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Altered purinergic signaling in colorectal dorsal root ganglion neurons contributes to colorectal hypersensitivity.

ABSTRACT: Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder characterized by pain and hypersensitivity in the relative absence of colon inflammation or structural changes. To assess the role of P2X receptors expressed in colorectal dorsal root ganglion (c-DRG) neurons and colon hypersensitivity, we studied excitability and purinergic signaling of retrogradely labeled mouse thoracolumbar (TL) and lumbosacral (LS) c-DRG neurons after intracolonic treatment with saline or zymosan (which reproduces 2 major features of IBS-persistent colorectal hypersensitivity without inflammation) using patch-clamp, immunohistochemical, and RT-PCR techniques. Although whole cell capacitances did not differ between LS and TL c-DRG neurons and were not changed after zymosan treatment, membrane excitability was increased in LS and TL c-DRG neurons from zymosan-treated mice. Purinergic agonist adenosine-5'-triphosphate (ATP) and ?,?-methylene ATP [?,?-meATP] produced inward currents in TL c-DRG neurons were predominantly P2X(3)-like fast (?70% of responsive neurons); P2X(2/3)-like slow currents were more common in LS c-DRG neurons (?35% of responsive neurons). Transient currents were not produced by either agonist in c-DRG neurons from P2X(3)(-/-) mice. Neither total whole cell Kv current density nor the sustained or transient Kv components was changed in c-DRG neurons after zymosan treatment. The number of cells expressing P2X(3) protein and its mRNA and the kinetic properties of ATP- and ?,?-meATP-evoked currents in c-DRG neurons were not changed by zymosan treatment. However, the EC(50) of ?,?-meATP for the fast current decreased significantly in TL c-DRG neurons. These findings suggest that colorectal hypersensitivity produced by intracolonic zymosan increases excitability and enhances purinergic signaling in c-DRG neurons.

SUBMITTER: Shinoda M

PROVIDER: S-EPMC3007642 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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Altered purinergic signaling in colorectal dorsal root ganglion neurons contributes to colorectal hypersensitivity.

Shinoda Masamichi M La Jun-Ho JH Bielefeldt Klaus K Gebhart G F GF

Journal of neurophysiology 20100922 6

Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder characterized by pain and hypersensitivity in the relative absence of colon inflammation or structural changes. To assess the role of P2X receptors expressed in colorectal dorsal root ganglion (c-DRG) neurons and colon hypersensitivity, we studied excitability and purinergic signaling of retrogradely labeled mouse thoracolumbar (TL) and lumbosacral (LS) c-DRG neurons after intracolonic treatment with saline or zymosan (whic ...[more]

PMID: 20861433

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Project description:Postoperative pain remains a complex problem that is difficult to manage in the clinical context, seriously affecting rehabilitation and the quality of life of patients after surgery. Nociceptors, of which the cell bodies are located in the dorsal root ganglion, are crucial for initiating and conducting the pain signal. The peripheral voltage-gated sodium channels, including Nav1.7, which is mainly expressed in the dorsal root ganglion, are key to understanding the mechanism underlying postoperative pain. Nav1.7, in particular, of which mutations in the encoding gene ( SCN9A) can determine whether pain occurs, has aroused most attention. Previous studies have shown that Nav1.7 in dorsal root ganglion is critical for the development of inflammatory pain and some neuropathic pain. However, the expression of Nav1.7 in the dorsal root ganglion after surgery and its role in postoperative pain hypersensitivity remain unclear. Therefore, in this study, in order to gain a better understanding of the role of dorsal root ganglion Nav1.7 in pain hypersensitivity following operation, we dynamically examined the pain-related behavior and expression of Nav1.7 in L4-L6 dorsal root ganglion before and after plantar incision in rats (an acute postoperative pain model). After plantar incision, the mechanical and thermal pain threshold decreased significantly, the cumulative pain score was increased significantly, meanwhile quantitative polymerase chain reaction and Western blotting results showed that expression of Nav1.7 in L4-L6 dorsal root ganglion was enhanced significantly. After pretreatment using SCN9A-RNAi-LV delivered via an intrathecal tube, immunohistochemistry showed that increased expression of Nav1.7 in L4-L6 dorsal root ganglion after plantar incision was inhibited, as also confirmed by quantitative polymerase chain reaction and Western blotting. Moreover, pain hypersensitivity was alleviated. These results suggested that Nav1.7 of L4-L6 dorsal root ganglion plays an important role in the development of pain hypersensitivity after plantar incision.

Dataset Information

Altered purinergic signaling in colorectal dorsal root ganglion neurons contributes to colorectal hypersensitivity.

Publications

Altered purinergic signaling in colorectal dorsal root ganglion neurons contributes to colorectal hypersensitivity.

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