Vagal afferents mediate antinociception of estrogen in a rat model of visceral pain: the involvement of intestinal mucosal mast cells and 5-hydroxytryptamine 3 signaling.
Estrogen reportedly facilitates visceral nociception at the spinal or supraspinal level. The present study was aimed to investigate whether estrogen modulates visceral pain through the vagal pathway. Ovariectomized rats received estradiol, which was administered subcutaneously (to act through both the vagal and spinal pathways) or intraduodenally (to preferentially act through the vagal pathway). Luminally applied estradiol induced a rapid and significant decrease in the visceromotor response to colorectal distension, with increased c-Fos expression in nodose ganglion neurons. Systemically injected estradiol increased visceromotor response and c-Fos expression in both nodose and dorsal root ganglion (T6-12) neurons. The antinociceptive effect of estrogen was abolished by surgical vagotomy or chemical denervation of vagal afferents. Both luminally and systemically administered estradiol elicited selective 5-hydroxytryptamine secretion from the duodenum. Granisetron, a 5-hydroxytryptamine 3 receptor antagonist, reversed the antinociceptive effect of estrogen. Intestinal mucosal mast cell stabilizers prevented estradiol-induced antinociception and 5-hydroxytryptamine secretion. Ultrastructural analysis revealed that estradiol caused piecemeal degranulation of intestinal mucosal mast cells. The actions of estradiol were inhibited by an estrogen receptor β antagonist and mimicked by an estrogen receptor β agonist. These results suggest that estrogen can trigger vagus-mediated antinociception, which is masked by its spinally mediated pronociception.


CONCLUSIONS
This study is the first to show a vagus-mediated estrogenic antinociception, in which the nongenomic estrogen receptor β-mediated, intestinal mucosal mast cell-derived 5-hydroxytryptamine/5-hydroxytryptamine 3 receptor pathway is involved. This work may provide new insights into the sex hormone modulation of visceral sensitivity related to irritable bowel syndrome and indicate potential therapeutic targets to manage this disease.
Department of Gastroenterology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China.
Xiu-Juan
XJ
Yan
Department of Gastroenterology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China.
Chen-Chen
CC
Feng
Department of Gastroenterology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China.
Qing
Q
Liu
Department of Gastroenterology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China.
Li-Yan
LY
Zhang
Department of Gastroenterology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China.
Xiao
X
Dong
Department of Gastroenterology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China.
Zong-Liang
ZL
Liu
Department of Gastroenterology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China.
Zhi-Jun
ZJ
Cao
Department of Gastroenterology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China.
Jian-Zhong
JZ
Mo
Department of Biology and Chemistry, City University of Hong Kong, Hong Kong SAR, China.
Ying
Y
Li
Department of Gastroenterology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China.
Jing-Yuan
JY
Fang
Department of Gastroenterology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China. Electronic address: slchenmd@hotmail.com.
Sheng-Liang
SL
Chen
D000344:Afferent Pathways / Q000187:drug effects / Q000503:physiopathology; D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D004386:Duodenum / Q000187:drug effects / Q000503:physiopathology; D004958:Estradiol / Q000008:administration & dosage / Q000494:pharmacology*; D004967:Estrogens / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D005727:Ganglia, Spinal / Q000187:drug effects / Q000503:physiopathology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000503:physiopathology / Q000648:ultrastructure; D008407:Mast Cells / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009620:Nodose Ganglion / Q000187:drug effects / Q000503:physiopathology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000378:metabolism; D044406:Receptors, Serotonin, 5-HT3 / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism; D014630:Vagus Nerve / Q000187:drug effects* / Q000503:physiopathology; D059265:Visceral Pain / Q000188:drug therapy* / Q000503:physiopathology*
D000700:Analgesics; D004967:Estrogens; D016760:Proto-Oncogene Proteins c-fos; D011960:Receptors, Estrogen; D044406:Receptors, Serotonin, 5-HT3; D012701:Serotonin; D004958:Estradiol
Visceral pain; intestinal mucosal mast cells; serotonin; sex hormone; vagal afferents