Visceral Neurophysiology
Laboratory
Research Projects
Mechanisms underlying the detection of pain in the gut
This project aims to identify the mechanisms that activate the spinal afferent nerve endings which detect painful stimuli (called nociceptors) within the rectal wall. Our laboratory has recently identified a particular mutant mouse that fails to detect pain in response to rectal distension. We are in the process of identifying the location and morphology of the specific nociceptors that detect noxious levels of rectal distension and signal pain to the central nervous system.
Recently, we made a major breakthrough in our NHMRC funded projects. We found that mutant mice, deficient in endothelin-3 peptide, lack the ability to detect visceral pain following noxious colorectal distension, but still elicited normal pain responses to noxious stimulation of other organs. In that study, we were able to identify a specific class of rectal afferent mechanoreceptor which had significantly impaired mechanosensitive properties, compared with all other major classes of rectal afferents. This major finding provided us with a substantial insight into which particular class of spinal afferent was likely important for activation of the VMR, following noxious mechanical stimulation of this region. The afferents of interest are a particular class of low threshold, wide dynamic range sensory fibre, known as the “muscular/mucosal” and “muscular” afferent, which respond to graded stretch and/or stimulation of the mucosa. High threshold rectal afferents have been studied electrophysiologically in the mouse rectum, but only appear to be activated by distension pressures >150mmHg, which is well beyond the nociceptive threshold in this particular region.
Figure 1. Recent work from our laboratory has shown the breakthrough discovery that mutant mice
deficient in endogenous endothelin-3 lack the ability to detect visceral pain following noxious colorectal distension.
Left side of panel shows control mouse pain reflexes (VMR) to increasing colorectal distension.
The same stimuli applied to mice deficient in endogenous endothelin-3 fails to respond to colorectal distension (see Zagorodnyuk et al, 2011).
Figure 2. Extracellular recording showing that functional spinal afferents of the rectal nerves
ramify within the aganglionic colorectum of endothelin-3 deficient mice.
Recording shows that circumferential stretch activates a discharge of action potentials in this rectal nerve,
even though all enteric ganglia are congenitally absent and the mucosa and submucosal plexus is removed.
This shows that mechanotransduction sites must innervate the aganglionic smooth muscle.
Calcium imaging of human colonic smooth
muscle
How the smooth muscle in the human colon is activated by intrinsic neurons to cause colonic propulsion is unclear. We have developed a novel calcium imaging technique which allows us to record the propagation of pacemaker activity over large segments of isolated human colonic smooth muscle and these pacemaker properties are contrasted with those obtained in a variety of colonic disease states, such as Crohn’s disease and ulcerative colitis.
Sensory innervation of the bladder
It was once thought that the bladder received only major class of sensory nerve. Dr Vladimir Zagorodnyuk has recently identified at least 5 major classes of spinal afferent nerve in the urinary bladder, that respond differentially to a variety of sensory stimuli. Dr Zagorodnyuk is now working on spinal afferent nerves in the rectum and bladder and has made substantial progress in identifying which specific class of sensory nerve is responsible for the detection of visceral pain.
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