G-Protein-Coupled Estrogen Receptor (GPER) in the Rostral Ventromedial Medulla Is Essential for Mobilizing Descending Inhibition of Itch

Abstract

Chronic itch is a troublesome condition and often difficult to cure. Emerging evidence suggests that the periaqueductal gray-rostral ventromedial medulla (PAG-RVM) pathway may play an important role in regulation of itch, but the cellular organization and molecular mechanisms remain incompletely understood. Here, we report that a group of RVM neurons distinctively express the G protein-coupled estrogen receptor (GPER), which mediates descending inhibition of itch. We found that GPER + neurons in RVM were activated in chronic itch conditions in rats and mice. Selective ablation or chemogenetic suppression of RVM GPER + neurons resulted in mechanical alloknesis and increased scratching in response to pruritogens, whereas chemogenetic activation of GPER + neurons abrogated itch responses, indicating that GPER + neurons are antipruritic. Moreover, GPER-deficient mice and rats of either sex exhibited hypersensitivity to mechanical and chemical itch, a phenotype reversible by μ type opioid receptor (MOR) antagonism. Additionally, significant MOR phosphorylation in the RVM was detected in chronic itch models in wild-type but not in GPER -/rats. Therefore, GPER not only identifies a population of medullary antipruritic neurons but may also determine the descending antipruritic tone through regulating μ-opioid signaling.4 Significance Statement (120 words maximum) Therapeutic options for itch are limited due to as yet incomplete understanding of the mechanisms of itch processing. Our data have provided novel insights into the cellular organization and molecular mechanisms of descending regulation of itch in normal and pathological conditions: GPER + neurons (largely GABAergic) in the RVM are anti-pruritic neurons under tonic opioidergic inhibition; activation of GPER promotes phosphorylation of MOR and dis-inhibition of the anti-pruritic GPER + neurons from inhibitory opioidergic inputs; failure to mobilize GPER + neurons may result in exacerbation of itch. Our data also illuminate on some of the outstanding questions in the field, such as the mechanisms underlying sex bias in itch, pain and opioid analgesia and the paradoxical effects of morphine on pain and itch.

Molecular identification of bulbospinal ON neurons by GPER, which drives pain and morphine tolerance

“…We obtained a line of Gper gene knockout rats (28,30), which showed significant reduction of GPER immunofluorescence in the RVM (Supplemental Figure 7). We compared the level of RVM neuronal activity between wild type and Gper -/rats in chronic inflammatory pain conditions by c-Fos immunostaining conducted at day 7 following intraplantar injection of CFA (with saline as control).…”

“…Wild type and transgenic Sprague-Dawley rats (male and female, either adult, 220-250 g, 10-12 weeks old, or neonatal, P12-15 days) and C57/BL6 mice were housed (4 animals per cage) in a temperature (22-25 °C) and humidity (50%) controlled room with a 12/12 h light/dark cycle, with food and water being available ad libitum. Gper-deficient (Gper -/-) rats (28) and mice (30) were generated by the Bioray Biotechnology company in Shanghai.…”

Inhibition of itch by neurokinin 1 receptor (Tacr1) -expressing ON cells in the rostral ventromedial medulla in mice

“…It was recently reported that activation of neurons in RVM that express the G-protein-coupled estrogen receptor (GPER) suppresses signs of acute and chronic itch ( Gao et al, 2021 ). It is currently not known if GPER-expressing neurons co-express Tacr1.…”

“…Descending modulation is also thought to underlie stress mediated changes in pain threshold, with acute stress inhibiting and chronic stress facilitating nociceptive transmission ( Butler and Finn, 2009 ; Fields, 2000 ; Jennings et al, 2014 ; Wager and Atlas, 2015 ). Recent studies indicate that the spinal transmission of pruriceptive information is also under descending modulatory influences, but it is not known whether itch is modulated in the same way as pain ( Agostinelli and Bassuk, 2021 ; Gao et al, 2021 ; Gao et al, 2019 ; Koga et al, 2020 ; Liu et al, 2019 ; Samineni et al, 2019 ; Wu et al, 2021 ).…”

Inhibition of itch by neurokinin 1 receptor (Tacr1) -expressing ON cells in the rostral ventromedial medulla

“…Descending modulation is also thought to underlie stress mediated changes in pain threshold, with acute stress inhibiting and chronic stress facilitating nociceptive transmission (Butler & Finn, 2009;Fields, 2000;Jennings et al, 2014;Wager & Atlas, 2015). Recent studies indicate that the spinal transmission of pruriceptive information is also under descending modulatory influences, but it is not known whether itch is modulated in the same way as pain (Agostinelli & Bassuk, 2021;Gao et al, 2021;Gao et al, 2019;Koga et al, 2020;Liu et al, 2019;Samineni et al, 2019;Wu et al, 2021).…”