Expression and Function of Galanin in Colonic Sensory Neurones

The gastrointestinal (GI) tract is innervated by both the enteric nervous system and the sensory nervous system, and it is the latter that is responsible for giving rise to conscious sensations arising from the GI tract, such as pain. In particular, the distal colon is a key source of visceral pain in both inflammatory bowel disease (e.g. ulcerative colitis and Crohn’s disease) and irritable bowel syndrome. In both conditions, pain relief is complicated by the GI side effects of commonly prescribed analgesics, such as non-steroidal anti-inflammatory drugs and opioids. Therefore, furthering knowledge about how sensory innervation of the GI tract is modulated in health and disease has the potential to identify new therapeutic avenues. Galanin is a neuropeptide that has various functions within the central and peripheral nervous systems, e.g. regulation of feeding and modulation of nociceptive pathways respectively. Galanin has been previously demonstrated to modulate the mechanosensitivity of vagal sensory afferents innervating the upper GI tract, but nothing is known about its role in the distal colon, i.e. the lower GI tract. Using mice, I therefore aimed to determine if galanin also modulates the lumbar splanchnic nerve (LSN), which innervates the distal colon, in both healthy and inflamed (hypersensitive) conditions. Using ex vivo LSN electrophysiological recordings I found that galanin dose-dependently inhibits LSN responses to mechanical stimuli and the mechanical hypersensitivity induced by acutely applied inflammatory mediators. Using galanin receptor agonists (GalR1: M671, GalR2: spexin), I identified that GalR1 mediates the inhibitory effects on LSN mechanosensitivity. Using a mouse model of colitis, I found that the LSN was hypersensitive to mechanical stimuli, but that galanin no longer produced any inhibitory effect. Immunohistochemistry experiments using thoracolumbar (T13-L1) and lumbosacral (L6-S1) dorsal root ganglia (DRG) retrograde labelled from the colon demonstrated that galanin is primarily expressed by putative nociceptors, but that no major expression changes occur during colitis. In summary, I have demonstrated that galanin inhibits LSN mechanosensitivity and inflammatory mediators induced mechanohypersensitivity, but that this inhibition is lost in an in vivo model. This work highlights the potential for targeting the galaninergic system to treat GI pain.Cambridge Trust - Vice Chancellor's Award Rosetrees Trust - Postdoctoral Grant (A1296) BBSRC - BB/R006210/