Axonal transport disruption is a major part of the mechanism of neuropathic pain. Following traumatic nerve injury there is complete cessation of axonal transport. When intact axons are inflamed, axonal transport is also disrupted. The main aim of the present study was to determine the role of axonal transport disruption along intact axons in the mechanisms of neuropathic pain. Low doses of vinblastine were applied to the rat sciatic nerve in order to disrupt axonal transport in the absence of axonal degeneration or inflammation. Comparisons were made to a model of local nerve inflammation (neuritis). An examination of evoked neuropathic pain behaviours revealed reversible signs of mechanical and cold allodynia following both vinblastine treatment and neuritis. Burrowing behaviour also showed signs of reduction in both models. In vivo electrophysiological recordings were performed to look for peripheral ongoing activity, which is reputed to drive central mechanisms that lead to neuropathic pain behaviours. Whereas ongoing activity developed in 25% of C-fibre neurons in the neuritis model, ongoing activity did not increase following vinblastine treatment. An electrophysiological examination of the spinal cord following neuritis revealed an increase in wind-up response in wide dynamic range neurons within deep laminae. Following vinblastine treatment, there was a reduction in mechanical responses of such neurons. Both vinblastine treatment and neuritis caused an increase in activity-dependent c-fos expression within superficial laminae, which indicates a central neuropathic pain mechanism in both models. Following vinblastine treatment, substance P expression was decreased in the dorsal horn, suggestive of altered nociceptor transmission into the spinal cord. Taken together, these findings infer a role for axonal transport disruption along intact axons in the development of neuropathic pain. The lack of increased ongoing activity following vinblastine treatment suggests that central mechanisms may be maintained by an alternative signal. Finally, vinblastine treated animals do not show any adverse effects, and therefore in terms of the 3Rs, this model provides an alternative less severe model to assess the mechanisms of neuropathic pain.
|Date of Award||2018|
|Supervisor||Andrew Dilley (Supervisor)|