Mechanisms of neuritis-induced c-fibre hyperexcitability : a role for nerve inflammation in chronic pain

Patients with chronic pain conditions such as repetitive strain injury and complex regional pain syndrome frequently lack signs of a nerve injury on routine clinical examination. Evidence from the neuritis animal model suggests that painful symptoms could be generated from inflamed primary sensory neurons in the absence of gross pathological changes. In this model, nociceptive neurons develop signs of increased excitability. The aim of this project was to determine the mechanisms underlying neuritis-induced hyperexcitability, in particular C-fibre neuron ongoing activity. This study revealed that the pro-inflammatory cytokines TNF-a and CCL2 can increase ongoing activity in a subgroup of neurons that are subtly inflamed. Labelling of their cognate receptors revealed that CCL2 may mediate its axonal effects via glial CCR2, whereas TNF-a is likely to act through axonal TNFR1 receptors. This study also examined the contribution of the sodium channel Na, 1.8 and hyperpolarisation-activated cyclic nucleotide-gated (HCN) channels to the maintenance of neuritis-induced ongoing activity. The HCN channel blocker Z07288, but not the Na, 1.8 blocker A803467, decreased the rate of C-fibre neuron ongoing activity. Z07288 also reversed neuritis- induced heat hyperalgesia. The HCN2 isoform was shown to be present in all sizes of L5 ORG neuron, and was upregulated in small diameter cell bodies following neuritis. Finally, the effect of axoplasmic transport disruption along the sciatic nerve on the development of ongoing activity was examined. Such disruption was not conclusively shown to contribute to neuritis-induced C-fibre neuron ongoing activity, although it is a likely mechanism underlying the development of axonal mechanical sensitivity. These findings suggest that HCN channels, as well as CCL2 and TNF-o, may be potential targets for the treatment of distressingly painful symptoms in the large group of patients whose conditions show neuropathic characteristics in the absence of a clinically detectable nerve injury.EThOS - Electronic Theses Online ServiceGBUnited Kingdo