Analgesic effects of Naja kaouthia snake venom and its fractions on inflammatory pain are mediated by peripheral opioid receptors

Research Article

J Venom Res (2022), Vol 12, 1-8

Published online: 06 Jan 2022

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Joyce T Da Silva1,2,3X, Milena F Freitas1X, Vanessa O Zambelli9, Vanessa P Gutierrez9, Renata Giorgi4,

Simone Flight5, Martin Lavin6, Michael Venning7, Peter Mirtschin8, Marucia Chacur1*

Received: 30 Sep 2021 | Revised: 09 Nov 2021 | Accepted: 02 Dec 2021 | Published: 06 Jan 2022

1Department of Anatomy, Institute of Biomedical Sciences, University of S o Paulo, Sao Paulo, Brazil

2Department of Neural and Pain Sciences, School of Dentistry, Center to Advance Chronic Pain Research, University of Maryland Baltimore,

Baltimore, USA

3Department of Psychiatry, School of Medicine, Johns Hopkins University, Baltimore, USA

4Laboratory of Pathophysiology, Butantan Institute, S o Paulo, Brazil

5BioPharma Regulatory Consulting, Queensland, Australia

6UQCCR, University of Queensland, Brisbane 4029, Australia

7School of Pharmacy and Medical Sciences, University of South Australia

8Venom Supplies Pty Ltd, Clayton Bay South Australia 5256.

9Laboratory of Pain and Signaling, Butantan Institute, Sao Paulo, Brazil

XThe authors share first authorship.

*Correspondence to: Marucia Chacur, E-mail:

Copyright: The Author(s). This is an open-access article, published under the terms of the Creative Commons Attribution Non-Commercial

License ( This license permits non-commercial use, distribution and reproduction of this article,

provided the original work is appropriately acknowledged, with correct citation details


Venom of cobras of genus Naja, including Naja kaouthia, can relieve pain in acute and chronic conditions. We

investigated the effects of oral and intraplantar administration of the Naja kaouthia venom and its fractions on painrelated

responses in an inflammatory pain model in rats. Male Wistar rats received a hind paw injection of prostaglandin

E2 (PGE2) to induce inflammatory pain and either oral or intraplantar administration of Naja kaouthia venom and

its fractions (fractions 1 to 5). In addition, separate groups of rats with oral administration of fraction 3 of the Naja

kaouthia venom also received either μ-, κ- or δ-opioid receptor antagonists, which were injected into the hind paw by

intraplantar route. Mechanical thresholds were assessed on the hind paw before and after treatments. Fractionation of

Naja kaouthia venom was performed using size exclusion chromatography. Naja kaouthia venom reduced pain-related

responses in the inflammatory pain model when administered by oral and intraplantar routes. Fractions 1, 3, 4 and 5 of

the Naja kaouthia venom administered by oral route decreased PGE2-induced pain sensitivity, while fraction 2 did not

modify pain-related responses. Hind paw injection of naloxone, a non-specific opioid receptor antagonist, abolished

the analgesic effects of the Naja kaouthia venom as well of that for fraction 3. Additionally, hind paw injection of

either μ-, κ- or δ-opioid receptor antagonists blocked the pain relief induced by fraction 3. This study indicates that the

Naja kaouthia venom and its fractionated forms, particularly fraction 3, may be potential therapeutic targets for pain

management and peripheral opioid receptors mediate the pain relief induced by fraction 3.

KEYWORDS: Naja kaouthia, thai cobra, snake venoms, inflammatory pain, opioid receptors