‘Spotting’ afferent pathways of hindgut sensations – role of endothelin‐3 signalling

Colorectal distension can result in both painful and non-painful sensations. These sensations of pain are carried by afferent nerves innervating the distal gut, but little is known about the specific afferent classes that mediate painful sensations, as well as responses to noxious and non-noxious colorectal stimulation. This is not only of scholarly importance, but also important in the clinical world, as many common gastrointestinal (GI) disorders, such as irritable bowel syndrome and colitis, are manifested by pain arising from the distal colon. In a recent issue of The Journal of Physiology, Zagorodnyuk et al. (2011) have used an interesting approach to provide us with further insight into this problem. They utilized a strain of mice deficient in endothelin-3 production, known as the ‘lethal spotted’ (ls/ls) mouse (so named from their unique spotted coat). This mouse is known to lack enteric ganglia in the distal colorectum, and thus serves as a mouse model of Hirschsprung's disease, a rare motility disorder characterized by failure of enteric neuronal development in the bowel – which leads to varying degrees of functional obstruction. The disorder usually presents in childhood, but milder forms may be unrecognized until adulthood (de Lorijn et al. 2007). The authors demonstrated that visceromotor reflexes (abdominal wall contractions in response to colorectal distension – often used as a correlate of visceral pain in rodents) are significantly attenuated in ls/ls mice, and that there is a loss of spinal innervation of the rectum in these animals. Recordings from afferent nerve fibres revealed a significant deficit in a functional class of fibres known as muscular (which respond to tissue stretch) and muscular- mucosal afferents (respond to stretch as well as mucosal stroking). These afferents function as low threshold, wide dynamic sensitivity mechanoreceptors, as they encode stimuli across the range, from low to high intensity (Brierley et al. 2004). Interestingly the function of high threshold afferents, widely believed to be critical in pain signalling (Blackshaw & Gebhart, 2002), was preserved. The deficit of this class of wide dynamic sensitivity fibres may underlie the lack of observed visceromotor responses (VMRs) to colorectal distension. Importantly the deficit in the VMR was limited to the colon, as responses to noxious stimulation of the bladder were not altered in ls/ls mice. This work offers a number of important insights, and clearly indicates that endothelin-3 signalling is critically important in development of the spinal innervation of the hindgut, and may in part explain the clinical observation that in Hirschsprung's disease autonomic function outside the enteric nervous system may also be altered (Staiano et al. 1999). However, equally importantly it opens the debate as to what classes of spinal afferents mediate hindgut pain. The loss of the VMR, thought by many to be a pseudoaffective/nocifensive reflex response to painful stimuli (Mayer et al. 2008), suggests that these wide dynamic range afferents may indeed be responsible for visceral pain, and that high threshold afferents (whose function was preserved in the present study) may not play as important a role as previously believed. However, caution should be exercised with this interpretation. Careful examination of visceromotor reflexes in the present study, as well as many others, reveals that the VMR is often activated a distension pressures that lie in the subnoxious range – indeed at pressures that the colon is likely to generate in physiological states. Thus the VMR may represent a continuum, where responses at lower pressure may activate abdominal wall contractions (perhaps to facilitate defecation) while stimuli in the noxious range elicit the more ‘nocifensive’ intense abdominal wall contraction. Indeed even in humans there is a continuum of conscious sensations produced by colorectal distension, ranging from sensation of fullness and need to defecate to discomfort and pain. Perhaps these wide dynamic fibres are responsible for this range of sensations, and perhaps dysfunction of these fibres in conditions such as irritable bowel syndrome or distal colitis can not only lead to pain – but a decreased threshold for the need to defecate. In addition, the tantalizing question is raised that the loss of responses of these extrinsic afferents at the subnoxious range may underlie the defective rectoanal inhibitory reflex seen in Hirschsprung's disease, previously believed to result from a loss of intrinsic enteric neurons. Nonetheless the present study is an excellent example of the use of a genetic defect to probe the function of the afferent innervation of the GI tract. It will remain a challenge for all visceral pain researchers to more clearly define pain behaviours in our animal models, as these models form the basis for developing new drug treatment strategies for common painful conditions of the GI tract such as irritable bowel syndrome.

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