Abstract
Chronic visceral pain is one of the primary symptoms of patients with irritable bowel syndrome (IBS), which affects up to 15% of the population world-wide. The detailed mechanisms of visceral pain remain largely unclear. Our previous studies have shown that neonatal maternal deprivation (NMD) followed by adult multiple stress (AMS) advances the occurrence of visceral pain, likely due to enhanced norepinephrine (NE)-β2 adrenergic signaling. This study was designed to explore the roles of P2X3 receptors (P2X3Rs) in the chronic visceral pain induced by combined stress. Here, we showed that P2X3Rs were co-expressed in β2 adrenergic receptor (β2-AR)-positive dorsal root ganglion neurons and that NE significantly enhanced ATP-induced Ca2+ signals. NMD and AMS not only significantly increased the protein expression of P2X3Rs, but also greatly enhanced the ATP-evoked current density, number of action potentials, and intracellular Ca2+ concentration of colon-related DRG neurons. Intrathecal injection of the P2X3R inhibitor A317491 greatly attenuated the visceral pain and the ATP-induced Ca2+ signals in NMD and AMS rats. Furthermore, the β2-AR antagonist butoxamine significantly reversed the expression of P2X3Rs, the ATP-induced current density, and the number of action potentials of DRG neurons. Overall, our data demonstrate that NMD followed by AMS leads to P2X3R activation, which is most likely mediated by upregulation of β2 adrenergic signaling in primary sensory neurons, thus contributing to visceral hypersensitivity.
Highlights
Irritable bowel syndrome (IBS) is a common gastrointestinal disorder characterized by intestinal dyskinesia and associated with chronic abdominal pain [1,2,3]
Our previous study confirmed that neonatal maternal deprivation (NMD) combined with adult multiple stress (AMS) induced visceral hyperalgesia in rats at 6 weeks and demonstrated that NE signaling is an important mechanism of combined stress-induced visceral hyperalgesia by regulating b2 adrenergic receptor (b2-adrenergic receptor (AR)) [30]
This study showed that the protein expression of P2X3 receptors (P2X3Rs) in T13–L2 dorsal root ganglion (DRG) was significantly up-regulated in the NMD?AMS model
Summary
Irritable bowel syndrome (IBS) is a common gastrointestinal disorder characterized by intestinal dyskinesia and associated with chronic abdominal pain [1,2,3]. The clinical treatment of chronic abdominal pain is very difficult [4,5,6]. Previous studies have deepened the understanding of the occurrence and regulation of chronic somatic pain [7,8,9,10], the exact pathophysiological mechanism of IBS abdominal pain has not been fully elucidated. Our previous studies have shown that neonatal maternal deprivation (NMD) followed by adult multiple stress (AMS) advances the occurrence of visceral hypersensitivity in rats, partly due to enhanced norepinephrine (NE)-b2 adrenergic signaling, while NMD alone does not Neurosci. The mechanism by which NE-b2 adrenergic signaling induces visceral pain remains unknown
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