title: Activation of corticotropin-releasing factor neurons and microglia in paraventricular nucleus precipitates visceral hypersensitivity induced by colorectal distension in rats.
abstract: Visceral hypersensitivity is a major contributor to irritable bowel syndrome and other disorders with visceral pain. Substantial evidence has established that glial activation and neuro-glial interaction play a key role in the establishment and maintenance of visceral hypersensitivity. We recently demonstrated that activation of spinal microglial toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88)/nuclear factor κB (NF-κB) signaling facilitated the development of visceral hypersensitivity in a rat model developed by neonatal and adult colorectal distensions (CRDs). Hypothalamic paraventricular nucleus (PVN) plays a pivotal role in the pathogenesis of chronic pain. In this study, we examined the mechanism by which microglia and neurons in PVN establish and maintain visceral hypersensitivity and the involvement of TLR4 signaling. Visceral hypersensitivity was precipitated by adult colorectal distension (CRD) only in rats that experienced neonatal CRDs. Visceral hypersensitivity was associated with an increase in the expression of c-fos, corticotropin-releasing factor (CRF) protein and mRNA in PVN, which could be prevented by intra-PVN infusion of lidocaine or small interfering RNA targeting the CRF gene. These results suggest PVN CRF neurons modulate visceral hypersensitivity. Adult CRD induced an increase in the expression of Iba-1 (a microglial marker), TLR4 protein, and its downstream effectors MyD88, NF-κB, as well as proinflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) only in rats that experienced neonatal CRDs. Intra-PVN infusion of minocycline, a nonselective microglial inhibitor, attenuated the hyperactivity of TLR4 signaling cascade, microglial activation, and visceral hypersensitivity. Taken together, these data suggest that neonatal CRDs induce a glial activation in PVN. Adult CRD potentiates the glial and CRF neuronal activity, and precipitates visceral hypersensitivity and pain. TLR4 signaling and proinflammatory cytokines TNF-α and IL-1β may participate in neuro-glial interaction during the pathogenesis of visceral hypersensitivity.
authors.affiliation: School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui 230032, China.
authors.forename: Gongliang
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou, Jiangsu 221002, China.
authors.forename: Le
authors.initials: L
authors.lastname: Yu
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou, Jiangsu 221002, China.
authors.forename: Zi-Yang
authors.initials: ZY
authors.lastname: Chen
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou, Jiangsu 221002, China.
authors.forename: Jun-Sheng
authors.initials: JS
authors.lastname: Zhu
authors.affiliation: Department of Emergency Medicine, The 97th Hospital of PLA, Xuzhou, Jiangsu 221002, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Hua
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou, Jiangsu 221002, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Qin
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou, Jiangsu 221002, China.
authors.forename: Jun-Li
authors.initials: JL
authors.lastname: Cao
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou, Jiangsu 221002, China. Electronic address: zhangym700@163.com.
authors.forename: Yong-Mei
authors.initials: YM
authors.lastname: Zhang
mesh_terms: D000818:Animals; D003106:Colon / Q000503:physiopathology; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism*; D004195:Disease Models, Animal; D043183:Irritable Bowel Syndrome / Q000378:metabolism*; D008297:Male; D017628:Microglia / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D010286:Paraventricular Hypothalamic Nucleus / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012007:Rectum / Q000503:physiopathology; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D059265:Visceral Pain / Q000378:metabolism*
chemical_list: C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D003346:Corticotropin-Releasing Hormone
keywords: Irritable bowel syndrome; Microglia; Paraventricular nucleus; Toll-like receptor 4; Visceral hypersensitivity