Involvement of the L-arginine/Nitric Oxide/Cyclic GMP/KATP Channel Pathway and PPARγ Receptors in the Peripheral Antinociceptive Effect of Carbamazepine

Abstract

Carbamazepine has been shown to exert analgesic effects in clinical and experimental pain situation. This study was conducted to evaluate its potential peripheral antinociceptive effects and the possible involvement of L-arginine/NO/cGMP/KATP channel pathway and PPARγ receptors in an animal model of pain. The antinociceptive effect induced by intraplantar administration of carbamazepine (100–1 000 μg/paw) was assessed using the formalin test in rats. To evaluate the involvement of L-arginine/NO/cGMP/KATP channel pathway in the antinociceptive action of carbamazepine, rats were pre-treated intraplantarlly with L-arginine (a nitric oxide precursor, 100 and 200 μg/paw), L-NAME (NOS inhibitor, 50 and 100 μg/paw), methylene blue (guanylyl cyclase inhibitor, 100 and 200 μg/paw), glibenclamide (KATP channel blocker, 100 and 200 μg/paw), and diazoxide (400 μg/paw). Moreover, to investigate the possible involvement of PPARγ receptors, pioglitazone (10 μg/paw; a PPARγ agonist) alone or in combination with GW9662 (3 μg/paw; a PPARγ antagonist) were pre-treated with carbamazepine. The local ipsilateral, but not contralateral, administration of carbamazepine into the hind paw produced dose-related analgesia during both early and late phases of formalin test. Moreover, pre-treatment with L-NAME, methylene blue, and glibenclamide dose-dependently prevented carbamazepine (300 μg/paw)-induced antinociception in both phases of the test. In addition, administration of L-arginine and diazoxide before the sub-effective dose of carbamazepine (100 μg/paw) produced an antinociceptive effect. Also, antinociception induced by carbamazepine plus pioglitazone (10 μg/paw) was blocked by GW-9662 in both phases of the test. In conclusion, carbamazepine induced a peripheral antinociceptive effect through PPARγ receptors and L-arginine/NO/cGMP/KATP channel pathway, with potential for a new topical analgesic drug.

Involvement of NO in Antinociception of NSAIDS in Murine Formalin Hind Paw Assay

“…This nociceptive increase is consistent with similar effects of LNAME in diazepam, clonazepam, chlordiazepoxide, tadalafil [18,19]. However, this nociceptive increase is not consistent with the decrease in the antinociception induced by LNAME in modafinil, ketamine, diclofenac, meloxicam and carbamazepine [19][20][21][22][23].…”

Citral inhibits the nociception in the rat formalin test: effect of metformin and blockers of opioid receptor and the NO-cGMP-K+ channel pathway

“…2020). This inconsistency has been reported with other drugs (Ghorbanzadeh et al 2018(Ghorbanzadeh et al , 2019Ortiz et al 2006;Kaster et al 2007;Ostadhadi et al 2017;Zhou et al 2014). For example, the local peripheral antinociceptive action of gabapentin was mediated by the activation D r a f t of ATP-sensitive K + -channel (Ortiz et al 2006).…”

“…Potassium channels can be modulated by changes in cell voltage, second messengers and many drugs that are capable of activating or inhibiting their opening or closing (Alexander et al 2019;Dascal and Kahanovitch 2015). Analgesic, antiinflammatory or neuromodulator drugs evaluated in different nociceptive models were able to modulate K + channels in peripheral tissues to produce their antinociceptive effects (De Paz-Campos et al 2012;Ortiz et al 2003Ortiz et al , 2005Ortiz et al , 2006Ortiz et al , 2020Ghorbanzadeh et al 2019). In the present study, local peripheral administrations of glipizide and glibenclamide (ATP-sensitive K + channel blockers (K ir 6.1-2) reverted the citral-produced antinociception in the two phases of the 1% formalin test; suggesting that citral could activate these channels to produce its antinociceptive action in the periphery.…”

“…NO and cGMP are produced in diverse physiological and pathological conditions. The participation of the NO-cGMP pathway in peripheral antinociception induced by analgesic, anti-inflammatory and neuromodulator drugs has been previously defined (Ghorbanzadeh et al 2018(Ghorbanzadeh et al , 2019Ortiz et al 2003Ortiz et al , 2006Ortiz et al , 2020. Previous studies demonstrated the inhibition of NO production by citral in cell cultures stimulated with lipopolysaccharides (Lin et al 2008;Katsukawa et al 2010;Lee et al 2008).…”

Interaction of Medicinal Plants and Their Active Constituents With Potassium Ion Channels: A Systematic Review

“…It may have a nociceptive or antinociceptive effect depending on the animal model, time, dose, and route of administration ( Sousa and Prado, 2001 ; Cury et al, 2011 ; Staurengo-Ferrari et al, 2014 ). Several studies have shown the involvement of the l -arginine/NO/cGMP/K ATP channel pathway in antinociceptive action ( Ghorbanzadeh et al, 2019 ; Alizamani et al, 2021 ).…”