pain transmission. There are no direct synaptic connections between DRG neurons but their activity is indirectly modulated. After injury, DRG neurons may become innervated by postganglionic axons in a neurotrophin-mediated process. C fibers may also modulate DRG sensitivity by altering intracellular calcium concentration affecting N-methyl-d-aspartate receptor configuration and sensitivity. Therefore, plastic reorganization of the DRG is one of the many mechanisms involved in pain sensitization and chronification.
Spinal cord
Most sensory fibers project from the DRG through the dorsal root and into the dorsal root entry zone (DREZ). There is evidence that the ventral roots also receive projections from unmyelinated fibers originating from DRG cells that are involved in sensation, including nociception, violating the Bell-Magendie law. At the DREZ, most unmyelinated and small myelinated axons project laterally to enter. Lissauer tract (see Fig. 1 ) fibers then extend vertically in this tract for several spinal segments before synapsing. Second-order neurons then cross to the opposite side, in the ventral decussation of the central canal of the spinal cord. The Lissauer tract contains both unmyelinated C fibers and myelinated A-delta fibers. A-delta fibers may ascend 3 to 4 segments in the Lissauer tract before finally terminating in lamina of Rexed I, II o , or V. C fibers typically ascend one segment before terminating, most often in Rexed lamina II.
Rexed lamina I, or the marginal layer, is composed of two main types of cells, nociceptive-specific neurons, and wide dynamic range neurons (WDRs). Nociceptive-specific neurons respond to noxious stimuli and express neuropeptides such as SP, CGRP, enkephalin, and serotonin. WDRs dynamic range neurons transmit both noxious and nonnoxious information. WDR display graded responses, proportional to the input stimulus by firing at a higher frequency. WDR neurons have a large receptive field, including a center that responds to both noxious and nonnoxious stimuli and surrounding area responds to noxious stimuli only. The large receptive fields of WDR neurons reflect its proposed integrative function that may contribute to allodynia through increased and disproportionate responsiveness to nonnoxious stimuli.
Lamina II (substantia gelatinous) may play a role modulating spinothalamic and spinobulbar projection neurons via its numerous inhibitory interneurons that primarily release GABA. C fibers and A-delta fibers are the primary afferent inputs of lamina II. Lamina II inhibitory neurons then arborize locally to other lamina, including I, II, III, and IV. There are very few projection neurons in lamina II. It has been hypothesized that disinhibition related to the functional loss of lamina II inhibitory neurons facilitates chronic neuropathic pain.
A-beta fibers project to lamina III and IV. Layer III also receives A-delta fiber mechanoreceptive input and may have sprouting of A-category neurons to lamina I and II after injury, possibly contributing to chronic pain and allodynia. Some layer IV neurons project to layer I, which contributes to integration of sensation. Lamina V receives input from A-delta and C fibers and neurons project to the spinothalamic tract (STT). Lamina V also contains a large number of WDR neurons with projections to reticular formation, periaqueductal gray, and medial thalamic nuclei, forming part of the mesial pathways that mediate the emotional characteristics of pain. Lamina X surrounds the spinal cord central canal. The function of this region is less well defined but likely is involved in visceral pain. It receives some direct input from A-delta fibers and may play a role in integration of nociception.
Dorsal horn (DH) nociceptive neurons form glutamatergic synapses that may also release neuropeptides, including SP, CGRP, vasoactive intestinal peptide (VIP), and somatostatin. Expression of these substances may be altered in the setting of injury, leading to sensitization, allodynia, and secondary hyperalgesia. WDR neurons have also been implicated in the development of these phenomena. Secondary hyperalgesia may occur due to central sensitization which is, in turn, mediated by abnormal connections between nonnociceptive neurons and centrally transmitting nociceptive pathways, as well as receptive field plasticity of DH neurons.
Spinothalamic pathways
The STT is oriented vertically along the ventrolateral portion of the spinal cord (see Fig. 1 ). It serves as the main conduit from the peripheral nerves to the brain by transmitting pain, temperature and deep touch signals to the thalamus. It receives projections from contralateral lamina I and IV-VI and is composed of two tracts: one dorsolateral, carrying axons from the superficial lamina, and the other ventrolateral, carrying axons from deeper lamina. Most projections are contralateral, although there is also an ipsilateral contribution. There is somatotopic organization of the STT with the lower limbs dorsolaterally and upper body and limbs positioned ventromedially. Cells projecting to ventral posterolateral nuclei originate from laminae I and V. Lateral STT neurons have small contralateral receptive fields and are most likely involved in sensory-discriminative aspects of pain signaling. Cells projecting to the medial thalamic nuclei originate from the deep dorsal laminae (ie, layer V; see above discussion) and ventral horn. The medial STT relays the motivational and affective components of noxious stimuli. These neurons have large receptive fields to support this purpose.
The paleospinothalamic tract projects to brainstem reticular formation, hypothalamus, and thalamic nuclei. Neurons in lamina VI, VII, and VIII have direct projections to reticular formation nuclei, some of which are bilateral. Neurons in lamina I, VII, and VIII project to pons. Neurons in the marginal zone, nucleus proprius, and lateral reticulated area project both to thalamus and hypothalamus. These neurons include both WDR neurons and nociceptive-specific neurons. They project to reticular formation, periaquaductal gray (PAG), and medial thalamic nuclei, and may also be involved in motivational-affective component of pain.
Most of the projections to the reticular formation arise from A fibers, although A and C fiber innervation has been described. Reticular formation response is proportional to noxious characteristics of the stimulus. The spinoreticular tract travels with STT in ventrolateral spinal cord. Fibers largely terminate in ventral medial portion of the medulla reticular formation, medullae oblongatae centralis, pars ventralis, and nucleus gigantocellularis. These cells have large receptive fields and exhibit heterotopic convergence. This tract functions to activate homeostatic mechanisms in brainstem autonomic centers as well as to provide input to antinociceptive systems and motivational-affective systems.
The spinomesencephalic tract originates in laminae I and IV-VI, with some contribution from lamina X and ventral horn. It projects to areas including periaqueductal gray, pretectal nuclei, red nucleus, Edinger-Westphal nucleus, and interstitial nucleus of Cajal. Neurons in this tract are nociceptive, and generally have large, complex receptive fields. They are involved in aversive behavior and orientation responses, and may activate descending antinociceptive systems.
The 1965 gate control theory of pain by Melzack and Wall proposed that there were three spinal cord systems involved in pain transmission: the substantia gelatinosa, dorsal column fibers, and central transmission cells in the DH ( Fig. 2 ). The substantia gelatinosa functions as a gate that modulates signals before they reach the brain. Large diameter fibers have inhibitory effects to “shut the gate” whereas small diameter fibers carrying noxious stimuli open the gate to pain transmission. In a simplistic view of this model, rubbing of the injured area promotes proprioceptive (ie, large diameter) fiber input and reduces pain perception. The gate-control theory has been criticized and revisited because it is inherently incomplete in its view of the nervous system. Nevertheless, it needs to be recognized for its key role in advancing the understanding of pain perception five decades ago and promoting the development of modern neurostimulation for pain management.
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