The L-arginine/nitric oxide/cyclic-GMP pathway apparently mediates the peripheral antihyperalgesic action of fentanyl in rats

Maegawa, Felipe Antonio Boff; Tonussi, Carlos Rogério

doi:10.1590/s0100-879x2003001200012

Cited by 7 publications

(6 citation statements)

References 27 publications

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“…Due to similar changes in f R and V T , each dose of fentanyl produced qualitatively similar changes in V E consisting of rapid and large decreases followed by a recovery period and then a rise to about 50% above pre-injection values. While the ability of opioids, such as morphine, to depress breathing and the mechanisms by which this occurs have been extensively studied ( Lalley, 2008 ; Pattinson, 2008 ; Dahan et al, 2010 ; Pattinson and Wise, 2016 ; Baby et al, 2018 ; Dahan et al, 2018 ; Bateman et al, 2021 ; Baby et al, 2021a ; Baby et al, 2021b ; Ramirez et al, 2021 ), the sites/mechanisms of action by which fentanyl exerts its cardiorespiratory and antinociceptive effects are less well understood ( Laubie et al, 1977 ; Fone and Wilson, 1986 ; Mayer et al, 1989 ; Yamakura et al, 1999 ; Lalley, 2003 ; Maegawa and Tonussi, 2003 ; Griffioen et al, 2004 ; Mastronicola et al, 2004 ; Nikolaishvili et al, 2004 ; Hajiha et al, 2009 ; Tschirhart et al, 2019 ; Webster and Rauck, 2021 ; Ramos-Matos et al, 2022 ). Mechanisms of action of fentanyl involve activation of μ-ORs in brainstem nuclei controlling cardiorespiratory and nociceptive functions ( Laubie et al, 1977 ; Fone and Wilson, 1986 ; Lalley, 2003 ; Griffioen et al, 2004 ; Nikolaishvili, et al, 2004 ; Hajiha, et al, 2009 ; Webster and Rauck, 2021 ; Ramos-Matos et al, 2022 ), and in peripheral structures, including the carotid body ( Mayer et al, 1989 ; Henderson et al, 2014 ; Tschirhart et al, 2019 ; Ramos-Matos et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

“…The involvement of nitrosyl factors, such as NO and SNOs, in the pharmacological actions of opioids has received considerable attention. For example, there is substantial evidence for nitrosyl factors playing roles in 1) opioid receptor (OR) signaling processes ( Pol, 2007 ; Toda et al, 2009a ; Toda et al, 2009b ; Rodríguez-Muñoz and Garzón, 2013 ), and 2) opioid effects on a) vascular function and reactivity ( Sahin et al, 2005 ; Kaye et al, 2006 ), b) pain processing ( Pelligrino, et al, 1996 ; Maegawa and Tonussi, 2003 ; Cury et al, 2011 ; Hervera et al, 2011 ; Mehanna et al, 2018 ; Ortiz et al, 2020 ), c) vision ( Someya et al, 2017 ), and d) inflammatory-immunoregulatory processes ( Bilfinger, et al, 1998 ; Jan et al, 2011 ). Additionally, nitrosyl factors are involved in opioid-induced catalepsy ( Erkent et al, 2006 ), tolerance to opioids ( Kissin et al, 2000 ; Ozdemir et al, 2011 ; Durmus et al, 2014 ), and fentanyl pre-conditioning ( Lu et al, 2014 ).…”

Section: Introductionmentioning

confidence: 99%

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S-Nitroso-L-Cysteine Stereoselectively Blunts the Deleterious Effects of Fentanyl on Breathing While Augmenting Antinociception in Freely-Moving Rats

Getsy

Baby²,

Gruber³

et al. 2022

Front. Pharmacol.

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Endogenous and exogenously administered S-nitrosothiols modulate the activities of central and peripheral systems that control breathing. We have unpublished data showing that the deleterious effects of morphine on arterial blood-gas chemistry (i.e., pH, pCO2, pO2, and sO2) and Alveolar-arterial gradient (i.e., index of gas exchange) were markedly diminished in anesthetized Sprague Dawley rats that received a continuous intravenous infusion of the endogenous S-nitrosothiol, S-nitroso-L-cysteine. The present study extends these findings by showing that unanesthetized adult male Sprague Dawley rats receiving an intravenous infusion of S-nitroso-L-cysteine (100 or 200 nmol/kg/min) markedly diminished the ability of intravenous injections of the potent synthetic opioid, fentanyl (10, 25, and 50 μg/kg), to depress the frequency of breathing, tidal volume, and minute ventilation. Our study also found that the ability of intravenously injected fentanyl (10, 25, and 50 μg/kg) to disturb eupneic breathing, which was measured as a marked increase of the non-eupneic breathing index, was substantially reduced in unanesthetized rats receiving intravenous infusions of S-nitroso-L-cysteine (100 or 200 nmol/kg/min). In contrast, the deleterious effects of fentanyl (10, 25, and 50 μg/kg) on frequency of breathing, tidal volume, minute ventilation and non-eupneic breathing index were fully expressed in rats receiving continuous infusions (200 nmol/kg/min) of the parent amino acid, L-cysteine, or the D-isomer, namely, S-nitroso-D-cysteine. In addition, the antinociceptive actions of the above doses of fentanyl as monitored by the tail-flick latency assay, were enhanced by S-nitroso-L-cysteine, but not L-cysteine or S-nitroso-D-cysteine. Taken together, these findings add to existing knowledge that S-nitroso-L-cysteine stereoselectively modulates the detrimental effects of opioids on breathing, and opens the door for mechanistic studies designed to establish whether the pharmacological actions of S-nitroso-L-cysteine involve signaling processes that include 1) the activation of plasma membrane ion channels and receptors, 2) selective intracellular entry of S-nitroso-L-cysteine, and/or 3) S-nitrosylation events. Whether alterations in the bioavailability and bioactivity of endogenous S-nitroso-L-cysteine is a key factor in determining the potency/efficacy of fentanyl on breathing is an intriguing question.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

S-Nitroso-L-Cysteine Stereoselectively Blunts the Deleterious Effects of Fentanyl on Breathing While Augmenting Antinociception in Freely-Moving Rats

Getsy

Baby²,

Gruber³

et al. 2022

Front. Pharmacol.

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“…On the other hand, the L-arginine/NO/cGMP pathway has an important role in peripheral antinociception induced by opioids. Peripheral antinociceptive effect induced by a μ-opioid receptor agonists morphine (Ferreira et al 1991) and fentanyl (Maegawa and Tonussi 2003) was inhibited by enzymatic NO biosynthesis blockers and by a guanylate cyclase inhibitor, specific cyclic GMP phosphodiesterase inhibitor. Furthermore, peripheral antinociception induced by κ-and δ-opioid receptor activation seems to be mediated by the NO/cGMP pathway (Amarante and Duarte 2002;Pacheco et al 2005).…”

Section: Introductionmentioning

confidence: 99%

Opioid receptor and NO/cGMP pathway as a mechanism of peripheral antinociceptive action of the cannabinoid receptor agonist anandamide

et al. 2009

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“…The NO/cGMP/ATP-sensitive K + channel pathway is one of the mechanism of action of some analgesics such as diclofenac and fentanyl. [4][5][6] However, according to our test results, the peripheral antinociceptive action of PCA involved another NO related pain pathway, not NO-cGMP-ATP sensitive K + channels pathway. The other possible NO related pain pathway involvement in PCA antinociception is still under investigation.…”

Section: Involvement Of Atp-sensitive K + Channel Pathwaymentioning

confidence: 66%

“…In vivo pharmacological studies imply that ATP-sensitive K + channels in peripheral sensory neurons may be activated indirectly via the NO/cGMP/ PKG pathway and this pathway is one of the mechanism of action for various analgesic drugs such as diclofenac and fentanyl. [4][5][6] The acetic acid induced writing test is one of the most commonly used methods for measuring peripheral analgesic activity in mice. 7 Previously, in another study, 8 we found that 150 and 300 mg/kg (p.o.)…”

Section: Introductionmentioning

confidence: 99%

The Involvement of NO–cGMP–ATP Sensitive K+ Channels Pathway in Protocatechuic Acid Peripheral Analgesia

Bektaş¹,

Arslan²

2017

IJPER

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Protocatechuic acid (PCA) is a widely distributed natural bioactive phenolic acid. The various pharmacological activities such as antioxidant, antidiabetic and anti-inflammatory activities have been identified. However, the studies focused on the analgesic effect of protocatechuic acid are limited and the action mechanisms of PCA still remain unclear. The NO-cGMP-ATP-sensitive K + channels pathway is one of the mechanism of action for various analgesic drugs. The present study was conducted to investigate the involvement of NO-cGMP-ATP sensitive K + channels pathway in analgesic effect of p.o. administration of 300 mg/kg protocatechuic acid in acetic acid-induced writhing test in mice. It was shown that pre-treatment with glibenclamide (10 mg/kg, i.p.), an ATPsensitive K + channel blocker, and methylene blue (20 mg/kg, i.p.), a guanylate cyclase inhibitor, did not notably change antinociception produced by 300 mg/kg protocatechuic acid, however administration of nitro-L-arginine methyl ester (10 mg/kg, i.p.), a nitric oxide synthase inhibitor, significantly reversed protocatechuic acid antinociception. The results show that the peripheral mechanism of action of protocatechuic acid-induced antinociception involved another nitric oxide related pain pathway, not NO-cGMP-ATP sensitive K + channels pathway.

show abstract

The L-arginine/nitric oxide/cyclic-GMP pathway apparently mediates the peripheral antihyperalgesic action of fentanyl in rats

Cited by 7 publications

References 27 publications

S-Nitroso-L-Cysteine Stereoselectively Blunts the Deleterious Effects of Fentanyl on Breathing While Augmenting Antinociception in Freely-Moving Rats

S-Nitroso-L-Cysteine Stereoselectively Blunts the Deleterious Effects of Fentanyl on Breathing While Augmenting Antinociception in Freely-Moving Rats

Opioid receptor and NO/cGMP pathway as a mechanism of peripheral antinociceptive action of the cannabinoid receptor agonist anandamide

The Involvement of NO–cGMP–ATP Sensitive K+ Channels Pathway in Protocatechuic Acid Peripheral Analgesia

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