Peripheral 5-HT3 Receptors Are Involved in the Antinociceptive Effect of Bunodosine 391.

Wilson Ferreira Junior,Jose De Freitas,Andre Zaharenko,Gisele Picolo,Vanessa Gutierrez,Yara Cury,Kohei Kazuma,Katsuhiro Konno

doi:10.3390/toxins10010012

Wilson Ferreira Junior, Jose De Freitas + Show 6 more

Open Access

https://doi.org/10.3390/toxins10010012

Copy DOI

Abstract

Bunodosine 391 (BDS 391), a low molecular weight compound isolated from the sea anemone Bunodosoma cangicum, increases the nociceptive threshold and inhibits inflammatory hyperalgesia. Serotonin receptors are involved in those effects. In this study, we have expanded the characterization of the antinociceptive effect of BDS 391 demonstrating that, in rats: (a) the compound inhibits (1.2–12 ng/paw) overt pain, in the formalin test, and mechanical hyperalgesia (0.6–6.0 ng/paw) detected in a model of neuropathic pain; (b) intraplantar administration of ondansetron, a selective 5-HT3 receptor antagonist, blocks the effect of BDS 391, whereas ketanserin, a 5-HT2 receptor antagonist, partially reversed this effect, indicating the involvement of peripheral 5-HT2 and 5-HT3 receptors in BDS 391 antinociception; and (c) in binding assay studies, BDS 391 was not able to displace the selective 5-HT receptor antagonists, suggesting that this compound does not directly bind to these receptors. The effect of biguanide, a selective 5-HT3 receptor agonist, was also evaluated. The agonist inhibited the formalin’s nociceptive response, supporting an antinociceptive role for 5-HT3 receptors. Our study is the first one to show that a non-peptidic low molecular weight compound obtained from a sea anemone is able to induce antinociception and that activation of peripheral 5-HT3 receptors contributes to this effect.

Highlights

We have previously demonstrated that the rise in the basal nociceptive threshold of the rats caused by Bunodosine 391 (BDS 391) was prevented by methysergide, a non-selective serotonin receptor antagonist [14]
391, a low molecular weight compound first isolated isolated from the Brazilian sea anemone
Bunodosoma peripherally administered from the Brazilian sea anemone

Summary

Introduction

Sea anemone venoms are a rich source of protein and peptide toxins, which have been characterized as pore forming membrane toxins (16–20 kDa) [1,2,3], serine protease inhibitors of Kunitz/BPTI family (6–7 kDa) [4,5,6] or neurotoxins acting on Kv, NaV, ASIC or TRPV channels [7,8,9,10,11,12].Mainly in the last two decades, experimental studies have demonstrated that, in addition to proteins and peptides, these venoms contain low (smaller than 1 KDa) molecular weight compounds [13]; the biological activity of these molecules is still not fully characterized. Toxins 2018, 10, 12 indicating that serotonin is involved in a variety of acute and chronic pain states [15,16], we have previously investigated the possible nociceptive effect of BDS 391. This compound, peripherally administered in low doses to rats, increases, per se, the nociceptive threshold of the animals and inhibits inflammatory hyperalgesia induced by carrageenan. These effects were not due to activation of opioid receptors or to a possible anti-inflammatory action of BDS 391, but mediated by activation of serotoninergic receptors [14]

Methods

Results

Conclusion