Neuropathic pain results from the damage of neurons or nerves through trauma, poisoning, or metabolic diseases. Damage of peripheral nerves through mechanical injury or metabolic diseases is probably the most frequent cause of neuropathic pain. As in inflammatory pain, the initial focus of research was on peripheral processes. It could be demonstrated that damaged nerves become spontaneously active (Sheen and Chung 1993) and that irregular electric contacts may be formed between nerve fibers (e.g., Seltzer and Devor 1979). Both processes probably explain some aspects of neuropathic pain, but they cannot fully account for all aspects of neuropathic pain syndromes. Central processes have therefore become the center of present research. During the last decade, a number of cytokines and other mediators have been identified that contribute to the development of pain after peripheral nerve injury (Sommer 2003). However, insight into how these mediators affect sensory information processing has only very recently been gained.
One of the most unpleasant sensations in neuropathic pain is the painful sensation of stimuli that are normally not sensed as painful, such as light touch. A consistent finding of many studies addressing this issue appears to be a loss of the inhibitory tone in the spinal cord dorsal horn. Although it might be speculated that the production of cytokines in the CNS after peripheral nerve trauma stimulates prostaglandin production, a significant contribution of cyclooxygenase-2 to neuropathic pain appears rather unlikely (e.g., Broom et al. 2004). Mice deficient in the EP2 receptor develop normal hyperalgesia and allodynia in the chronic constriction injury model of neuropathic pain, although they completely lack the pronociceptive effects of spinally administered prostaglandin E2 (Hosl et al., in prepara tion). However, several recent publications suggest that relief from GABAergic or glyciner-gic inhibition of spinal nociceptive neurons through prostaglandin-independent mechanisms contributes to neuropathic pain. Possible actions include an inhibition of glycine or GABA release from inhibitory interneurons; a reduction in the transmembrane chloride gradient, rendering inhibition by glycinergic and GABAergic synaptic input less efficient; and a loss of inhibitory innervation due to a selective death of GABAergic or glycinergic interneurons.
There is indeed experimental evidence for all three possibilities, but their contribution to pain sensitization is far from being fully clear. A reduction in the transmembrane chloride gradient in dorsal horn neurons following peripheral nerve injury has recently been reported by Coull et al. (2003). Peripheral nerve trauma induces a transsynaptic reduction in the expression of the potassium chloride exporter KCC2 in dorsal horn neurons and thereby shifts the chloride equilibrium potential to more depolarized values. This shift reduces the inhibitory effect of GABA and glycine receptor activation, yet it might even cause glycinergic or GABAergic input to become excitatory.
Another extensively discussed report suggests that peripheral nerve injury induces a specific loss of spinal inhibitory GABAergic neurotransmission in the dorsal horn of rats in the chronic constriction injury model and the spared nerve injury model of neuropathic pain (Moore et al. 2002a). This original report has suggested that the loss of GABAergic input was due to the selective apoptotic death of GABAergic interneurons. Subsequent studies have, however, shown that such a loss is at least unnecessary for the development of thermal hyperalgesia in the chronic nerve injury model of neuropathic pain (Polgar et al. 2003, 2004).
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