Peripheral nitric oxide signaling directly blocks inflammatory pain

Gomes, Francisco Isaac Fernandes; Cunha, Fernando Q.; Cunha, Thiago Mattar

doi:10.1016/j.bcp.2020.113862

Cited by 49 publications

(36 citation statements)

References 179 publications

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“…NO’s role in analgesia involves the downregulation of neuronal pain transmission by obstructing Ca 2+ influx whiles activating K + channels opening. These lead to hyperpolarization and subsequent inhibition of action potentials generation, thus curtailing the transmission of nociceptive signals peripherally and centrally ( Stefano and Kream, 2007 ; Cury et al, 2011 ; Galdino et al, 2015 ; Gomes et al, 2020 ). The extract, therefore, may be involved in a cascade of events (particularly via the opioidergic pathway) that possibly led to the activation of nitric oxide synthase, an enzyme required for the production of pain-relieving nitric oxide.…”

Section: Discussionmentioning

confidence: 99%

Analgesic Effect of Ziziphus abyssinica Involves Inhibition of Inflammatory Mediators and Modulation of KATP Channels, Opioidergic and Nitrergic Pathways

et al. 2021

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The diversity offered by natural products has timelessly positioned them as a good source for novel therapeutics for the management of diverse medical conditions, including pain. This study evaluated hydro-ethanolic root bark extract of Ziziphus abyssinica (ZAE) as well as β-amyrin and polpunonic acid isolated from the plant for analgesic property. The study also investigated the mechanism responsible for this action in the extract. The antinociceptive potential of ZAE (30, 100, and 300 mg/kg, p. o.) was assessed using the tail-immersion test (TIT), acetic acid-induced writhing test (AAT), and formalin test (FT). The extract’s effect on acute and chronic musculoskeletal pain was also assessed by administering carrageenan unilaterally into the rat gastrocnemius muscles and measuring pain at 12 h and 10 days for acute and chronic pain respectively. The involvement of pro-inflammatory mediators (prostaglandin E2, bradykinin, TNF-α, and IL-1β) was assessed. The possible pathways mediating the observed analgesic effect of ZAE were further assessed using the antagonists: naloxone, glibenclamide, NG-L-nitro-arginine methyl ester (L-NAME), atropine, nifedipine, and yohimbine in the FT. Also the analgesic effect of two triterpenoid compounds, β-amyrin and polpunonic acid, previously isolated from the plant was assessed using the TIT. The anti-nociceptive activity of ZAE was demonstrated in the TIT by the significant (p < 0.05) increase in tail withdrawal threshold in ZAE-treated mice. ZAE also markedly reduced writhing and paw licking responses in both AAT and FT and significantly (p < 0.05) attenuated both acute and chronic musculoskeletal pain. ZAE also significantly reversed hyperalgesia induced by intraplantar injection of PGE2, bradykinin, TNF-α, and IL-1β. Furthermore, data revealed the involvement of opioidergic, ATP-sensitive K+ channels and NO-cGMP pathways in the analgesic effect of ZAE. Both β-amyrin and polpunonic acid exhibited analgesic activity in the tail suspension test. Our study demonstrates ZAE as an important source of new therapeutic agents for pain management.

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Section: Discussionmentioning

confidence: 99%

Analgesic Effect of Ziziphus abyssinica Involves Inhibition of Inflammatory Mediators and Modulation of KATP Channels, Opioidergic and Nitrergic Pathways

et al. 2021

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“…For example, researchers have shown that activation of NO/cGMP signaling pathways by peripheral administration of NO donors yields analgesia in models of peripheral inflammatory pain and that NOS and cGMP inhibitors block these analgesic effects 97,98. Also supporting the anti-nociceptive effects of NO signaling are a number of preclinical investigations indicating that opioid-induced peripheral analgesia in inflammatory pain is dependent on the activation of NO/cGMP signaling in peripheral sensory nerves 99. Further, reports suggest NO may transiently have anti-nociceptive properties within the spinal cord, depending on the type of neurons activated 100.…”

Section: The Role Of No Signaling In Pain—a Balancing Actmentioning

confidence: 99%

Nitric oxide and sickle cell disease—Is there a painful connection?

Hallmark

Almeida

Kamimura

et al. 2020

Exp Biol Med (Maywood)

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Sickle cell disease is the most common hemoglobinopathy and affects millions worldwide. The disease is associated with severe organ dysfunction, acute and chronic pain, and significantly decreased life expectancy. The large body of work demonstrating that hemolysis results in rapid consumption of the endogenous vasodilator nitric oxide, decreased nitric oxide production, and promotion of vaso-occlusion provides the basis for the hypothesis that nitric oxide bioavailability is reduced in sickle cell disease and that this deficit plays a role in sickle cell disease pain. Despite initial promising results, large clinical trials using strategies to increase nitric oxide bioavailability in sickle cell disease patients yielded no significant change in duration or frequency of acute pain crises. Further, recent investigations showed that sickle cell disease patients and mouse models have elevated baseline levels of blood nitrite, a reservoir for nitric oxide formation and a product of nitric oxide metabolism, regardless of pain phenotype. These conflicting results challenge the hypotheses that nitric oxide bioavailability is decreased and that it plays a significant role in the pathogenesis in sickle cell disease acute pain crises. Conversely, a large body of work demonstrates that nitric oxide, as a neurotransmitter, has a complex role in pain neurobiology, contributes to the development of central sensitization, and can mediate hyperalgesia in inflammatory and neuropathic pain. These results support an alternative hypothesis: one proposing that altered nitric oxide signaling may contribute to the development of neuropathic and/or inflammatory pain in sickle cell disease through its role as a neurotransmitter.

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“…Interestingly, previous reports described that nitric oxide (NO) and soluble guanylyl cyclase (sGC) inhibitors prevented DIP‐mediated analgesia, suggesting a potential contribution of the NO‐cGMP pathway to its mechanism of action [11,12]. More recently, we have identified that the activation of NO signaling pathway, which is also involved in the peripheral antinociceptive action of opioids, is triggered by the activation of PI3Kγ/AKT signaling pathway [13–15]. Therefore, we hypothesized that the same molecular pathway would be involved in the peripheral antinociceptive activity of DIP.…”

Section: Introductionmentioning

confidence: 97%

The PI3Kγ/AKT signaling pathway mediates peripheral antinociceptive action of dipyrone

Cecílio

Souza

Alves‐Filho

et al. 2020

Fundamemntal Clinical Pharma

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Dipyrone (DIP), also known as metamizole, is an over‐the‐counter analgesic used in Europe and Latin America. Evidence suggesting that inflammatory pain attenuation by DIP is associated with a direct impact on peripheral primary nociceptive neurons through the stimulation of nitric oxide signaling pathway. However, the molecular mechanism by which DIP activates this pathway remains unknown. The PI3Kγ/AKT signaling cascade activation is one of the well‐known molecular mechanisms that promote nitric oxide production in sensory neurons. Herein, we investigated the role of the PI3Kγ/AKT signaling cascade in the context of peripheral analgesic effect of DIP. DIP was administered into PGE2 pre‐sensitized paws of rats and mechanical hyperalgesia was determined using electronic von Frey test after 1 h. Nonselective or selective pharmacological inhibitors of PI3Kγ and AKT were also administered in DIP‐treated rats under paws sensitized with PGE2. Intraplantar injection of DIP attenuated PGE2‐induced hyperalgesia in a dose‐dependent manner. Treatment with nonselective (wortmannin or LY294002) or selective (AS605240) pharmacological inhibitors of PI3Kγ reduced the peripheral antihypernociceptive effect of DIP. Consistently, AKT selective inhibitor also reversed analgesic DIP effects. Corroborating these data, we found that DIP induced AKT phosphorylation in cultured dorsal root ganglion neurons, which was prevented in the presence of PI3Kγ selective inhibitor. Taken together, these findings provide evidence that peripheral analgesic effect of DIP is dependent on the activation of PI3Kγ/AKT signaling pathway.

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Peripheral nitric oxide signaling directly blocks inflammatory pain

Cited by 49 publications

References 179 publications

Analgesic Effect of Ziziphus abyssinica Involves Inhibition of Inflammatory Mediators and Modulation of KATP Channels, Opioidergic and Nitrergic Pathways

Analgesic Effect of Ziziphus abyssinica Involves Inhibition of Inflammatory Mediators and Modulation of KATP Channels, Opioidergic and Nitrergic Pathways

Nitric oxide and sickle cell disease—Is there a painful connection?

The PI3Kγ/AKT signaling pathway mediates peripheral antinociceptive action of dipyrone

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