The calcium channel ␣ 2 ␦-1 subunit is a structural subunit important for functional calcium channel assembly. In vitro studies have shown that this subunit is the binding site for gabapentin, an anticonvulsant that exerts antihyperalgesic effects by unknown mechanisms. Increased expression of this subunit in the spinal cord and dorsal root ganglia (DRG) has been suggested to play a role in enhanced nociceptive responses of spinal nerve-injured rats to innocuous mechanical stimulation (allodynia). To investigate whether a common mechanism underlies allodynic states derived from different etiologies, and if so, whether similar ␣ 2 ␦-1 subunit up-regulation correlates with these allodynic states, we compared DRG and spinal cord ␣ 2 ␦-1 subunit levels and gabapentin sensitivity in allodynic rats with mechanical nerve injuries (sciatic nerve chronic constriction injury, spinal nerve transection, or ligation), a metabolic disorder (diabetes), or chemical neuropathy (vincristine neurotoxicity). Our data indicated that even though allodynia occurred in all types of nerve injury investigated, DRG and/or spinal cord ␣ 2 ␦-1 subunit up-regulation and gabapentin sensitivity only coexisted in the mechanical and diabetic neuropathies. Thus, induction of the ␣ 2 ␦-1 subunit in the DRG and spinal cord is likely regulated by factors that are specific for individual neuropathies and may contribute to gabapentin-sensitive allodynia. However, the calcium channel ␣ 2 ␦-1 subunit is not the sole molecular change that uniformly characterizes the neuropathic pain states.Peripheral nerve injury can lead to a neuropathic pain state, termed tactile allodynia, in which innocuous tactile stimulation elicits pain behavior. Spinal administration of gabapentin, a novel anticonvulsant that binds to the ␣ 2

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These data demonstrate that upregulation of glial TNF-alpha is associated with the expression of the p55 receptor on adjacent neurons. This association may have induced the expression of several cytokines and immediate early genes in dorsal root ganglion and spinal cord neurons via the TNF signaling pathway. These findings may be related to the pathogenesis of neuropathic pain.

This review article on the degeneration and regeneration of peripheral nerve fibers was presented as a Plenary Lecture at the 2001 meeting of the Peripheral Nerve Society. It is accompanied by a reprint of Augustus Waller's 1850 article, which gave rise to the pathologic process termed Wallerian degeneration. This review is focused on the role of neuroinflammation in Wallerian degeneration and how immune mediators contribute to both axonal degeneration and regeneration. Similarities and differences between the PNS and CNS in terms of inflammation and microglial activation after nerve injury are discussed, and point towards progress in understanding the failure of nerve fiber regeneration in the CNS.

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