Activation of intestinal spinal afferent endings by changes in intra‐mesenteric arterial pressure

Abstract

Key pointsr A major class of mechano-nociceptors to the intestine have mechanotransduction sites on extramural and intramural arteries and arterioles ('vascular afferents').r These sensory neurons can be activated by compression or axial stretch of vessels. r Using isolated preparations we showed that increasing intra-arterial pressure, within the physiological range, activated mechano-nociceptors on vessels in intact mesenteric arcades, but not in isolated arteries. This suggests that distortion of the branching vascular tree is the mechanical adequate stimulus for these sensory neurons, rather than simple distension.r The same rises in pressure also activated intestinal peristalsis in a partially capsaicin-sensitive manner indicating that pressure-sensitive vascular afferents influence enteric circuits.r The results identify the mechanical adequate stimulus for a major class of mechano-nociceptors with endings on blood vessels supplying the gut wall; these afferents have similar endings to ones supplying other viscera, striated muscle and dural vessels.Abstract Spinal sensory neurons innervate many large blood vessels throughout the body. Their activation causes the hallmarks of neurogenic inflammation: vasodilatation through the release of the neuropeptide calcitonin gene-related peptide and plasma extravasation via tachykinins. The same vasodilator afferent neurons show mechanical sensitivity, responding to crushing, compression or axial stretch of blood vessels -responses which activate pain pathways and which can be modified by cell damage and inflammation. In the present study, we tested whether spinal afferent axons ending on branching mesenteric arteries ('vascular afferents') are sensitive to increased intravascular pressure. From a holding pressure of 5 mmHg, distension to 20, 40, 60 or 80 mmHg caused graded, slowly adapting increases in firing of vascular afferents. Many of the same afferent units showed responses to axial stretch, which summed with responses evoked by raised pressure. Many vascular afferents were also sensitive to raised temperature, capsaicin and/or local compression with von Frey hairs. However, responses to raised pressure in single, isolated vessels were negligible, suggesting that the adequate stimulus is distortion of the arterial arcade rather than distension per se. Increasing arterial pressure often triggered peristaltic contractions in the neighbouring segment of intestine, an effect that was mimicked by acute exposure to capsaicin (1 μM) and which was reduced after desensitisation to capsaicin. These results indicate that sensory fibres with perivascular endings are sensitive to pressure-induced distortion of branched arteries, in addition to compression and axial stretch, and that they contribute functional inputs to enteric motor circuits.

Identification of different functional types of spinal afferent neurons innervating the mouse large intestine using a novel CGRPα transgenic reporter mouse

“…One candidate ending for LF afferents is vascular afferent endings (also referred to as serosal, mesenteric, or high-threshold mechanoreceptors) (1). Comprising ϳ30% of pelvic afferent neurons (16), they can fire phasically to mechanical stimulation (24). In addition, they often express CGRP, have somata in lumbosacral ganglia, and fire at low average frequencies, with longer-duration action potentials and flatter distension-response curves than other distension-sensitive afferents (7).…”

Spinal Afferent Innervation of the Colon and Rectum

“…As discussed below, the peripheral endings of many afferents display specialized anatomical structures, rather than the “free nerve endings” that they were traditionally thought to possess (Brookes et al, 2013). Afferents that do have free nerve endings appear to correspond to the putative nociceptive vascular/serosal/mesenteric class, whose simple endings terminate adjacent the gut and mesenteric vasculature (Brunsden et al, 2007; Song et al, 2009; Humenick et al, 2015). The known specialized endings include the long studied intraganglionic laminar endings of vagal (Lawerentjew, 1929; Nonidez, 1946; Rodrigo et al, 1975; Berthoud et al, 1995), and spinal origin (Lynn et al, 2003; Olsson et al, 2004) that correspond with low-threshold tension receptors.…”

“…As discussed above at least 5 distinct classes of mechanosensitive gastrointestinal afferent endings may occur (Brookes et al, 2013). These include the low threshold, tension-sensitive intraganglionic laminar endings (Zagorodnyuk and Brookes, 2000; Zagorodnyuk et al, 2001; Lynn et al, 2003), medium/high-threshold vascular afferents (Song et al, 2009; Humenick et al, 2015), low-threshold intramuscular arrays (Lynn and Brookes, 2011), low-threshold muscular-mucosal afferents (Brookes et al, 2013), and mucosal afferents (Brookes et al, 2013). The latter two classes currently lack direct correlations between sensory transduction sites and their neuroanatomical structures.…”

“…Besides the “pelvic” and “splanchnic” anatomical distinction of spinal afferents to the colorectum, numerous other classification schemes have also been applied to determine “sub-types” or “subclasses” of afferents (Brierley et al, 2004, 2008, 2009). Such studies have employed a variety of techniques including (i) electrophysiological recording methods alone (Brierley et al, 2004, 2008, 2009; Page et al, 2004, 2005, 2007; Hughes et al, 2009b; Osteen et al, 2016; Bellono et al, 2017; Castro et al, 2017) or (ii) electrophysiological recordings with subsequent anatomical analysis (Lynn et al, 2003; Spencer et al, 2008b; Zagorodnyuk et al, 2010; Lynn and Brookes, 2011; Humenick et al, 2015; Hibberd et al, 2016), or (iii) anatomical analysis without electrophysiological recordings (Spencer et al, 2014), or (iv) on the basis of gene expression alone (Hockley et al, 2018b). Therefore, a major task for afferent neurobiology is to integrate the various classification schemes applied to colonic afferents in order to identify basic afferent subtypes and ascertain a more unified classification scheme.…”

Nociceptors: Their Role in Body’s Defenses, Tissue Specific Variations and Anatomical Update

“…The visceral nociceptive system is primarily represented by unmyelinated C-type slow fibers, including peptidergic nociceptors responding to pH changes and inflammation. 19 , 24 In hollow organs and in the capsule of parenchymatous organs there is a special kind of mechanoreceptors responding to stretching and pressure changes in the mesenteric vessels 26 , 27 (for example, intestinal obstruction, biliary colic or hepatic congestion). 28 A major portion of all nociceptors in internal organs is represented by a specific type of nociceptors known as “sleeping” mechanoreceptors.…”