Understanding the role of Neuregulin 1-erbB signalling in microglia in the context of neuropathic pain.

Neuregulin 1 (NRG1) is a growth factor required for peripheral nerve development and functional recovery following nerve injury. However, its importance in regulating neuropathic pain via microglial signaling remains unclear. Previous pharmacological studies suggest NRG1 regulates microglial proliferation, mechanical allodynia and cold hypersensitivity through binding to extracellular tyrosine kinase receptors (e.g. erbB2, erbB3 and erbB4) found on microglia. The aim of this thesis was to further dissect the role of NRG1 in regulating pain behaviour during neuropathic pain by using transgenic systems that conditionally ablate NRG1 expression in adulthood or erbB receptor expression specifically within microglia. In our hands it was determined that the CX3CR1 Cre is more efficient than the Cd11b Cre system in effectively targeting tissue specific gene ablation. Using animal models of nerve injury, gene expression analysis showed that NRG1 and erbB gene expression levels are dysregulated in the peripheral nervous system and the spinal cord, in neuropathic pain models. A novel cold pain behaviour assay was optimised to measure cold pain behaviour. With conditional NRG1 ablation, and the use of the spared nerve injury model, it was determined that NRG1 regulates cold hypersensitivity in the delayed stages of nerve injury but does not regulate mechanical hypersensitivity or attenuate microglial proliferation. Similarly, conditional ablation of erbB3 and erbB4 receptors in microglia suggests that the NRG1-erbB signaling pathway does not regulate mechanical hypersensitivity or microglial proliferation. However, NRG1-erbB signaling does regulate cold hypersensitivity in the delayed stages of nerve injury through microglia. The work presented in this thesis has further refined the role of the NRG1-erbB signaling pathway in the context of peripheral nerve injury neuropathic pain.