Development of a refined model of neuropathic pain: a model without frank nerve injury

Aims

This project aims to investigate whether existing, non-reversible nerve injury models of neuropathic pain can be replaced with a refined, reversible and non-surgical model.

Background

Neuropathic pain occurs as a result of a lesion in the nervous system. It is a debilitating condition that has become a major healthcare issue because of a lack of effective treatments. Much of the understanding of the mechanisms of neuropathic pain has been gained through the use of nerve injury rodent models involving cutting or ligation of axons. The disruption of axonal transport drives the development of neuropathic pain. However these are severe models that cause significant suffering for the animals and there is a need for refined models of neuropathic pain.

Research details and methods

Previous work has shown that the local application of an anti-mitotic agent, vinblastine, causes transient disruption of axonal transport along intact axons, and the rapid development of allodynia, a sign of neuropathic pain, that reverses by week two. These changes occur with no obvious adverse effects to the animals, and suggest that the local application of low doses of anti-mitotic agents to the rat sciatic nerve provides a way of mimicking nerve injury. This project will examine the effects of the chemotherapy agents vinblastine and paclitaxel on pain behaviours and neuronal physiology, and compare these findings to the literature on nerve injury models with a view to establishing the new model as a refined alternative to conventional neuropathic pain models. 

Neuropathic pain occurs as a result of a lesion in the nervous system. It is a debilitating condition that due to the lack of effective treatments has become a major healthcare issue. Much of our understanding of the mechanisms of neuropathic pain has been gained through the use of nerve injury models. These are severe models that cause significant suffering for the animals. There is an urgent need for better models of neuropathic pain that reduce suffering with fewer adverse effects. In nerve injury models, cutting or ligating axons causes cessation of axonal transport. Axonal transport disruption leads to physiological changes that drive neuropathic pain mechanisms. Work from our laboratory has shown that the local application of the anti-mitotic agent, vinblastine, causes the transient disruption of axonal transport along intact axons and the rapid development of mechanical allodynia (hypersensitivity to touch), a sign of neuropathic pain, that reverses by week two. These changes occur in the absence of axonal degeneration with no obvious adverse effects to the animals. Our data suggests that the local application of low doses of anti-mitotic agents to the rat sciatic nerve provides a way of mimicking nerve injury. This studentship will extend our initial studies and investigate whether the local application of mitotic agents can replace existing nerve injury models as a refined model of neuropathic pain without the adverse effects. It will also determine whether a non-surgical method for induction is possible. It will specifically examine the effects of the chemotherapy agents vinblastine and paclitaxel on pain behaviours and neuronal physiology and compare these findings to the literature on nerve injury models. Since both agents can cause chemotherapy-induced peripheral neuropathy (CIPN) we anticipate that this model will also provide a novel model for investigating CIPN with a view to future prevention of this very disabling complication of chemotherapy.