Wellcome Trust PhD Programme for Clinicians at the University of Dundee: Neurosteroids: endogenous analgesics? (360G-Wellcome-090667_Z_09_A)

Peripheral neuropathy affects the normal function of the nerves connecting the spinal cord to muscle, skin and internal organs. Neuropathic pain is often a disabling symptom associated with neuropathy. Diabetes neuritis accounts for ~ 30% of cases of painful neuropathy. Treatment of diabetic neuropathy is often sub-optimal and the underlying aetiology is poorly understood. Both peripheral and central mechanisms are implicated in the development of diabetic neuritis and in particular, spinal dorsal horn neurones display hyperexcitability in neuropathic animal models of type I diabetes. The host laboratory demonstrated in rodents that a naturally occurring analgesic, the neurosteroid 5?3?, potently augments spinal inhibition by enhancing the function of synaptic and extrasynaptic GABAA receptors expressed on lamina II neurones of the dorsal horn. Furthermore, spinal neurosteroid levels are increased in inflammatory pain and consequently act as a protective analgesic. We will employ a multidisciplinary approach to investigate in mice which spinal neurone GABAA receptors mediate the analgesic effects of neurosteroids. The putative role of these steroids as endogenous analgesics in a mouse model of diabetic neuropathy will be determined. Given the recent clinical trial of a drug that enhances neurosteroid synthesis these studies may lead to new therapeutic treatments for neuropathic pain.