Mechanisms Of Pain In Peripheral Neuropathy

The Peripheral Neuropathy Solution

Peripheral Neuropathy Solution By Dr. Randall Labrum

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Normally, impulses are generated at sensory nerve terminals or in cell bodies. In pathological states, impulses may arise from the damaged part of the axon and propagate toward both the central nervous system and the periphery. Such ectopic discharges may also arise from local patches of demyelination, neuromas, and soma in the dorsal root ganglia. The mechanisms underlying neuropathic pain have been reviewed elsewhere.1,2,3 Persistent primary pain is attributed to activity in noci-ceptor C-fibers, which in turn leads to central changes. Similar activity in large myelinated A-fibers may produce paresthesiae, and they mediate secondary allodynia and hyperalgesia in the setting of central changes. The mechanism of ectopic discharges is attributed to changes in the expression and distribution of membrane ion channels, especially sodium channels. Two types of sodium channel are found in sensory neurons. The first are sensitive to a neurotoxin derived from the puffer fish - tetrodotoxin (TTX) - and are found in all sensory neurons. The second types are resistant to tetrodotoxin, and are found predominantly in nociceptor sensory neurons. The TTX-resistant channels have much slower activation and inactivation kinetics than TTX-sensitive channels and are implicated in pathological pain states. Channel proteins are synthesized in the cell body and transported by axoplasmic mechanisms to their peripheral targets, which include nodes of Ranvier and axon terminals. Accumulation of sodium channels at sites of ectopic impulse generation has been postulated to play a role in the ectopic discharges.4 Changes in the distribution of two TTX-resistant channels - Nav 1.8 (SNS/PN3) and Nav 1.9 (NaN/SNS2), preferentially expressed in nociceptors - have been identified in sensory neurons.5,6,7 Nav 1.8 (SNS/PN3) has been shown to accumulate preferentially at the site of nerve injury and also in nerve fibers in skin from patients with mechanical allodynia and hyperalgesia,5 and appears to be an attractive target for the development of novel sensory neuron-specific sodium channel blockers for mechanism-based analgesia. Changes in other ion channels have also been implicated in the pathogenesis of pain. Specific potassium channels have been found to be decreased in the rat dorsal root ganglion after axotomy.8 Thus, changes in potassium and sodium channel expression following axonal injury have the potential to change the electrical excitability of dorsal root ganglion (DRG) neurons and lead to chronic pain states.8 Other mechanisms contributing to pain include ephaptic transmission, nociceptor sensitization, adrenergic che-mosensitivity of regenerating axons, and nerve trunk inflammation.

There are many sensory symptoms of peripheral nerve disorders, such as their spread beyond the territory of the injured nerve, which could not be explained solely in terms of alterations in peripheral functions. It is now well established that peripheral stimuli can lead to central changes in spinal cord, including wind up, disinhibition, and sensitization,9,10 and altered rostral processing.1,2,3 These mechanisms need to be understood in molecular terms, and targeted in association with peripheral strategies.

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