Neuropathic pain results from damage to an afferent pathway that can be the result of a disease, trauma, or dysfunction.
Ectopic nerve activity/Peripheral Sensitization
This mechanism is responsible for pain sensed in the absence of external stimuli. Spontaneous nerve activity has been shown in both the injured nerve as well as uninjured neighboring nerves. This spontaneous activity is thought to be related to an increase in voltage gated sodium channel expression. This increased expression allows for decreased activation thresholds and increased membrane excitability. Additional expressional changes of other channels (i.e. K+) are also likely to occur but are less studied at this point.
Protein regulation is also altered with nerve damage. For example, a protein TRPV1 (transient receptor protein V1) that is activated at noxious stimuli around 40 Celsius is down regulated at injured fibers but upregulated at nearby uninjured fibers. This may decrease the activation temperature (i.e. to 38 Celsius, near body temperature) and result in the sensation of noxious heat/burning stimuli near the site.
Regular discharge from peripheral nerves causes release of excitatory neuropeptides and amino acids in the dorsal horn. This leads to phosphorylation of NMDA and AMPA receptors and expression of voltage gated sodium channels (similar to ectopic nerve activity). This results in neuronal hyper-excitability that can lead to allodynia and hyperalgesia via activation of mechanosensitive A-beta and A-delta afferent fibers connecting with second order nociceptive neurons.
Inflammation results in activation of microglia in the nerve as well as the dorsal root ganglion. A proinflammatory milieu is created including cytokines, chemokines, substance P, TNF alpha, etc. These factors facilitate neuropathic pain by further enhancing neuroexcitability.
Defined by: Nate Paulson, MD