| Autor: |
Peiris, M, Hockley, JR, Reed, DE, Smith, ESJ, Bulmer, DC, Blackshaw, LA |
| Přispěvatelé: |
Hockley, James [0000-0002-9578-6071], Smith, Ewan [0000-0002-2699-1979], Bulmer, David [0000-0002-4703-7877], Apollo - University of Cambridge Repository |
| Jazyk: |
angličtina |
| Rok vydání: |
2017 |
| Předmět: |
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| Popis: |
$\textbf{Background}$ Chronic visceral pain is a defining symptom of many gastrointestinal disorders. The K$_V$7 family (K$_V$7.1-K$_V$7.5) of voltage-gated potassium channels mediates the M current that regulates excitability in peripheral sensory nociceptors and central pain pathways. Here, we use a combination of immunohistochemistry, gut-nerve electrophysiological recordings in both mouse and human tissues, and single-cell qualitative real-time polymerase chain reaction of gut-projecting sensory neurons, to investigate the contribution of peripheral K$_V$7 channels to visceral nociception. $\textbf{Results}$ Immunohistochemical staining of mouse colon revealed labelling of K$_V$7 subtypes (K$_V$7.3 and K$_V$7.5) with CGRP around intrinsic enteric neurons of the myenteric plexuses and within extrinsic sensory fibres along mesenteric blood vessels. Treatment with the K$_V$7 opener retigabine almost completely abolished visceral afferent firing evoked by the algogen bradykinin, in agreement with significant co-expression of mRNA transcripts by single-cell qualitative real-time polymerase chain reaction for KCNQ subtypes and the B$_2$ bradykinin receptor in retrogradely labelled extrinsic sensory neurons from the colon. Retigabine also attenuated responses to mechanical stimulation of the bowel following noxious distension (0-80 mmHg) in a concentration-dependent manner, whereas the K$_V$7 blocker XE991 potentiated such responses. In human bowel tissues, K$_V$7.3 and K$_V$7.5 were expressed in neuronal varicosities co-labelled with synaptophysin and CGRP, and retigabine inhibited bradykinin-induced afferent activation in afferent recordings from human colon. $\textbf{Conclusions}$ We show that K$_V$7 channels contribute to the sensitivity of visceral sensory neurons to noxious chemical and mechanical stimuli in both mouse and human gut tissues. As such, peripherally restricted K$_V$7 openers may represent a viable therapeutic modality for the treatment of gastrointestinal pathologies. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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