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Journal of Pain Research and Management

ISSN: 3067-9427

Original Research Open Access

The involvement of nitrergic pathway in the peripheral antinociceptive action of epoxyeicosatrienoic acids (EETs)

Flávia C.S. Fonseca 1, Walace C.P. Barra 1, Daniel P.D. Machado 1, Douglas L. de Almeida 1, Danielle D. Aguiar 1, Bárbara F.G. de Queiroz 1, Andrea C. Perez 1, Thiago R.L. Romero 1, Igor D.G. Duarte 1,*
  • 1Laboratory of Pain and Analgesia, Department of Pharmacology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil
+ Affiliations - Affiliations

Corresponding Author

Igor D.G. Duarte, dimitri@icb.ufmg.br

Received Date: September 03, 2025

Accepted Date: January 05, 2026

Citation:

Fonseca FCS, Barra WCP, Machado DPD, de Almeida DL, Aguiar DD, de Queiroz BFG, et al. The involvement of nitrergic pathway in the peripheral antinociceptive action of epoxyeicosatrienoic acids (EETs). J Pain Res Manag. 2026;2(1):1-9.


Copyright: © 2026 Fonseca FCS, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Introduction: Our group has described the nitrergic pathway as a key analgesic mechanism of drugs and as part of the endogenous control of peripheral inflammatory pain. Studies have shown that epoxyeicosatrienoic acids (EETs) can activate different isoforms of nitric oxide synthase, leading to nitric oxide release and subsequent vasodilation.

Aim: Therefore, the goal of this study was to determine whether the nitrergic pathway mediates the peripheral antinociceptive effects of EETs.

Methods: The mechanical paw pressure test was used as an algesimetric method. Hyperalgesia was induced by intraplantar injection of prostaglandin E2 to assess the effects of exogenous EETs administration and its impact on inhibiting the nitrergic pathway. The EETs (5,6-, 8,9-, 11,12-, and 14,15-EET) and drugs targeting the nitrergic pathway were administered intraplantarly to male Swiss mice (n = 4). Statistical analysis was performed using ANOVA followed by Bonferroni post-test.

Results: The peripheral antinociceptive effects of 5,6-, 8,9-, 11,12-, and 14,15-EET were antagonized by L-NOArg (12, 18, and 24 µg/paw), a non-selective nitric oxide synthase (NOS) inhibitor. The selective inhibitors of inducible (iNOS) (LNIL; 24 μg/paw) and endothelial (eNOS) (LNIO; 24 μg/paw) isoforms partially reduced the antinociceptive effects of EETs. In contrast, selective inhibition of neuronal NOS (nNOS) with LNPA (24 µg/paw) did not affect the peripheral antinociceptive effects of EETs. The soluble guanylate cyclase (sGC) inhibitor ODQ (50, 100, and 200 μg/paw) decreased the peripheral antinociceptive effects of EETs. Conversely, Zaprinast (50 μg/paw), a selective phosphodiesterase (PDE) inhibitor, enhanced the peripheral antinociceptive effects of low doses of EETs. The results suggest that EETs may be linked with iNOS and eNOS activation, but not nNOS, and this process leads to the production of nitric oxide, which stimulates sGC, raises cGMP, and ultimately produces the antinociceptive effect observed with these substances.

Keywords

Epoxyeicosatrienoic acids, Peripheral antinociception, Nitric oxide

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