Correlation Between Visceral Pain Induced Peripheral Sensitization And Pruriceptor Activation

Background & Aims

Visceral diseases are usually accompanied with hyperaesthesia phenomenon on specific parts of the body surface, which induces spontaneous scratching or pressing on itchy loci for pleasure sensation (Head, 1893; Mackenzie,1895; Cevikbas and Lerner,2020). The recently discovered dorsal root ganglion-expressed peripheral itch receptor, Mas-gene-related G protein-coupled receptors A3 (Mrgpra3), is the specific candidate for studies of the scratching behavior (Liu et al., 2009; Han et al., 2013). Such receptors exhibit to be excitative mood during visceral disease, therefore promoting more scratch and stimulus behavior for regulating inner functions.

Methods

In this study, by using transgenic technology combined with behavior test, opto- and chemo-genetic approaches, morphological methods, and in vivo electrophysiological recording of dorsal root ganglion, we mainly focus on the activation of Mrgpra3+ receptor related to ulcerative colitis mice model.

Results

By crossin Mrgpra3GFP-Cre mice with ROSA26tdTomato reporter mice, the Mrgpra3+ neurons can be visualized directly by epifluorescence without immunohistochemical staining. Immunohistochemical staining of thoracic and lumbar dorsal root ganglion (DRG) and skin revealed colocalization of Mrgpra3+ neurons in a subset of small and middle-diameter sensory neurons. Of the td+ neurons we examined, most expressed the nonpeptidergic nociceptive marker IB4 with lower colocalization with peptidergic marker SP or CGRP. We then generate Mrgpra3GFP-Cre mice with ChR2-eYFP line (Ai32) to generate mice with ChR2-eYFP expression in Mrgpra3 neurons. Notably, Mrgpra3;Ai32 mice exhibited significant scratching behaviors during blue light stimulation trails at 20Hz, whereas Mrgpra3WT;Ai32 mice showed almost no scratching. Furthermore, Mrgpra3;Ai32 mice with ulcerative colitis represented increased scratching behavior during blue light stimulation compared with control group.

Conclusions

Our study delves into the response pattern of Mrgpra3+ neurons during visceral inflammatory disease, shedding light on the peripheral mechanisms inducing itch sensitization. Additionally, the research elucidates the behavioral effects of visceral nociceptive stimulus-induced itch sensitization, providing a mechanistic basis for peripheral somato-stimulation, such as acupuncture. These findings contribute to a better understanding of the correlation between visceral pain-induced peripheral sensitization and pruriceptor activation, offering insights for potential therapeutic interventions.

References

1. Head H. On disturbances of sensation with especial reference to the pain of visceral disease. Brain.1893;16:1-133.
2. Mackenzie J. Heart pain and sensory disorders associated with heart failure. The Lancet. 1895:16-22.
3. Cevikbas F, Lerner EA. Physiology and Pathophysiology of Itch. Physiol Rev. 2020;100(3):945-82.
4. Liu Q, Tang Z, Surdenikova L, Kim S, Patel KN, Kim A, Ru F, Guan Y, Weng HJ, Geng Y, Undem BJ, Kollarik M, Chen ZF, Anderson DJ, Dong X. Sensory neuron-specific GPCR Mrgprs are itch receptors mediating chloroquine-induced pruritus. Cell. 2009 Dec 24;139(7):1353-65.
5. Han L, Ma C, Liu Q, Weng HJ, Cui Y, Tang Z, Kim Y, Nie H, Qu L, Patel KN, Li Z, McNeil B, He S, Guan Y, Xiao B, Lamotte RH, Dong X. A subpopulation of nociceptors specifically linked to itch. Nat Neurosci. 2013 Feb;16(2):174-82.

Presenting Author