Neuritis and vinblastine-induced axonal transport disruption lead to signs of altered dorsal horn excitability

Abstract

BackgroundMany patients with neuropathic pain present without signs of nerve injury on routine clinical examination. Some of these patients may have inflamed peripheral nerves (neuritis). In this study, we have examined whether neuritis causes changes within the dorsal horn that may contribute to a central pain mechanism. Comparisons have been made to a model of axonal transport disruption induced using vinblastine, since neuritis disrupts such processes.ResultsAt the peak of cutaneous hypersensitivities, recordings from wide dynamic range neurons revealed increases in wind-up following neuritis but not vinblastine treatment. Ongoing activity from these neurons was unchanged. Vinblastine treatment caused a reduction in the responses of wide dynamic range neurons to noxious mechanical stimulation of the receptive field. The response of neurons to innocuous mechanical stimulation was also reduced in wide dynamic range neurons that were at a depth ≥550 µm following vinblastine treatment. An examination of the superficial dorsal horn revealed an increase in c-Fos–positive neurons in both groups following electrical stimulation of the sciatic nerve. The area of dorsal horn expressing substance P was also decreased following vinblastine treatment.ConclusionThese findings indicate that a minor nerve insult, such as neuritis, can lead to changes within the dorsal horn that are consistent with a central neuropathic pain mechanism.

Aberrant Neuronal Activity in a Model of Work-Related Upper Limb Pain and Dysfunction

“…Such activity, if present in humans with work-related musculoskeletal disorders, may underlie spontaneous pain or drive spinal mechanisms that lead to central sensitization. 43 Evidence of central sensitization was reported following localized neuritis, 54 and is consistent with the development of mechanical and cold cutaneous hypersensitivities in our animals.…”

Does peripheral neuroinflammation predict chronicity following whiplash injury? Protocol for a prospective cohort study

“…Consistent with a role for neuroinflammation, animals with a localised neuritis develop tactile and thermal-evoked cutaneous hypersensitivities in the absence of axonal degeneration. [15][16][17] Of note, intact nociceptive axons become mechanically sensitive responding to pressure and stretch, [17][18][19][20] similar to the neural mechanosensitivity observed in people with WAD2.…”

“…Based on these findings, we propose that some people diagnosed with WAD2 may have an undetected nerve pathology, such as peripheral neuroinflammation, which could be a cause of chronicity. Consistent with a role for neuroinflammation, animals with a localised neuritis develop tactile and thermal-evoked cutaneous hypersensitivities in the absence of axonal degeneration 15–17. Of note, intact nociceptive axons become mechanically sensitive responding to pressure and stretch,17–20 similar to the neural mechanosensitivity observed in people with WAD2.…”

Chronic pain and local pain in usually painless conditions including neuroma may be due to compressive proximal neural lesion

“…Transient local tissue hypersensitivity is a common experience after traumas and in inflammatory conditions that involve skin. Clinically important central sensitization manifests as abnormal extraterritorial hypersensitivity of non-lesioned tissue and seems to be an inevitable result of peripheral sensitization [see, e.g., Satkeviciute and Dilley ( 66 ) and Torebjörk et al ( 67 )], which in turn can be induced by tissue injury, inflammation, and nerve injury ( 25 , 68 ). Notably, nerve damage produces stronger sensitizing input than peripheral non-neural lesions: skin hypersensitivity lasts up to 24 h after capsaicin injection ( 69 ), ten days after incision ( 70 ), and over two months after nerve injury ( 65 ).…”

“…Central sensitization can also be caused by direct CNS damage, which may lead to secondary peripheral sensitization by retrograde excitation of DRG neurons ( 5 , 111 ). CNS involvement can account for bilateral neuropathy symptoms, which may be due to DRGn hyperactivity-induced hyperexcitability of wide dynamic range neurons and activation of commissural neurons of the spinal cord ( 66 ), or, also supposedly, due to systemic neuroinflammation-mediated mechanisms ( 42 , 66 ). Extraterritorial hypersensitivity may be shaped by neuron crosstalk not only in the CNS ( 112 , 113 ) but also in the DRG ( 83 ).…”