Effects of visceral inflammation and nerve injury on nociceptors expressing receptors for the GDNF family ligands

Abstract

Members of the glial cell line-derived neurotrophic factor (GDNF) family of ligands (GFL) comprising GDNF, neurturin and artemin, show efficacy in rat neuropathic pain models and promote regeneration after injury. Their receptors, GFRα1-3 respectively, are expressed by adult dorsal root ganglion neurons and have distinct central projections, suggesting different functions. This thesis used immunohistochemical techniques to investigate the impact of nerve injury and visceral inflammation on nociceptors expressing the GFRs in adult rats. Somatic and visceral nerve injury had profound effects on GFR-expressing neurons and their central terminals. Bladder afferent neurons expressing GFRs were characterised and effects of chronic bladder inflammation investigated. GDNF and artemin target different functional groups of bladder afferent neurons, potentially regulating different components of bladder function but were unaffected by inflammation. A population of bladder neurons undergoing structural remodelling during inflammation was identified. The final study demonstrated that GFRα3 labels specific populations of afferent axons, sympathetic noradrenergic vasoconstrictor axons and glia in the bladder. Results from this thesis indicate GFLs and their receptors represent promising targets for therapies aimed at regeneration and development of pain. Visceral and somatic afferents may have different growth factor sensitivities that may impact the degree of regeneration or development of sensitization.