Following noxious chemical, mechanical, or thermal stimulation, transduction occurs at the peripheral sensory nerve terminal through a poorly understood process, causing depolarization of the distal nerve fibers and transmission of nociceptive impulses up the sensory axons to the dorsal root ganglion (DRG) and dorsal nerve roots. Axons carrying nociceptive information are divided into three primary groups: (1) the heavily myelinated, rapidly conducting, intermediate-diameter beta fibers; (2) the finely myelinated, slower conducting, small-diameter A-delta fibers; and (3) the unmyelinated, very slowly conducting, very-small-diameter C fibers. Local factors at the site of injury may sensitize nociceptors and cause hyperalgesia, including potassium leaked from damaged cells, histamine, and bradykinin, whereas prostaglandin and leukotriene formation concurrently cause vasodilatation, local edema, and erythema.

A normally propagated nociceptive action potential may also rebound antidromically through other axonal branches at a site of injury, resulting in the release of substance P from the distal sensory nerve terminal. Substance P activates other C fibers and contributes to the release of histamine, further promoting nociception, vasodilation, and enlarging the region of hypersensitivity. Substance P also acts as a nociceptive neurotransmitter in the dorsal horn of the spinal cord, exciting the relay neurons that modulate pain transmission.

Sensory axons carrying nociceptive impulses project to the spinal cord via the DRG and terminate in the dorsal horn. There, Rexed laminae I, II, and V play a role in modulating nociceptive transmission. Layer I, the marginal zone, caps the top of the dorsal horn and the A-delta nociceptors largely terminate here. Most lamina I cells are nociceptive-specific, responding only to noxious stimuli, and ultimately project to the contralateral midbrain and thalamus. The majority of C-fiber nociceptors terminate in lamina II (i.e., substantia gelatinosa). Very few laminae-II neurons project to sites rostral to the spinal cord, instead forming interneuronal connections that modify input from the primary sensory neurons. Lamina V receives some direct input from the A-delta neurons, but the receptive fields of the neurons in this lamina are larger than those in the lamina I, suggesting more neuronal convergence at this level, and some dendrites from laminae V extend dorsally into laminae I and II. Cells in the deeper layers of the spinal cord gray matter have extremely complex receptive fields and wide areas of cutaneous input, with some input from deeper tissues.

Many nociceptive impulses ultimately pass contralaterally, across the spinal cord through the anterior commissure, to the spinothalamic tract, before ascending to brain stem targets, including the reticular formation in the rostral medulla and the periaqueductal gray matter in the dorsal midbrain. Most of the spinothalamic neurons ultimately ascend to the ventroposterolateral nucleus of the thalamus, although they may branch to provide input to these brain stem targets. However, some axons terminate solely in these bulbar regions, which then send projections to thalamic nuclei.

The periaqueductal gray matter, the reticular formation, and the raphe magnus nucleus also harbor neurons containing endorphins or having endorphin receptors. Endorphins are endogenous chemical transmitters whose receptors may also be activated by morphine and other exogenous narcotics; this collection of neurons is known as the enkephalinergic system. After synapsing in the thalamus, a final group of neurons convey primary nociceptive information through the posterior limb of the internal capsule to the postcentral gyrus. Many nociceptive axons also project to a much wider area, the full range of which has not been fully defined.

The sensation and the subjective experience of pain are produced by a complex series of interactions. Transmission of nociception in spinal neurons depends not only on input from peripheral nociceptive neurons but also on input from nonnociceptive primary afferents as well as modulation at several levels. Enkephalinergic neurons play a critical role in the modulation of nociceptive input, extending from the cortex and hypothalamus through the periaqueductal gray matter of the midbrain and the rostral medulla to the dorsal horn of the spinal cord. Nociceptive, cortical, and other inputs activate neurons in the reticular formation and the raphe magnus, which then descend to the substantia gelatinosa (Rexed lamina II) in the dorsal horn of the spinal cord, to inhibit nociceptive input from peripheral neurons, thereby diminishing pain.

Unlike the discriminative somatosensory experience, the affective component of pain varies considerably between individuals and may help explain the substantial differences in pain tolerance in the general population. Central pathways proposed as mediators of the affective experience of pain include the reticular formation and its projections to the thalamus as well as the medial thalamic nuclei and their projections to the frontal lobes. The discharge of neurons within the reticular formation correlates with escape behavior in animals, and frontal lobe lesions (e.g., frontal lobotomy) as well as bilateral medial thalamic lesions produce subjective indifference to pain in humans, despite normal somatosensory discrimination. Psychological factors, including the anxiety level, unpleasant memories of physically painful experiences, the anticipation of imminent physical injury or possible death, and others may also bear on our perception of pain. Both psychological factors and the physiologic modulation of the nociceptive impulse are influenced by changes in serotonergic activity.

Transection of a peripheral nerve induces retrograde shrinkage of both myelinated and unmyelinated axons and reduced conduction velocities. Axonal sprouting from the proximal nerve stump is a normal reaction to such injury, and these sprouts grow toward the distal nerve stump in an attempt to restore axonal continuity. Within 1 to 2 days, multiple unmyelinated sprouts appear and grow from transected axons. If these sprouts fail to enter a Schwann cell tube in the distal nerve segment, they curl to form a mass containing fibrous tissue, blood vessels, clusters of unmyelinated axons, and Schwann cells, known as a neuroma. Division of an entire nerve trunk with prevention of regeneration (e.g., amputation) yields a nerve-end neuroma, whereas total division with partial regeneration (e.g., surgical nerve repair) may create a neuroma-in-continuity at the site of the anastomosis. Trauma over the length of a nerve, even without transection (e.g., stretch injury), may damage small axon fascicles or individual axons at multiple levels, creating disseminated microneuromas. Neuromas may also appear following crush injury. Unfortunately, neuroma formation favors nociceptive afferents.

Neuromas are a source of both spontaneous and evoked electrical discharges, as indicated by recording from dorsal root filaments with the injured nerve at rest. These discharges increase with mechanical stimulation at the site of the neuroma and are more likely to affect sensory rather than motor or autonomic fibers. Chronic discharges, particularly, appear to originate primarily in the C fibers. Ectopic neuropacemakers remain near thresholds for repetitive firing and often generate repetitive afterdischarges following a single depolarization. This activity may be due to the high density of sodium channels, originally destined for the transected distal axon, that accumulate in the stump neuroma, enhancing sodium influx and chronically lowering the membrane potential toward the depolarization threshold. Close contact between the disorganized axonal sprouts within the neuroma may also cause current to be passed laterally from one axon to another, a short circuit called ephaptic transmission. Recurrent after discharges and other sustained activity may also result from the cyclic passage of current back and forth in a loop between two ephapses (i.e., circus propagation, as seen in some cardiac arrhythmias).

Faulty axonal regeneration and ephapse formation may also appear in nerves chronically injured by demyelination or axonal degeneration, in the absence of external trauma. Spontaneous discharges may be induced not only by mechanical stimulation but also by heat, cold, ischemia, chemical irritation, and metabolic stimuli. Mechanical stimulation may induce a burst of discharges and afterdischarges, and heating and cooling modulate discharge rates and patterns. Peptides and other neuroactive substances, especially α-adrenergic agonists, increase activity in experimental neuromas.

Ectopic pacemaker activity has been recorded in the phantom limb syndrome and may explain the hypersensitivity to heat and
cold in that syndrome. Many of the core features of painful neuropathy and neuralgia, such as spontaneous electric, burning, and aching dysesthesias and hyperesthesia, could also be related to ectopic discharges. Sensitivity to mechanical stimulation in neuralgia or compressive mononeuropathy, which may provoke pain long outlasting the inciting stimulus, may result from the repetitive discharges and afterdischarges provoked by neuroma compression.

Although the aforementioned peripheral mechanisms play a role in neuropathic pain, central mechanisms are also important and may predominate in chronic peripheral nerve injury. The failure of measures designed to interrupt peripheral input from the painful region to fully relieve the pain of phantom limb syndrome, including pharmacologic blockade of the damaged nerve proximal to the site of injury, dorsal rhizotomy, and even spinal and other CNS block illustrates the confounding influence of central mechanisms. After peripheral nerve injury, the aberrant rerouting of impulses within the brain and spinal cord may result in the diversion of impulses from nonnociceptive pathways to nociceptive pathways. This has been demonstrated experimentally in mapping studies of the spinal cord and brain, done before and after transection of a single peripheral nerve in one limb. Initially, the central pain pathways serving the denervated area fall silent, but electrical activity gradually resumes within a few days. Some of this activity may be induced by nonnociceptive stimulation of areas supplied by an uninjured nerve that is remote from the dermatomes supplied by the injured nerve, suggesting spread of nonnociceptive impulses from normal routes into nociceptive pathways that were previously supplied by the injured nerve.

This phenomenon, known as somatotopic reorganization, could result from limited axonal sprouting over short distances within the spinal cord, and the formation of new synapses, prompted when primary sensory input is interrupted. Another explanation is that the loss of primary afferent input to a central spinal pathway following peripheral nerve injury may unmask previously quiescent synapses. These synapses, supplied by nearby spinal axons serving sensation in other regions, enable surreptitious stimulation of the denervated pathway, and produce phantom sensations, including pain.

Afferent fiber discharges may trigger cell death of neurons in the dorsal horn, where inhibitory interneurons are concentrated, possibly through an excitotoxic mechanism. This may result in increased pain transmission.

C-fiber afferents release glutamate and synapse on second-order neurons in the dorsal horn to have excitatory effects on glutamate synapses at AMPA receptors, which results in depolarization of the membrane. This depolarization releases the inhibition of the NMDA receptor by the magnesium ion, and there is an influx of calcium. Second-order neurons are gradually depolarized and responses are amplified, changing the response of neurons to subsequent input.

Two processes that are distinct occur at the dorsal horn, which are designated “windup” and “central sensitization.” Windup results from repetitive C-fiber firing at low frequencies that results in a progressive buildup of the amplitude of the response of the dorsal horn neuron, only during the repetitive train. Central sensitization is an abnormal sensitivity with a spread of hypersensitivity to uninjured sites and pain resulting from stimulation of low-threshold Aβ mechanoreceptors. Central sensitization follows a brief highfrequency input, and the increased response to subsequent inputs may be prolonged, after the high-frequency input ceases. Both can be blocked by NMDA receptor antagonists. Central sensitization can result from windup. This is a result of the calcium influx through the NMDA receptor following depolarization of the dorsal horn membrane. The intracellular calcium activates a number of kinases, among which protein kinase C (PKC) is likely important. PKC enhances the NMDA receptor, which results in subsequent glutamate binding of the NMDA receptor generating an inward current. Although windup can result in central sensitization, it is not necessary for central sensitization to occur.

Similar observations were noted long ago by Denny-Brown, who described an enlarged and hypersensitive dermatomal region in primates after severance of the surrounding nerve roots distal to the DRG, compared to section proximal to the DRG. This suggested plasticity of the dorsal horn neurons secondary to input from the DRG.