Mechanisms of Neuropathic Pain

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In terms of the experience of pain, it must be remembered that noxious stimuli are not just passively conducted from the periphery to the central nervous system as a large number of mechanisms serve to attenuate, magnify, and extend the organism's perception and experience of pain. The current understanding of the pathogenesis of neuropathic pain suggests that multiple mechanisms appear to mediate the symptoms of neuropathic pain including, but not limited to, temporal and spatial summation, recruitment of inactive neurons, peripheral and central sensitization, phenotypic switching, and central neuronal reorganization. Although a systematic review of the pathophysiological mechanisms underlying neuropathic pain is beyond the scope of this chapter, they have been reviewed extensively within recent years by others in the field (Baron 2000, Besson 1999, Pace et al. 2006, Pasero 2004, Waxman 2006).

Normal activity in the peripheral nervous system involves a reciprocal balance between neuronal excitation and inhibition. Pain arises when the balance shifts toward excitation, and inhibition is altered. Damage to peripheral nerves results in hyperexcitability in the primary afferent nociceptors (peripheral sensitization) that leads to hyperexcitability in central neurons (central sensitization) and the generation of spontaneous impulses within the axon, as well as the dorsal root ganglion of the peripheral nerves. When the nerve is able to repair itself, the sensitization resolves; however, if the nerve is unable to effect this repair or the insult continues, continued sensitization and altered processes in nociceptors lead to further generation of spontaneous symptoms.

Unresolved peripheral nerve injury causes a multitude of changes in gene transcription and activation of various kinases and proteins involved in the transmission and amplification of noxious stimuli, including enhanced N-methyl-D-aspartate (NMDA) receptor activity (Wilson et al. 2005, Ultenius et al. 2006). At the cellular level these alterations can lead to the formation of new channels, upregulation of certain receptors and downregulation of others, and altered local or descending inhibition which are some of the biological features that can contribute to hyperexcitability, factors assumed to be a sine qua non for chronic pain (Waxman et al. 2000, Matthews et al. 2007, Cummins et al. 2007).

It is the altered expression of these channels that results in neurons becoming hyperex-citable and generating ectopic activity, which is thought to lead to the genesis of spontaneous and paroxysmal pain. Beyond this, neuronal hyperexcitability has a wide spectrum of secondary manifestations including expansion of neuronal receptive fields, change of modality to which neurons respond, recruitment of silent neurons or circuits, and a neuronal reorganization in the dorsal horn and within the central nervous system.

Additionally, non-neuronal cells, which consist of microglia, astrocytes, and oligoden-drocytes, also become activated in the spinal cord on the side of a nerve injury in both the dorsal and ventral horns (Coyle 1998). These cells may then begin to express purinergic receptors which allow them to be activated by various neurotransmitters including adenosine triphosphate (ATP) and following activation, release various proinflammatory and prono-ciceptive cytokines, such as interleukin-1 (IL-1), tumor necrosis factor alpha (TNF-a), and neurotrophins, including brain-derived neurotrophic factor, which in turn modulate and/or amplify nociceptive transmission contributing to the sensitization and maintenance of neuropathic pain (Coyle 1998, Hains and Waxman 2006, Zhao et al. 2007, Terayama et al. 2008).

It is not entirely unexpected that a genetic component may also contribute to the individual experience of neuropathic pain and may contribute to the diverse phenotype of individuals with apparently similar lesions, some of whom develop chronic neuropathic pain and many others do not. In the past many genes have been identified that contribute to the development of non-neuropathic pain conditions; however, only one gene, thus far - GTP cyclohydrolase 1 (GCH1) - has been implicated specifically in neuropathic pain (Tegeder et al. 2006). In a recent investigation, Campbell et al. (2009) analyzed the association of five GCH1 single nucleotide polymorphisms (SNPs) with ratings of pain induced by the use of high concentration (10%) topical capsaicin applied to the skin of 39 normal human volunteers (Campbell et al. 2009). Each of the GCH1 polymorphisms was associated with lower pain ratings. When combined, three of the five accounted for a surprisingly high 35% of the inter-individual variance in pain ratings. They conclude that SNPs of the GCH1 gene previously identified profoundly affect the ratings of pain induced by capsaicin. While these recent data suggest a "protective" (i.e., less pain) haplotype in the GTP cyclohydrolase (GCH1) gene, other research has failed to confirm this association and this remains an area of active ongoing investigation (Kim and Dionne 2007).

It is, therefore, not surprising that given the multiplicity of cellular alterations occurring subsequent to nerve injury, a host of neuroplastic changes take place in which the somatosensory information can be distorted in several ways secondary to the reorganization of all of the structures participating in the transduction, transmission, and translational processing of noxious information.

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