Visceral and somatic pain modalities reveal Na_V1.7‐independent visceral nociceptive pathways

Abstract

Voltage-gated sodium channel Na 1.7 is required for acute and inflammatory pain in mice and humans but its significance for visceral pain is unknown. Here we examine the role of Na 1.7 in visceral pain processing and the development of referred hyperalgesia using a conditional nociceptor-specific Na 1.7 knockout mouse (Na 1.7 ) and selective small-molecule Na 1.7 antagonist PF-5198007. Na 1.7 mice showed normal nociceptive behaviours in response to intracolonic application of either capsaicin or mustard oil, stimuli known to evoke sustained nociceptor activity and sensitization following tissue damage, respectively. Normal responses following induction of cystitis by cyclophosphamide were also observed in both Na 1.7 and littermate controls. Loss, or blockade, of Na 1.7 did not affect afferent responses to noxious mechanical and chemical stimuli in nerve-gut preparations in mouse, or following antagonism of Na 1.7 in resected human appendix stimulated by noxious distending pressures. However, expression analysis of voltage-gated sodium channel α subunits revealed Na 1.7 mRNA transcripts in nearly all retrogradely labelled colonic neurons, suggesting redundancy in function. By contrast, using comparative somatic behavioural models we identify that genetic deletion of Na 1.7 (in Na 1.8-expressing neurons) regulates noxious heat pain threshold and that this can be recapitulated by the selective Na 1.7 antagonist PF-5198007. Our data demonstrate that Na 1.7 (in Na 1.8-expressing neurons) contributes to defined pain pathways in a modality-dependent manner, modulating somatic noxious heat pain, but is not required for visceral pain processing, and advocate that pharmacological block of Na 1.7 alone in the viscera may be insufficient in targeting chronic visceral pain.

Nociceptor plasticity: A closer look

“…NaV 1.7 appears to be involved in chronic pain mechanisms as upregulation of NaV channels has been detected after disc injury in murine models; moreover, the administration of anti‐NaV 1.7 antibodies decreased CGRP expression in mice after lumbar disc injury (Nojima et al, ). Conversely, the role of this channel in visceral pain remains unknown; in fact, Nav 1.7 seems not to be required for visceral pain processing, and a very recent study advocates that pharmacological block of NaV 1.7 alone in the viscera may be insufficient in targeting chronic visceral pain (Hockley et al, ). NaV 1.8 is involved in different adaptive and neuroplasticity‐related mechanisms on which light has been shed with NaV 1.8 gene knock‐out models: different investigations detected a marked hyperalgesia after nociceptive stimulation in mice (Dong, Sun, Lu, Wang, & Wu, ); also, if a Chronic Constriction Injury (CCI) was provoked in mice, mRNA alteration and protein rearrangement were observed in cells (Wang, Wang, et al, ).…”

The influence of voltage‐gated sodium channels on human gastrointestinal nociception

“…antagonist (PF-5198007) demonstrated no significant impact on visceral sensory afferent activity in response to painful stimuli. 44 This same investigation also demonstrated no impact of Na V 1.7 antagonism on afferent neuronal activity associated with excised human appendices exposed to significant intraluminal distension. In other human studies, however, biopsy samples from patients diagnosed with idiopathic rectal hypersensitivity and paroxysmal extreme pain disorder (PEPD) (aka familial rectal pain) demonstrated that Na V 1.7positive nerve fibers were observed more frequently in these patients compared to healthy controls.…”

“…However, the large majority of intestinally innervating afferent nerves demonstrate elements that are most characteristic for Na V 1.8 (eg, high threshold, slowly inactivating, TTX‐resistant) . Evidence for all nine VGSC isoforms has been demonstrated at the level of mRNA transcript and/or protein expression in sensory afferent neurons and other cell types associated with gut nociception . However, some of these isoforms (eg, Na V 1.2, Na V 1.4) have, as of yet, no experimentally delineated role in visceral pain perception and so will not be discussed further.…”

“…Rodent models suggest that it is much more abundant early in development compared to adulthood . Its mRNA is expressed on intestinal spinal afferents in some animal models, but it has yet to demonstrate a direct functional role in gut nociception. Interestingly, it is relatively highly expressed (compared to the other VGSC isoforms) on enterochromaffin (EC) cells found within the mucosal lining of the intestinal tract .…”

“…Na V 1.7 mRNA expression was shown to increase in lower lumbar DRG neurons in the setting of a chronic stress and colitis models in rats. However, another study utilizing a conditional nociceptor‐specific Na V 1.7 knockout mouse model and selective Na V 1.7 antagonist (PF‐5198007) demonstrated no significant impact on visceral sensory afferent activity in response to painful stimuli . This same investigation also demonstrated no impact of Na V 1.7 antagonism on afferent neuronal activity associated with excised human appendices exposed to significant intraluminal distension.…”