In normal primary afferent neurons, it is rare for firing threshold to be reached without the input of a stimulus.
Table 1.2 An overview of pathophysiological events which are likely to be related to the generation of neuropathic pain.
Central nervous system
Sensitization and spontaneous activity in sensory neurons Abnormal ion channel expression Altered neuronal biochemistry
Sensory neuron apoptosis Immune-neuronal interactions
Loss of trophic support for neurons
Spinal reorganization Changes in inhibitory systems Glial cell activation Alterations in descending modulation Cortical reorganization
However, following a nerve injury, many injured axons and associated cell bodies in the DRG undergo an increase in their intrinsic electrical excitability. As a result they begin to generate impulse discharge spontaneously or with only minimal stimulation linked to the injury site.35 This has been termed ectopic discharge36 and has also been demonstrated in humans, suffering from neuropathic pain.37 Ectopic discharge originating in the peripheral nervous system (PNS) can result in excess spontaneous and stimulus-evoked electrical impulses feeding into the central nervous system (CNS) (Figure 1.4).39 Ectopic afferent activity may also trigger and maintain central sensitization amplifying the afferent signal from the remaining afferents that innervate the partly denervated skin and deep tissues leading to tenderness to touch ("tactile allodynia'').38
Furthermore, oscillations in resting membrane potential in primary sensory neurons are thought to contribute to their ectopic potential. A small number of A-fibers (10 percent) exhibit subthreshold membrane oscillations in their resting state or under depolarization conditions. An increase in these oscillations is observed in sensory neurons from axotomized rats.40 Due to the sensitivity of such oscillations to tetrodotoxin (TTX), a role for changes in sodium channel function in the nerve in DRG has been proposed. Increases in oscillations lead to increased ectopic activity in these neurons that may underlie paresthesiae, dysesthesiae, as well as frank pain.
Abnormal discharges may also arise at the site of nerve injury, at other points along the nerves or in the cell body in the DRG.41 Myelinated and unmyelinated primary afferent axons may become spontaneously active after nerve injury.38'42 Wallerian degeneration of an injured, spontaneously active myelinated fiber allows cross-excitation of neighboring unmyelinated fibers (termed "ephaptic transmission'') inducing ectopic discharge even in an uninjured axon.43,44 Such ectopic discharge present in both low-threshold mechanoreceptors and in noci-ceptors may contribute to allodynia and hyperalgesic components of neuropathic pain.
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