The Involvement of l-Arginine-Nitric Oxide-cGMP-ATP-Sensitive K+ Channel Pathway in Antinociception of BBHC, a Novel Diarylpentanoid Analogue, in Mice Model.

Hui Ming Ong,Enoch Kumar Perimal,Daud Ahmad Israf,Ahmad Akira Omar Farouk,Ahmad Farhan Ahmad Azmi,Faridah Abas,Sze Wei Leong,Mohd Roslan Sulaiman

doi:10.3390/molecules26247431

Abstract

The present study focuses on the possible involvement of l-arginine-nitric oxide-cGMP-ATP-sensitive K+ channel pathway in the antinociceptive activity of a novel diarylpentanoid analogue, 2-benzoyl-6-(3-bromo-4-hydroxybenzylidene)cyclohexen-1-ol (BBHC) via a chemical nociceptive model in mice. The antinociceptive action of BBHC (1 mg/kg, i.p.) was attenuated by the intraperitoneal pre-treatment of l-arginine (a nitric oxide synthase precursor) and glibenclamide (an ATP-sensitive K+ channel blocker) in acetic acid-induced abdominal constriction tests. Interestingly, BBHC’s antinociception was significantly enhanced by the i.p. pre-treatment of 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), a selective inhibitor of soluble guanylyl cyclase (p < 0.05). Altogether, these findings suggest that the systemic administration of BBHC is able to establish a significant antinociceptive effect in a mice model of chemically induced pain. BBHC’s antinociception is shown to be mediated by the involvement of l-arginine-nitric oxide-cGMP-ATP-sensitive K+ channel pathway, without any potential sedative or muscle relaxant concerns.

Highlights

Nitric oxide (NO) is a membrane permeable, free radical gas that has been identified as a potent biological mediator with diverse physiologic functions including synaptic transmission and central sensitization in the nociceptive process [1,2]
Nitric oxide and its byproduct called L-citrulline are synthesized from L-arginine through an enzymatic reaction by neuronal or non-neuronal nitric oxide synthases (NOS) [3,4,5]
Our present results have shown that the administration of glibenclamide, an adenosine triphosphate (ATP)-sensitive K+ channel inhibitor, significantly antagonized the antinociceptive effect of BBHC in acetic acid-induced nociception model

Summary

Introduction

Nitric oxide (NO) is a membrane permeable, free radical gas that has been identified as a potent biological mediator with diverse physiologic functions including synaptic transmission and central sensitization in the nociceptive process [1,2]. The resulting excitability in the spinal area is called a central sensitization. N-methyl-D-aspartate (NMDA) receptors are activated to amplify the release of glutamate from presynaptic endings in the spinal cord and further increases the intracellular level of calcium ions. This action causes the stimulation of calmodulin-sensitive nitric oxide synthase [6,7,8]

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