Biology subjects

Taylor, T. S.

Publications and source records attributed to Taylor, T. S..

3 recordsLinked to original sources

bioRxiv2022

Sensitisation of colonic nociceptors by TNFα is dependent on TNFR1 expression and p38 MAPK activity

Visceral pain is a leading cause of morbidity in gastrointestinal diseases, which is exacerbated by the gut related side-effects of many analgesics. New treatments are needed and further understanding of the mediators and mechanisms underpinning visceral nociception in disease states is required to facilitate this. The pro-inflammatory cytokine TNF is linked to pain in both patients with inflammatory bowel disease and irritable bowel syndrome, and has been shown to sensitise colonic sensory neurons. Somatic, TNF- triggered thermal and mechanical hypersensitivity is mediated by TRPV1 signalling and p38 MAPK activity respectively, downstream of TNFR1 receptor activation. We therefore hypothesised that TNFR1-evoked p38 MAPK activity may also be responsible for TNF sensitisation of colonic afferent responses to the TRPV1 agonist capsaicin, and noxious distension of the bowel. Using Ca2+ imaging of dorsal root ganglion sensory neurons, we observed TNF-mediated increases in intracellular [Ca2+] and sensitisation of capsaicin responses. The sensitising effects of TNF were dependent on TNFR1 expression and attenuated by p38 MAPK inhibition. Consistent with these findings, ex vivo colonic afferent fibre recordings demonstrated enhanced response to noxious ramp distention of the bowel and bath application of capsaicin following TNF pre-treatment. Responses were reversed by p38 MAPK inhibition and absent in tissue from TNFR1 knockout mice. Our findings demonstrate a contribution of TNFR1, p38 MAPK and TRPV1 to TNF-induced sensitisation of colonic afferents, highlighting the potential utility of these drug targets for the treatment of visceral pain in GI disease. Abstract figure legendTNF sensitised Ca2+ responses to the TRPV1 agonist capsaicin in dorsal root ganglion sensory neurons. Sensitisation was TNFR1-dependent and attenuated by inhibition of p38 MAPK. Direct Ca2+ responses to TNF were TRPV1-and TRPA1-dependent. In ex vivo colonic afferent recordings, TNF increased sensitivity to noxious ramp distension and capsaicin, both of which were absent in TNFR1-/- tissue or blocked by inhibition of p38 MAPK. These findings establish a role for TNFR1, p38 MAPK and TRPV1 in TNF-mediated sensitisation of colonic afferents. Key Points SummaryO_LITNF sensitises sensory neurons and colonic afferents to the TRPV1 agonist capsaicin. C_LIO_LITNF-mediated sensitisation of sensory neurons and colonic nociceptors is dependent on TNFR1 expression. C_LIO_LITNF sensitisation of sensory neurons and colonic afferents to capsaicin and noxious ramp distension is abolished by inhibition of p38 MAPK. C_LI

neuroscience↗

bioRxiv2019

Galanin inhibits visceral afferent responses to noxious mechanical and inflammatory stimuli

Galanin is a neuropeptide expressed by sensory neurones innervating the gastrointestinal (GI) tract. Galanin displays inhibitory effects on vagal afferent signalling within the upper GI tract, and the goal of this study was to determine the actions of galanin on colonic spinal afferent function. Specifically, we sought to evaluate the effect of galanin on lumbar splanchnic nerve (LSN) mechanosensitivity to noxious distending pressures and the development of hypersensitivity in the presence of inflammatory stimuli and colitis. Using ex vivo electrophysiological recordings we show that galanin produces a dose-dependent inhibition of colonic LSN responses to mechanical stimuli and prevents the development of hypersensitivity to acutely administered inflammatory mediators. Using galanin receptor (GalR) agonists, we show that GalR1 activation, but not GalR2/3 activation, inhibits mechanosensitivity. The inhibitory effect of galanin on colonic afferent activity was not observed in tissue from mice with dextran sodium sulphate-induced colitis. We conclude that galanin has a marked inhibitory effect on colonic mechanosensitivity at noxious distending pressures and prevents the acute development of mechanical hypersensitivity to inflammatory mediator, an effect not seen in the inflamed colon. These actions highlight a potential role for galanin in the regulation of mechanical nociception from the bowel and the therapeutic potential of targeting galaninergic signalling to treat visceral hypersensitivity.\n\nKey point summaryO_LIGalanin inhibits visceral afferent mechanosensitivity to noxious phasic distension of the colon via GalR1.\nC_LIO_LIGalanin attenuates afferent mechanical hypersensitivity induced by the application of inflammatory mediators.\nC_LIO_LIInhibition of afferent mechanosensitivity by galanin is not observed in tissues isolated from mice undergoing DSS-induced colitis\nC_LIO_LIGalanin inhibits the transmission of noxious mechanical stimuli by colonic afferents and its sensitisation by inflammatory mediators highlighting an antinociceptive role for galanin in the colon.\nC_LI

neuroscience↗

bioRxiv2019

Acid and inflammatory sensitisation of naked mole-rat colonic afferent nerves

Acid sensing in the gastrointestinal tract is required for gut homeostasis and the detection of tissue acidosis caused by ischaemia, inflammation and infection. In the colorectum, activation of colonic afferents by low pH contributes to visceral hypersensitivity and abdominal pain in human disease including during inflammatory bowel disease. The naked mole-rat (Heterocephalus glaber; NMR) shows no pain-related behaviour to subcutaneous acid injection and cutaneous afferents are insensitive to acid, an adaptation thought to be a consequence of the subterranean, likely hypercapnic, environment in which it lives. As such we sought to investigate NMR interoception within the gastrointestinal tract and how this differed from the mouse (Mus Musculus). Here we show the presence of calcitonin gene regulated peptide (CGRP) expressing extrinsic nerve fibres innervating both mesenteric blood vessels and the myenteric plexi of the smooth muscle layers of the NMR colorectum. Using ex vivo colonic-nerve electrophysiological recordings we show differential sensitivity of NMR, compared to mouse, colonic afferents to acid and the prototypic inflammatory mediator bradykinin, but not direct mechanical stimuli. In NMR, but not mouse, we observed mechanical hypersensitivity to acid, whilst both species sensitised to bradykinin. Collectively, these findings suggest that NMR colonic afferents are capable of detecting acidic stimuli, however, their intracellular coupling to downstream molecular effectors of neuronal excitability and mechanotransduction likely differs between species.

neuroscience↗