THE role of different classes of afferents in neuropathic pain is a controversial issue. The debate revolves around two questions: (1) What is the role of injured and uninjured afferents in neuropathic pain? (2) What is the role of myelinated and unmyelinated fibers? Although it is commonly accepted that sensitization of central pain-processing neurons is involved in neuropathic pain, it is unclear what afferents induce and maintain central sensitization under neuropathic conditions. A better understanding of the changes in injured and uninjured afferents after nerve injury is needed to improve strategies for the treatment of chronic pain. In this issue of Anesthesiology, Sapunar et al. 1describe the electrophysiologic properties of isolated neurons from the L4 and L5 dorsal root ganglia after an L5 spinal nerve injury in rats. An advantage of the L5 spinal nerve ligation (SNL) model2is that injured and uninjured neurons reside in different dorsal root ganglia, but their axons commingle in the sciatic nerve and target tissue (fig. 1). Like other animal models of neuropathic pain, SNL results in behavioral signs of spontaneous and stimulus evoked pain (i.e. , mechanical and thermal hyperalgesia).
What is the evidence that injured afferents are to blame for neuropathic pain? An obvious clinical example comes from patients with a traumatic nerve lesion that resulted in the development of a neuroma: Touching or tapping the neuroma produces paraesthesia and pain. Injection of local anesthetics at the site of the nerve injury may relieve not only ongoing pain but also mechanical hyperalgesia in the surrounding skin.3Neuroma resection and relocation of the proximal nerve end may also produce pain relief in these patients. In animal neuroma models, ectopic mechanical sensitivity, thermosensitivity, and chemosensitivity as well as spontaneous activity are found in injured myelinated and unmyelinated afferents,4and this is thought to be the neuronal basis of pain generated from neuromas in humans.
Similar to other lesions of peripheral nerves, SNL results in neuroma formation. After SNL, however, development of spontaneous activity in injured afferents is restricted to myelinated nerve fibers, because it seems to be absent in injured unmyelinated afferents.5The article by Sapunar et al. provides additional evidence that myelinated (but not unmyelinated) injured (but not uninjured) neurons develop enhanced excitability. Input from injured afferents seems to be important for the neuropathic pain behavior because application of tetrodotoxin to the L5 dorsal root ganglion reduces signs of mechanical hyperalgesia after SNL6and because application of neomycin or gadolinium to the proximal, cut end of the L5 spinal nerve immediately after injury prevents or diminishes signs of mechanical hyperalgesia.7Signs of mechanical hyperalgesia develop within hours after the lesion, similar to development of spontaneous activity in injured myelinated afferents, suggesting a causal link between the two.5Studies that have used dorsal rhizotomies in the SNL model to directly investigate the role of injured afferents in neuropathic pain have unfortunately led to contradictory results: Some found reversal of neuropathic pain behavior,8whereas others reported that an L5 dorsal rhizotomy did not prevent or reverse mechanical hyperalgesia.9The interpretation of these data are complicated by the finding that dorsal rhizotomy by itself can produce signs of neuropathic pain.10
Is there a role for injured, unmyelinated afferents in neuropathic pain? Evidence for a role comes from the observation that artemin reversed the behavioral signs of neuropathic pain11and normalized the SNL-induced changes in small L5 DRG neurons as well (e.g. , IB4 binding; expression of P2X3, CGRP, galanin, and NPY). Artemin is a member of the glial-derived neurotrophic factor family, and the accessory protein GFRα3, through which it signals, is predominantly expressed in unmyelinated, nociceptive primary afferent neurons.12
The presence of mechanical hyperalgesia after an L5 ganglionectomy13or an L5 ventral rhizotomy13,14is direct evidence for a role of uninjured afferents in neuropathic pain. Both manipulations exclude injured primary afferents as contributors to neuropathic pain because either the soma of the injured neuron is removed (ganglionectomy) or only motor efferents are injured (ventral rhizotomy). Furthermore, there is accumulating indirect evidence for a role of uninjured afferents in neuropathic pain. The following evidence was mainly but not exclusively obtained in the SNL model. Uninjured afferents develop adrenergic sensitivity15,16and an increased sensitivity to tumor necrosis factor α.17Uninjured afferents also up-regulate neuropeptides,18,19neurotrophic factors,20,21and signal transduction proteins (e.g. , TRPV1).22After L5 spinal nerve injury, the percentage of cold-sensitive neurons in the L4 DRG is increased,23and the responsiveness of uninjured, unmyelinated L4 afferents to natural stimuli is augmented.24NaV1.8, a tetrodotoxin-resistant sodium channel, is redistributed into the peripheral axons of uninjured afferents after spinal nerve injury.25Antisense oligonucleotides directed against NaV1.8 reverse neuropathic pain in the SNL model.25Morphologic studies furthermore suggest that uninjured, unmyelinated afferents sprout into the “injured” L5 spinal cord segment.26,In vivo recordings from the L4 dorsal root, L4 spinal nerve, or peripheral primary afferents have shown that uninjured myelinated and unmyelinated nerve fibers develop spontaneous activity after spinal nerve injury.16,27,28Spontaneous activity in uninjured, unmyelinated nociceptive afferents was present in rats within 24 h after SNL. Although the rate of discharge was low, approximately half of the unmyelinated fibers showed spontaneous activity; therefore, this low rate of discharge could be sufficient to induce central sensitization. Microneurographic recordings from unmyelinated fibers in patients with neuropathic pain reveal that mechanically insensitive afferents become spontaneously active and responsive to mechanical stimuli.29
The mechanisms inducing changes in uninjured afferents are not understood. Because intact axons commingle with degenerating axons, factors associated with Wallerian degeneration may be involved. Neuropathic pain behavior is reduced in situations where Wallerian degeneration is delayed or diminished.30,31Wallerian degeneration leads to the generation of multiple factors, some of which are classic inflammatory mediators known to excite or to sensitize nociceptive afferents. Some of these mediators are released within hours after peripheral nerve lesion32and therefore could induce the early changes seen in uninjured L4 afferents after L5 SNL.
Changes in uninjured afferents may also occur and contribute to neuropathic pain accompanying infectious (e.g. , human immunodeficiency virus, herpes zoster) and metabolic (e.g. , diabetes) diseases or in neuropathy due to drug treatment (e.g. , vincristine). In neuropathic pain, several etiologies may be at work simultaneously: the primary disease (e.g. , trauma, diabetes) and secondary events (e.g. , Wallerian degeneration). The relative importance of these factors to the development and maintenance of neuropathic pain remains to be resolved.
* Johns Hopkins University, Baltimore, Maryland. firstname.lastname@example.org