CGRPα within the Trpv1-Cre population contributes to visceral nociception

Abstract

The role of calcitonin gene-related peptide (CGRP) in visceral and somatic nociception is incompletely understood. CGRPα is highly expressed in sensory neurons of dorsal root ganglia and particularly in neurons that also express the transient receptor potential cation channel subfamily V member 1 (Trpv1). Therefore, we investigated changes in visceral and somatic nociception following deletion of CGRPα from the Trpv1-Cre population using the Cre/lox system. In control mice, acetic acid injection (0.6%, ip) caused significant immobility (time stationary), an established indicator of visceral pain. In CGRPα-mCherry;Trpv1-Cre mice, the duration of immobility was significantly less than controls, and the distance CGRPα-mCherry;Trpv1-Cre mice traveled over 20 min following acetic acid was significantly greater than controls. However, following acetic acid injection, there was no difference between genotypes in the writhing reflex, number of abdominal licks, or forepaw wipes of the cheek. CGRPα-mCherry;Trpv1-Cre mice developed more pronounced inflammation-induced heat hypersensitivity above baseline values compared with controls. However, analyses of noxious acute heat or cold transmission revealed no difference between genotypes. Also, odor avoidance test, odor preference test, and buried food test for olfaction revealed no differences between genotypes. Our findings suggest that CGRPα-mediated transmission within the Trpv1-Cre population plays a significant role in visceral nociceptive pathways underlying voluntary movement. Monitoring changes in movement over time is a sensitive parameter to identify differences in visceral nociception, compared with writhing reflexes, abdominal licks, or forepaw wipes of the cheek that were unaffected by deletion of CGRPα- from Trpv1-Cre population and likely utilize different mechanisms. NEW & NOTEWORTHY The neuropeptide calcitonin gene-related peptide (CGRP) is highly colocalized with transient receptor potential cation channel subfamily V member 1 (TRPV1)-expressing primary afferent neurons, but the functional role of CGRPα specifically in these neurons is unknown in pain processing from visceral and somatic afferents. We used cre-lox recombination to conditionally delete CGRPα from TRPV1-expressing neurons in mice. We show that CGRPα from within TRPV1-cre population plays an important role in visceral nociception but less so in somatic nociception.

Calcitonin Gene Related Peptide Α Is Dispensable for Many Danger-related Motivational Responses

“…Our results contrast to a previous study suggesting αCGRP in TRPV1-expressing primary afferents to be important for visceral nociceptive signaling 24 .…”

“…In addition to being expressed in the PBN, αCGRP is found in a large population of primary afferents 24 .…”

Calcitonin gene related peptide α is dispensable for many danger-related motivational responses

“…This is perhaps not surprising at first sight given that we primarily selected tests that are known to be dependent on the activation of parabrachial neurons. On the other hand, it should be pointed out, that αCGRP is found in a large population of primary afferents 25 and several of the behavioral responses tested in this study are dependent on primary afferents. Nevertheless, we found no obvious differences between wt mice and mice lacking αCGRP in the pain-related responses studied.…”

The enteric nervous system in gastrointestinal disease etiology

“…However, whether TRPV1, which has been the focus of many studies on visceral hypersensitivity [184], is expressed by enteric neurons is still a matter of debate [185][186][187][188]. Recent single-cell mRNA sequencing data and studies using transgenic Trpv1-Cre reporter mice seem to further support the notion that TRPV1 expression observed in the gut wall is of extrinsic neuronal origin [9,12,13,189,190]. It, therefore, remains to be determined whether submucosal enteric neurons are involved in the reduced abdominal pain and visceral hypersensitivity observed in IBS patients after histamine receptor H1 (H1R) blocking [191].…”