Exploration of Sensory and Spinal Neurons Expressing Gastrin-releasing Peptide in Itch and Pain Related Behaviors

Overview

Journal Nat Commun

Specialty Biology

Date 2020 Mar 15

PMID 32170060

Citations 38

Authors

Devin M Barry

Xue-Ting Liu

Benlong Liu

Xian-Yu Liu

Fang Gao

Xiansi Zeng

Juan Liu

Qianyi Yang

Steven Wilhelm

Jun Yin

Ailin Tao

Zhou-Feng Chen

Affiliations

Soon will be listed here.

Abstract

Gastrin-releasing peptide (GRP) functions as a neurotransmitter for non-histaminergic itch, but its site of action (sensory neurons vs spinal cord) remains controversial. To determine the role of GRP in sensory neurons, we generated a floxed Grp mouse line. We found that conditional knockout of Grp in sensory neurons results in attenuated non-histaminergic itch, without impairing histamine-induced itch. Using a Grp-Cre knock-in mouse line, we show that the upper epidermis of the skin is exclusively innervated by GRP fibers, whose activation via optogeneics and chemogenetics in the skin evokes itch- but not pain-related scratching or wiping behaviors. In contrast, intersectional genetic ablation of spinal Grp neurons does not affect itch nor pain transmission, demonstrating that spinal Grp neurons are dispensable for itch transmission. These data indicate that GRP is a neuropeptide in sensory neurons for non-histaminergic itch, and GRP sensory neurons are dedicated to itch transmission.

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References

Sun Y, Zhong-Qiu Zhao , Meng X, Yin J, Liu X, Chen Z . Cellular basis of itch sensation. Science. 2009; 325(5947):1531-4. PMC: 2786498. DOI: 10.1126/science.1174868. View

Jeffry J, Kim S, Chen Z . Itch signaling in the nervous system. Physiology (Bethesda). 2011; 26(4):286-92. PMC: 3684411. DOI: 10.1152/physiol.00007.2011. View

Lawson S, Waddell P . Soma neurofilament immunoreactivity is related to cell size and fibre conduction velocity in rat primary sensory neurons. J Physiol. 1991; 435:41-63. PMC: 1181449. DOI: 10.1113/jphysiol.1991.sp018497. View

Liu T, Berta T, Xu Z, Park C, Zhang L, Lu N . TLR3 deficiency impairs spinal cord synaptic transmission, central sensitization, and pruritus in mice. J Clin Invest. 2012; 122(6):2195-207. PMC: 3366391. DOI: 10.1172/JCI45414. View

Munanairi A, Liu X, Barry D, Yang Q, Yin J, Jin H . Non-canonical Opioid Signaling Inhibits Itch Transmission in the Spinal Cord of Mice. Cell Rep. 2018; 23(3):866-877. PMC: 5937707. DOI: 10.1016/j.celrep.2018.03.087. View

Caterina M, Leffler A, Malmberg A, Martin W, Trafton J, Koltzenburg M . Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science. 2000; 288(5464):306-13. DOI: 10.1126/science.288.5464.306. View

Liu X, Liu Z, Sun Y, Ross M, Kim S, Tsai F . Unidirectional cross-activation of GRPR by MOR1D uncouples itch and analgesia induced by opioids. Cell. 2011; 147(2):447-58. PMC: 3197217. DOI: 10.1016/j.cell.2011.08.043. View

Barry D, Li H, Liu X, Shen K, Liu X, Wu Z . Critical evaluation of the expression of gastrin-releasing peptide in dorsal root ganglia and spinal cord. Mol Pain. 2016; 12. PMC: 4972254. DOI: 10.1177/1744806916643724. View

Akiyama T, Nagamine M, Carstens M, Carstens E . Behavioral model of itch, alloknesis, pain and allodynia in the lower hindlimb and correlative responses of lumbar dorsal horn neurons in the mouse. Neuroscience. 2014; 266:38-46. PMC: 4063361. DOI: 10.1016/j.neuroscience.2014.02.005. View

10.

Mishra S, Hoon M . The cells and circuitry for itch responses in mice. Science. 2013; 340(6135):968-71. PMC: 3670709. DOI: 10.1126/science.1233765. View

11.

Zhu H, Aryal D, Olsen R, Urban D, Swearingen A, Forbes S . Cre-dependent DREADD (Designer Receptors Exclusively Activated by Designer Drugs) mice. Genesis. 2016; 54(8):439-46. PMC: 4990490. DOI: 10.1002/dvg.22949. View

12.

Nattkemper L, Zhong-Qiu Zhao , Nichols A, Papoiu A, Shively C, Chen Z . Overexpression of the gastrin-releasing peptide in cutaneous nerve fibers and its receptor in the spinal cord in primates with chronic itch. J Invest Dermatol. 2013; 133(10):2489-2492. PMC: 3737283. DOI: 10.1038/jid.2013.166. View

13.

Madisen L, Zwingman T, Sunkin S, Oh S, Zariwala H, Gu H . A robust and high-throughput Cre reporting and characterization system for the whole mouse brain. Nat Neurosci. 2009; 13(1):133-40. PMC: 2840225. DOI: 10.1038/nn.2467. View

14.

Wilson S, The L, Batia L, Beattie K, Katibah G, McClain S . The epithelial cell-derived atopic dermatitis cytokine TSLP activates neurons to induce itch. Cell. 2013; 155(2):285-95. PMC: 4041105. DOI: 10.1016/j.cell.2013.08.057. View

15.

Bell A, Gutierrez-Mecinas M, Polgar E, Todd A . Spinal neurons that contain gastrin-releasing peptide seldom express Fos or phosphorylate extracellular signal-regulated kinases in response to intradermal chloroquine. Mol Pain. 2016; 12. PMC: 4937990. DOI: 10.1177/1744806916649602. View

16.

Pagani M, Albisetti G, Sivakumar N, Wildner H, Santello M, Johannssen H . How Gastrin-Releasing Peptide Opens the Spinal Gate for Itch. Neuron. 2019; 103(1):102-117.e5. PMC: 6616317. DOI: 10.1016/j.neuron.2019.04.022. View

17.

Gutierrez-Mecinas M, Watanabe M, Todd A . Expression of gastrin-releasing peptide by excitatory interneurons in the mouse superficial dorsal horn. Mol Pain. 2014; 10:79. PMC: 4320531. DOI: 10.1186/1744-8069-10-79. View

18.

Gong X, Xiong H, Liu S, Liu Y, Yin L, Tu C . Qingpeng Ointment Ameliorates Inflammatory Responses and Dysregulation of Itch-Related Molecules for Its Antipruritic Effects in Experimental Allergic Contact Dermatitis. Front Pharmacol. 2019; 10:354. PMC: 6465648. DOI: 10.3389/fphar.2019.00354. View

19.

Kim S, Barry D, Liu X, Yin S, Munanairi A, Meng Q . Facilitation of TRPV4 by TRPV1 is required for itch transmission in some sensory neuron populations. Sci Signal. 2016; 9(437):ra71. PMC: 5310287. DOI: 10.1126/scisignal.aaf1047. View

20.

Zhong-Qiu Zhao , Huo F, Jeffry J, Hampton L, Demehri S, Kim S . Chronic itch development in sensory neurons requires BRAF signaling pathways. J Clin Invest. 2013; 123(11):4769-80. PMC: 3809799. DOI: 10.1172/JCI70528. View