Pronociceptive Effect of 5-HT1A Receptor Agonist on Visceral Pain Involves Spinal NMDA Receptor

The functional role of serotonergic 5-HT1A receptors in the modulation of visceral pain is controversial. The objective of this study was to systematically examine the mechanism and site of action of a selective 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (DPAT) on visceral pain. In the behavioral model of visceral pain, systemic injection (5 to 250μg/kg) of DPAT produced a significant increase in the viscero-motor response (VMR) to colorectal distension (CRD) and this effect was blocked by the selective 5-HT1A receptor antagonist WAY-100135 (5mg/kg, s.c.). Similarly, intrathecal (i.t.) injection (5μmol) of DPAT into the lumbo-sacral (L6-S1) spinal cord produced a significant increase in VMR. The administration of N-methyl D-aspartate (NMDA) receptor antagonist AP5 (50μg/kg) prior to DPAT injection completely blocked the pronociceptive effect of DPAT. Similarly, DPAT failed to increase VMR in rats chronically treated with NR1 subunit targeted antisense oligoneucleotide (ON), whereas the drug increased VMR in rats treated with mismatched-ON. Chronic i.t. injection of allylglycine (AG), a γ-amino decarboxylase (GAD) enzyme inhibitor, produced significant increase in VMRs, suggesting that the inhibition of GABA synthesis produces pronociception. In AG-treated rats, i.t. injection of DPAT failed to further increase in VMR, suggesting that the DPAT action is linked to GABA release. Similarly, WAY-100135 failed to attenuate VMR in AG-treated rats, suggesting that unlike DPAT, AG action is not via the activation of 5-HT1A receptors. In electrophysiology experiments, DPAT (50μg/kg) significantly increased the responses of spinal neurons to CRD, but did not influence the mechanotransduction property of CRD-sensitive pelvic nerve afferent fibers. The effect of DPAT on spinal neurons remained unaffected when tested in spinal transected (C1– C2) rats. These results indicate that the 5-HT1A receptor agonist DPAT produces pronociceptive effects, primarily via the activation of presynaptic 5-HT1A receptors in GABAergic neuron to restrict GABA release and thereby disinhibits the excitatory glutamatergic neurons in the spinal cord. © 2012 IBRO. Published by Elsevier Ltd. All rights reserved. Corresponding author: Jyoti N. Sengupta, PhD. , Division of Gastroenterology and Hepatology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, Tel: 414-456-4011, Fax: 414-456-6361, sengupta@mcw.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Conflict of Interest Statement: None of the contributing authors have any conflict of interest. All authors are in agreement with the content of this manuscript. NIH Public Access Author Manuscript Neuroscience. Author manuscript; available in PMC 2013 September 06. Published in final edited form as: Neuroscience. 2012 September 6; 219: 243–254. doi:10.1016/j.neuroscience. 2012.05. 030. N IH PA Athor M anscript N IH PA Athor M anscript N IH PA Athor M anscript