Faculty Collaboration Database

Pronociceptive effect of 5-HT(1A) receptor agonist on visceral pain involves spinal N-methyl-D-aspartate (NMDA) receptor. Neuroscience 2012 Sep 06;219:243-54

Date

05/26/2012

Pubmed ID

22626644

Pubmed Central ID

PMC3402596

DOI

10.1016/j.neuroscience.2012.05.030

Scopus ID

2-s2.0-84864075446 (requires institutional sign-in at Scopus site)   10 Citations

Abstract

The functional role of serotonergic 5-HT(1A) 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-HT(1A) receptor agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (DPAT) on visceral pain. In the behavioral model of visceral pain, systemic injection (5-250 μg/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-HT(1A) receptor antagonist WAY-100135 (5 mg/kg, s.c.). Similarly, intrathecal (i.t.) injection (5 μmol) 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 (50 μg/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 oligonucleotide (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-HT(1A) receptors. In electrophysiology experiments, DPAT (50 μg/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-HT(1A) receptor agonist DPAT produces pronociceptive effects, primarily via the activation of presynaptic 5-HT(1A) receptors in GABAergic neuron to restrict GABA release and thereby disinhibits the excitatory glutamatergic neurons in the spinal cord.

Author List

Mickle A, Kannampalli P, Bruckert M, Miranda A, Banerjee B, Sengupta JN

Authors

Banani Banerjee PhD Associate Professor in the Medicine department at Medical College of Wisconsin
Adrian Miranda MD Adjunct Professor in the Pediatrics department at Medical College of Wisconsin
Jyoti N. Sengupta PhD Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
GABAergic Neurons
Male
Rats
Rats, Sprague-Dawley
Receptor, Serotonin, 5-HT1A
Receptors, N-Methyl-D-Aspartate
Serotonin 5-HT1 Receptor Agonists
Spinal Cord
Visceral Pain