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MicroRNA–mediated downregulation of potassium-chloride-cotransporter and vesicular γ-aminobutyric acid transporter expression in spinal cord contributes to neonatal cystitis–induced visceral pain in rats

Zhang, Jiana; Yu, Jamesa; Kannampalli, Pradeepa; Nie, Linghuib; Meng, Huic; Medda, Bidyut K.a; Shaker, Rezaa; Sengupta, Jyoti N.a; Banerjee, Banania,*

doi: 10.1097/j.pain.0000000000001057
Research Paper

Loss of GABAergic inhibition in pain pathways has been considered to be a key component in the development of chronic pain. In the present study, we intended to examine whether miR-92b–mediated posttranscriptional dysregulation of spinal potassium chloride cotransporter (KCC2) and vesicular γ-aminobutyric acid transporter (VGAT) plays a major role in the development and maintenance of long-term visceral hyperalgesia in neonatal zymosan–treated rats. Neonatal cystitis was induced by transurethral zymosan administration from postnatal (P) days 14 to 16 (protocol 1). Two other zymosan protocols were also used: adult rechallenge on P57 to 59 following neonatal P14 to 16 exposures (protocol 2), and adult zymosan exposures on P57 to 59 (protocol 3). Both neonatal and adult bladder inflammation protocols demonstrated an increase in spinal miR-92b-3p expression and subsequent decrease in KCC2 and VGAT expression in spinal dorsal horn neurons. In situ hybridization demonstrated a significant upregulation of miR-92b-3p in the spinal dorsal horn neurons of neonatal cystitis rats compared with saline-treated controls. In dual in situ hybridization and immunohistochemistry studies, we further demonstrated coexpression of miR-92b-3p with targets KCC2 and VGAT in spinal dorsal horn neurons, emphasizing a possible regulatory role both at pre- and post-synaptic levels. Intrathecal administration of lentiviral pLSyn-miR-92b-3p sponge (miR-92b-3p inhibitor) upregulated KCC2 and VGAT expression in spinal dorsal horn neurons. In behavioral studies, intrathecal administration of lentiviral miR-92b-3p sponge attenuated an increase in visceromotor responses and referred viscerosomatic hypersensitivity following the induction of cystitis. These findings indicate that miR-92b-3p–mediated posttranscriptional regulation of spinal GABAergic system plays an important role in sensory pathophysiology of zymosan-induced cystitis.

This study emphasizes that the miRNA-mediated downregulation of spinal GABAergic function in zymosan-induced cystitis may play a role in the development of chronic pelvic pain.

aDivision of Gastroenterology and Hepatology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA

Departments of bSurgery and

cPathology, Medical College of Wisconsin, Milwaukee, WI, USA

Corresponding author. Address: Division of Gastroenterology, Medical College of Wisconsin, Milwaukee, WI 53226, USA. Tel.: 414-456-4493; fax: 414-456-6361. E-mail address: (B. Banerjee).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Received April 10, 2017

Received in revised form August 21, 2017

Accepted August 28, 2017

© 2017 International Association for the Study of Pain
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