GnRH Peripherally Modulates Nociceptor Functions, Exacerbating Mechanical Pain

Overview

Journal Front Mol Neurosci

Specialty Molecular Biology

Date 2024 May 24

PMID 38783903

Authors

Haiyan Zheng

Minseok Kim

Chaeun Kim

Yerin Kim

Pyung Sun Cho

Ji Yeon Lim

Hojin Lee

Hye-In Yun

Jungmin Choi

Sun Wook Hwang

Affiliations

Soon will be listed here.

Abstract

The function of peripheral nociceptors, the neurons that relay pain signals to the brain, are frequently tuned by local and systemic modulator substances. In this context, neurohormonal effects are emerging as an important modulatory mechanism, but many aspects remain to be elucidated. Here we report that gonadotropin-releasing hormone (GnRH), a brain-specific neurohormone, can aggravate pain by acting on nociceptors in mice. GnRH and GnRHR, the receptor for GnRH, are expressed in a nociceptor subpopulation. Administration of GnRH and its analogue, localized for selectively affecting the peripheral neurons, deteriorated mechanical pain, which was reproducible in neuropathic conditions. Nociceptor function was promoted by GnRH treatment , which appears to involve specific sensory transient receptor potential ion channels. These data suggest that peripheral GnRH can positively modulate nociceptor activities in its receptor-specific manner, contributing to pain exacerbation. Our study indicates that GnRH plays an important role in neurohormonal pain modulation via a peripheral mechanism.

References

Yoo S, Lim J, Hwang S . Resolvins: Endogenously-Generated Potent Painkilling Substances and their Therapeutic Perspectives. Curr Neuropharmacol. 2014; 11(6):664-76. PMC: 3849791. DOI: 10.2174/1570159X11311060009. View

Camprubi-Robles M, Planells-Cases R, Ferrer-Montiel A . Differential contribution of SNARE-dependent exocytosis to inflammatory potentiation of TRPV1 in nociceptors. FASEB J. 2009; 23(11):3722-33. DOI: 10.1096/fj.09-134346. View

Grundker C, Emons G . The Role of Gonadotropin-Releasing Hormone in Cancer Cell Proliferation and Metastasis. Front Endocrinol (Lausanne). 2017; 8:187. PMC: 5543040. DOI: 10.3389/fendo.2017.00187. View

Bhave G, Zhu W, Wang H, Brasier D, Oxford G, Gereau 4th R . cAMP-dependent protein kinase regulates desensitization of the capsaicin receptor (VR1) by direct phosphorylation. Neuron. 2002; 35(4):721-31. DOI: 10.1016/s0896-6273(02)00802-4. View

Zhang W, Delay R . Gonadotropin-releasing hormone modulates voltage-activated sodium current and odor responses in Necturus maculosus olfactory sensory neurons. J Neurosci Res. 2007; 85(8):1656-67. DOI: 10.1002/jnr.21297. View

Ji R, Samad T, Jin S, Schmoll R, Woolf C . p38 MAPK activation by NGF in primary sensory neurons after inflammation increases TRPV1 levels and maintains heat hyperalgesia. Neuron. 2002; 36(1):57-68. DOI: 10.1016/s0896-6273(02)00908-x. View

Corder G, Castro D, Bruchas M, Scherrer G . Endogenous and Exogenous Opioids in Pain. Annu Rev Neurosci. 2018; 41:453-473. PMC: 6428583. DOI: 10.1146/annurev-neuro-080317-061522. View

Choi S, Lim J, Yoo S, Kim H, Hwang S . Emerging Role of Spinal Cord TRPV1 in Pain Exacerbation. Neural Plast. 2016; 2016:5954890. PMC: 4738952. DOI: 10.1155/2016/5954890. View

Choi G, Hwang S . Modulation of the Activities of Neuronal Ion Channels by Fatty Acid-Derived Pro-Resolvents. Front Physiol. 2016; 7:523. PMC: 5099253. DOI: 10.3389/fphys.2016.00523. View

10.

Bang S, Hwang S . Polymodal ligand sensitivity of TRPA1 and its modes of interactions. J Gen Physiol. 2009; 133(3):257-62. PMC: 2654089. DOI: 10.1085/jgp.200810138. View

11.

Watanabe H, Vriens J, Prenen J, Droogmans G, Voets T, Nilius B . Anandamide and arachidonic acid use epoxyeicosatrienoic acids to activate TRPV4 channels. Nature. 2003; 424(6947):434-8. DOI: 10.1038/nature01807. View

12.

Shin J, Cho H, Hwang S, Jung J, Shin C, Lee S . Bradykinin-12-lipoxygenase-VR1 signaling pathway for inflammatory hyperalgesia. Proc Natl Acad Sci U S A. 2002; 99(15):10150-5. PMC: 126639. DOI: 10.1073/pnas.152002699. View

13.

Choi G, Yang T, Yoo S, Choi S, Lim J, Cho P . TRPV4-Mediated Anti-nociceptive Effect of Suberanilohydroxamic Acid on Mechanical Pain. Mol Neurobiol. 2018; 56(1):444-453. DOI: 10.1007/s12035-018-1093-x. View

14.

Kim C, Kim Y, Lim J, Kim M, Zheng H, Kim M . Pamoic acid-induced peripheral GPR35 activation improves pruritus and dermatitis. Br J Pharmacol. 2023; 180(23):3059-3070. DOI: 10.1111/bph.16201. View

15.

Kupari J, Usoskin D, Parisien M, Lou D, Hu Y, Fatt M . Single cell transcriptomics of primate sensory neurons identifies cell types associated with chronic pain. Nat Commun. 2021; 12(1):1510. PMC: 7940623. DOI: 10.1038/s41467-021-21725-z. View

16.

Nassini R, Gees M, Harrison S, De Siena G, Materazzi S, Moretto N . Oxaliplatin elicits mechanical and cold allodynia in rodents via TRPA1 receptor stimulation. Pain. 2011; 152(7):1621-1631. DOI: 10.1016/j.pain.2011.02.051. View

17.

Edvinsson L, Haanes K, Warfvinge K . Does inflammation have a role in migraine?. Nat Rev Neurol. 2019; 15(8):483-490. DOI: 10.1038/s41582-019-0216-y. View

18.

Utreras E, Keller J, Terse A, Prochazkova M, Iadarola M, Kulkarni A . Transforming growth factor-β1 regulates Cdk5 activity in primary sensory neurons. J Biol Chem. 2012; 287(20):16917-29. PMC: 3351291. DOI: 10.1074/jbc.M111.329979. View

19.

Kuhn M, Letunic I, Jensen L, Bork P . The SIDER database of drugs and side effects. Nucleic Acids Res. 2015; 44(D1):D1075-9. PMC: 4702794. DOI: 10.1093/nar/gkv1075. View

20.

Zheng H, Lim J, Kim Y, Jung S, Hwang S . The role of oxytocin, vasopressin, and their receptors at nociceptors in peripheral pain modulation. Front Neuroendocrinol. 2021; 63:100942. DOI: 10.1016/j.yfrne.2021.100942. View