Postulated mechanisms for pathology in the pathways that lead to neuropathic pain

What are the postulated mechanisms for pathology in the pathways that lead to neuropathic pain?

Experimental evidence exists for multiple mechanisms of neuropathic pain, and different mechanisms may be relevant in different neuropathic pain conditions. These mechanisms can include peripheral sensitization, central sensitization, deafferentation pain, and alterations in descending pain modulation.

  • • Peripheral nerve disease may result in spontaneous discharges and, as a result, paresthesias or sharp, shooting pains, via several mechanisms. For example, reduced metabolic capacity may result in difficulty maintaining the sodium-potassium pump, leading to spontaneous depolarization. Injured axons can also develop a pacemaker capability, also resulting in spontaneous depolarizations in the absence of external stimuli. Frequent peripheral stimulation or depolarization can result in phosphorylation of peripheral receptors, increasing their sensitivity, increased receptor translation and hence receptor density, increased sensitivity to catecholamines, and activation of “silent nociceptors” that are only active in pathological states.
  • • Increased firing of primary afferent neurons may result in sensitization of dorsal horn neurons via several mechanisms. These include removal of magnesium-mediated blockade of -methyl- d -aspartate (NMDA) receptors, increased calcium and sodium channel expression, and phenotypic switch, a postulated mechanism in which dorsal horn neurons develop de novo ability to respond to nociceptive input. There is also evidence that glial activation in the spinal cord can sensitize dorsal horn neurons. As a result of these plastic changes in afferent neurons, a given stimulus, such as skin warming to a non-noxious degree, can result in an inappropriately high firing frequency, which will in turn be interpreted as indicating the presence of a noxious stimulus.
  • • Deafferentation pain is a postulated mechanism of neuropathic pain in the setting of loss of afferent input to thalamus or cortex. It has been demonstrated that in the absence of afferent input, thalamic neurons can develop spontaneous depolarizations. In addition there is some evidence that deafferentation via amputation may lead to alterations in cortical representation of the limb that is associated with the sensation of phantom limb pain (PLP). Thus there are several potential mechanisms of pain due to loss of afferent input, but it is a well-recognized phenomenon in the setting of thalamic or cortical sensory stroke, spinal cord injury, severe ganglionopathy, or amputation.
  • • Finally, several experimental paradigms have demonstrated alterations in conditioned pain modulation, or descending modulation of pain, in recognized neuropathic pain states as well as other chronic pain states such as fibromyalgia. The degree to which descending modulatory pathways contribute to neuropathic pain states is not well understood, but there is good evidence that pharmacologic manipulation of this pathway (principally norepinephrine reuptake inhibition) can alleviate neuropathic pain.

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