Endocrine Abstracts

The spinal cord dorsal horn acts as a hub for the modulation of sensory information, relying heavily upon the interplay of a heterogenous cell population (endothelial cells, astrocytes) with sensory neurons. We have identified in rodent models of hyperglycemic neuropathic pain that spinal microvasculature is damaged. A pathological hallmark of chronic pain is astrogliosis, acting as a potent source of inflammatory response and impacting vessel integrity and sensory neuronal activity. To date, it remains unclear how diabetic neuropathic pain develops and how microvessels are damaged. Here we use chemogenetic manipulation of astrocytes in healthy and hyperglycaemic rodents to elucidate the role of astrogliosis in the modulation of the blood-spinal cord-barrier and nociception. For spinal astrocyte activation, intrathecal injection of AAV GFAP-hM3D(Gq)-mCherry in C57/Bl6J male mice (n=10). Clozopine-N-Oxide (CNO, n=10) or vehicle (PBS, n=5) was delivered via intraperitoneal injection 2 weeks later. Hargreaves latency testing was performed prior to and 30minutes post-CNO/vehicle delivery to evaluate nociceptive withdrawal behaviours. To investigate the inactivation of spinal astrocytes during hyperglycaemia, C57/Bl6J male mice (n=10) were intrathecal injection of AAV GFAP-hM4D(Gi)-mCherry and fed on a 60% high-fat diet for 8 weeks. CNO (n=5) or vehicle (PBS, n=5) was delivered via intraperitoneal injection (2.5mg/kg) in week 8 for 4 consecutive days. Hargreaves latency testing was performed before diet feed, each week during diet feed and 30mins post-CNO/vehicle delivery to evaluate nociceptive withdrawal behaviours. Reduced heat-induced paw withdrawal thresholds were demonstrated post-CNO dosing compared to vehicle treatment within the spinal astrocyte activation cohort (hM3D(Gq)). Whereas during astrocyte inactivation (hM4D(Gi)) via CNO delivery, high-fat diet-induced thermal hypersensitivity was alleviated compared to vehicle treatment in hyperglycaemic mice. This data indicates that spinal astrocyte activation mediates nociceptive behavioural changes which can be targeted in a hyperglycaemic state for pain alleviation.