Diclofenac-induced peripheral antinociception is associated with ATP-sensitive K+ channels activation

Alves, Daniela Pereira; Tatsuo, Maria A.F; Leite, Rômulo; Duarte, Igor Dimitri Gama

doi:10.1016/j.lfs.2003.10.012

Cited by 86 publications

(60 citation statements)

References 37 publications

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“…However, this is the first time that this connection has been established in the immune system. Diclofenac functions as a channel opener, activating ATP-dependent K + channels and triggering anti-nociceptive effects by reducing pain sensation in response to different stimuli [12]. This is in agreement with the diclofenacdependent abrogation of leukocyte activation that we found.…”

Section: Discussionsupporting

confidence: 92%

“…This effect seems to be dependent on the mechanism of each NSAID, as other compounds of this family do not involve potassium channel activity 5 [11]. ATP-dependent potassium channels (K ATP ) play a key role in the anti-nociceptive effect of diclofenac on rat paw [12]. Moreover, diclofenac, and not other NSAIDs, inhibits sodium currents in sensory neurons, which contributes to its analgesic activity [13].…”

Section: Introductionmentioning

confidence: 99%

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Immunomodulatory effects of diclofenac in leukocytes through the targeting of Kv1.3 voltage-dependent potassium channels

Villalonga

David

Bielańska

et al. 2010

Biochemical Pharmacology

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This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 and IL-2 production in stimulated Jurkat T-cells were also blocked by pharmacological doses of diclofenac. These effects were mimicked by Margatoxin, a specific Kv1.3 inhibitor, and Charybdotoxin, which blocks both Kv1.3 and Ca 2+ -activated K + channels (K Ca 3.1). Because Kv1.3 is a very good target for autoimmune therapies, the effects of diclofenac on Kv1.3 are of high pharmacological relevance.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Immunomodulatory effects of diclofenac in leukocytes through the targeting of Kv1.3 voltage-dependent potassium channels

Villalonga

David

Bielańska

et al. 2010

Biochemical Pharmacology

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“…The NO/cGMP pathway and the activation of the KATP channels on the peripheral antinociception was demonstrated for several analgesics: morphine (Rodrigues and Duarte, 2000;Cunha et al, 2010), ketorolac (Lázaro-Ibáñez et al, 2001); dipyrone (Alves and Duarte, 2002); diclofenac (Ortiz et al, 2003;Alves et al, 2004), xylazine Duarte, 2009a, 2009b), for the agonist of the cannabinoid receptor CB 1 , anandamide (Reis et al, 2011), for the agonist of the cannabinoid receptor CB 2 , palmitoylethanolamide (PEA) (Romero and Duarte, 2012a), among others, and in the present study, we observed that tingenone induced a peripheral antinociceptive effect by this pathway activation, with potential to be an analgesic drug. Fig.…”

Section: Discussionmentioning

confidence: 99%

“…The L-arginine/NO/cGMP pathway and activation of KATP was described as the peripheral antinociceptive mechanism for opioid agonists (Ferreira et al, 1991;Rodrigues and Duarte, 2000;Pacheco et al, 2005), ketorolac (Lázaro-Ibáñez et al, 2001); diclofenac (Ortiz et al, 2003;Alves et al, 2004), cannabinoids (Reis et al, 2011;Romero and Duarte, 2012a), dipyrone and myrcene (terpene) (Duarte et al, 1992), melatonin (Hernández-Pacheco et al, 2008), among others. In a previous study accomplished by Veloso et al (2014b), it was demonstrated that tingenone administered into the right hind paw induced a local antinociceptive effect that was antagonized by naloxone, a non-selective antagonist to opioid receptors, suggesting that the opioidergic system participates in the peripheral antinociception induced by tingenone.…”

Section: Introductionmentioning

confidence: 99%

Tingenone, a pentacyclic triterpene, induces peripheral antinociception due to NO/cGMP and ATP-sensitive K+ channels pathway activation in mice

Veloso

Rodrigues

Ferreira

et al. 2015

European Journal of Pharmacology

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Substances derived from plants play an important role in the development of new analgesic drugs, among them, triterpenoids. The connection between the participation of L-arginine/NO/cGMP pathway and the activation of ATP-sensitive K(+) channels (KATP) has been established on the peripheral antinociception induced by various drugs. The study assessed the involvement of L-arginine/NO/cGMP/KATP pathway in the antinociceptive effect induced by tingenone, from Maytenus imbricata, against the hyperalgesia evoked by prostaglandin E2 (PGE2) in peripheral pathway. The paw pressure test was used, with hyperalgesia induced by intraplantar injection of PGE2 (2 μg). Tingenone (200 µg/paw) administered into the right hind paw induced a local antinociceptive effect, that was antagonized by l-NOArg, nonselective nitric oxide synthase (NOS) inhibitor and by L-NPA, selective neuronal NOS (nNOS) inhibitor. The L-NIO, selective inhibitor of endothelial (eNOS), and the L-NIL, selective inhibitor of inducible (iNOS), did not alter the peripheral antinociceptive effect of the tingenone. The ODQ, selective soluble guanylyl cyclase inhibitor, prevented the antinociceptive effect of tingenone, and zaprinast, inhibitor of the phosphodiesterase that is cyclic guanosine monophosphate (cGMP) specific, intensified the peripheral antinociceptive effect of the smaller dose of tingenone. Glibenclamide, ATP-sensitive K(+) channels (KATP) blocker, but not tetraethylammonium chloride, voltage-dependent K(+) channel blocker; dequalinium dichloride, blocker of the small conductance Ca(2+)-activated K(+) channel, and paxilline, a potent blocker of high-conductance Ca(2+)-activated K(+) channels, respectively, prevented the peripheral antinociceptive effect of tingenone. The results demonstrate that tingenone induced a peripheral antinociceptive effect by L-arginine/NO/cGMP/KATP pathway activation, with potential for a new analgesic drug.

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“…Several studies have determined that opening of the ATP-sensitive K + (K ATP ) channels is the final stage of the peripheral antinociceptive mechanism of morphine (7), dipyrone (8), and diclofenac (9). The antinociceptive action mechanism induced by various agonists of different receptors, including α 2 -adrenoceptor agonists, at supraspinal and spinal sites is also dependent of K + channels (6).…”

Section: Introductionmentioning

confidence: 99%

Involvement of ATP-Sensitive K+ Channels in the Peripheral Antinociceptive Effect Induced by the α2-Adrenoceptor Agonist Xylazine

Romero

Duarte

2009

J Pharmacol Sci

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Abstract. Xylazine is an α 2 -adrenergic agonist extensively used in veterinary medicine and animal experimentation for producing antinociception, sedation, and muscle relaxation. The nitric oxide (NO) / cGMP / ATP-sensitive K + (K ATP ) channel pathway has been proposed as the action mechanism of peripheral antinociception of several groups of drugs, including opioids and nonsteroidal analgesics. Considering the lack of knowledge regarding the mechanisms involved in xylazine effects, the present study investigated the contribution of K + channels on peripheral antinociception induced by xylazine using the rat paw pressure test, in which hyperalgesia was induced by intraplantar injection of prostaglandin E 2 . Xylazine administered into the right hind paw elicited a local antinociceptive effect, since only much higher doses produced a systemic effect in the contralateral paw. The peripheral antinociceptive effect induced by xylazine was antagonized by glibenclamide, a specific blocker of K ATP channels. In another experiment, tetraethylammonium, a voltage-dependent K + -channel blocker, and paxilline and dequalinium, which are selective blockers for the large-and small-conductance Ca 2+ -activated K + channels, respectively, were ineffective at blocking xylazine antinociception. These results provide evidence that the peripheral antinociceptive effect of xylazine probably results from K ATP -channel activation, while the voltage-dependent K + channels, small-and large-conductance Ca 2+-activated K + channels, appear not to be involved in this mechanism.

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Diclofenac-induced peripheral antinociception is associated with ATP-sensitive K+ channels activation

Cited by 86 publications

References 37 publications

Immunomodulatory effects of diclofenac in leukocytes through the targeting of Kv1.3 voltage-dependent potassium channels

Immunomodulatory effects of diclofenac in leukocytes through the targeting of Kv1.3 voltage-dependent potassium channels

Tingenone, a pentacyclic triterpene, induces peripheral antinociception due to NO/cGMP and ATP-sensitive K+ channels pathway activation in mice

Involvement of ATP-Sensitive K+ Channels in the Peripheral Antinociceptive Effect Induced by the α2-Adrenoceptor Agonist Xylazine

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