Spinothalamic and Spinoreticular Nociceptive Processing in the Spinal Cord

Neural injury triggers a range of processes affecting primary afferent receptors, their axons and cell bodies, as well as unleashing a complex immune response in central neurons and glial cells. Some of these processes facilitate healing and normative repair, for example, removal of cell and myelin debris, recruitment of antiapoptotic strategies, induction of axonal growth and sprouting, synaptic remodeling, and remyelination. In contrast, animal neurophysiologic studies demonstrate that some of these secondary effects have a maladaptive effect. Other well-characterized effects leading to chronic pain include central sensitization, ectopic impulse generation, reduced central inhibition, neuronal loss, and glial scarring.

PERIPHERAL SENSITIZATION

Various signaling molecules, including cytokines, chemokines, neurotransmitters, neurotrophic factors, and excess protons released due to tissue injury and inflammation, directly activate or sensitize nociceptors. Increased expression of ion channels involved in pain transmission is an important mechanism leading to development of peripheral sensitization. Peripheral nerve injury leads to increased expression of specific voltage-gated sodium (Nav) channels and transient receptor potential vanilloid receptor 1 (TRPV1) cation channels in the primary afferent terminals, in axonal sprouts at the lesion site, demyelinated areas, and adjacent unharmed nociceptors in the site of injury. These channel changes are significant for the expression of neuropathic pain.

Peripheral sensitization has several important rami-fications. It reduces the threshold for nociceptor activation, causes primary hyperalgesia (augmentation of normally noxious stimuli), and elicits spontaneous depolarization in primary afferent fibers (ectopic activity). Concomitantly, the peripheral injury enables these neurotrophic factors to migrate in a retrograde direction, thus affecting dorsal root ganglion and dorsal horn cells.

ECTOPIC IMPULSE GENERATION

The persistence of an unpleasant sensory and emotional experience in the absence of an identifiable ongoing stimulus is a characteristic feature of neuropathic pain. This spontaneous pain occurs as a result of ectopic action potential generation in primary afferent neurons. It may originate both from ectopic activity in nociceptors and from low-threshold large myelinated afferents due to central sensitization and altered connectivity in the spinal cord. Ectopic discharges originating in the cell body of injured primary afferents may cause antidromic stimulation, the release of mediators, and neurogenic inflammation at the periphery. Ectopic impulses can also generate along neuromas and from the sprouting of sympathetic efferents, forming “baskets” around dorsal root ganglion (DRG) cells. Sympathetic sensory coupling is believed to play an important role in the pathophysiology of inflammatory pain, complex regional pain syndrome (CRPS), diabetic neuropathy, postherpetic neuralgia, phantom limb sensations, and other conditions. Also deafferentation (loss of normal afferent input) can lead to sensitization and ectopic discharges in spinal cord or thalamic neurons.

Voltage-gated sodium channels are important influences on the generation of ectopic activity; their role in the pathogenesis of neuropathic pain is supported by the reversal of nociceptive effects by nonselective sodium channel blockers such as local anesthetics. Dorsal root ganglion neurons express several types of sodium channels that are either sensitive or resistant to tetrodotoxin.

CENTRAL SENSITIZATION

This is a form of activity-dependent synaptic plasticity that also has a pivotal role in the pathophysiology of neuropathic pain. It is responsible for secondary hyperalgesia characterized as increased pain intensity to noxious stimuli experienced beyond the distribution of the inciting area of injury, and tactile allodynia, defined as pain due to a normally innocuous stimulus. Central sensitization represents amplification in the functional status of neurons and nociceptive circuits, caused by reduced inhibition, increased membrane excitability, and enhanced synaptic efficacy. Because these changes appear in the central nervous system (CNS) neurons, the perceived pain does not reflect the presence, intensity, or duration of peripheral stimuli. On the contrary, it corresponds to a pathologic state of responsiveness or increased activity of the nociceptive system.

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