Kaurenoic Acid Reduces Ongoing Chronic Constriction Injury-Induced Neuropathic Pain: Nitric Oxide Silencing of Dorsal Root Ganglia Neurons

Author:

Zaninelli Tiago H.1ORCID,Mizokami Sandra S.1ORCID,Bertozzi Mariana M.1ORCID,Saraiva-Santos Telma1,Pinho-Ribeiro Felipe A.1,de Oliveira Gabriele Inácio2,Streck Renata3,Araújo Eduardo J. A.3,Arakawa Nilton S.2,Borghi Sergio M.1ORCID,Casagrande Rubia2ORCID,Verri Waldiceu A.1ORCID

Affiliation:

1. Laboratory of Pain, Inflammation, Neuropathy, and Cancer, Department of Pathology, Center of Biological Sciences, Londrina State University, Londrina 86057-970, Paraná, Brazil

2. Department of Pharmaceutical Sciences, Center of Health Sciences, Londrina State University, Londrina 86039-440, Paraná, Brazil

3. Department of Histology, Londrina State University, Londrina 86057-970, Paraná, Brazil

Abstract

Kaurenoic acid (KA) is a diterpene extracted from Sphagneticola trilobata (L.) Pruski. KA presents analgesic properties. However, the analgesic activity and mechanisms of action of KA in neuropathic pain have not been investigated so far; thus, we addressed these points in the present study. A mouse model of neuropathic pain was induced by chronic constriction injury (CCI) of the sciatic nerve. Acute (at the 7th-day post-CCI surgery) and prolonged (from 7–14th days post-CCI surgery) KA post-treatment inhibited CCI-induced mechanical hyperalgesia at all evaluated time points, as per the electronic version of von Frey filaments. The underlying mechanism of KA was dependent on activating the NO/cGMP/PKG/ATP-sensitive potassium channel signaling pathway since L-NAME, ODQ, KT5823, and glibenclamide abolished KA analgesia. KA reduced the activation of primary afferent sensory neurons, as observed by a reduction in CCI-triggered colocalization of pNF-κB and NeuN in DRG neurons. KA treatment also increased the expression of neuronal nitric oxide synthase (nNOS) at the protein level as well as the intracellular levels of NO in DRG neurons. Therefore, our results provide evidence that KA inhibits CCI neuropathic pain by activating a neuronal analgesic mechanism that depends on nNOS production of NO to silence the nociceptive signaling that generates analgesia.

Funder

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) grant call Universal

CNPq senior research fellowship

Fundação Nacional de Desenvolvimento do Ensino Superior Particular

Decit/SCTIE/MS intermediated by CNPq

SETI/Fundação Araucária and MCTI/CNPq, and Governo do Estado do Paraná

CAPES

Publisher

MDPI AG

Subject

Drug Discovery,Pharmaceutical Science,Molecular Medicine

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