Tingenone, a Pentacyclic Triterpene, Induces Peripheral Antinociception Due to Opioidergic Activation

Veloso, Clarice de Carvalho; Rodrigues, Vanessa Gregório; Ferreira, Renata Cristina; Duarte, Lucienir Pains; Klein, André; Duarte, Igor Dimitri Gama; Romero, Thiago Roberto Lima; Perez, Andrea de Castro

doi:10.1055/s-0034-1383147

Cited by 13 publications

(7 citation statements)

References 33 publications

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“…The use of such substance as an inducer of hyperalgesia presents, over other models of hyperalgesic induction, such as the use of the inflammatory molecule carrageenan, the advantage of eliminating the possibility that the peripheral effects of the tested compound are the results of its interaction and modulation of the mediators produced during the inflammatory process. Our results are in agreement with previous studies, which demonstrate that PGE 2 produces an intense nociceptive effect when administered peripherally, at a dose of 2 μg per paw (Pacheco et al , ; Veloso et al , ). Therefore, using PGE 2 to induce hyperalgesia in our model, we demonstrated that PnPP‐19 produced a peripheral antinociceptive effect, in a dose‐dependent manner.…”

Section: Discussionsupporting

confidence: 94%

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PnPP‐19, a spider toxin peptide, induces peripheral antinociception through opioid and cannabinoid receptors and inhibition of neutral endopeptidase

Freitas

Pacheco

Machado

et al. 2016

British J Pharmacology

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Background and Purpose The synthetic peptide PnPP‐19 has been studied as a new drug candidate to treat erectile dysfunction. However, PnTx2–6, the spider toxin from which the peptide was designed, induces hyperalgesia. Therefore, we intended to investigate the role of PnPP‐19 in the nociceptive pathway. Experimental Approach Nociceptive thresholds were measured by paw pressure test. PnPP‐19 was administered intraplantarly alone or with selective cannabinoid or opioid receptor antagonists. The hydrolysis of PnPP‐19 by neutral endopeptidase (NEP) (EC 3.4.24.11), an enzyme that cleaves enkephalin, was monitored by HPLC and the cleavage sites were deduced by LC–MS. Inhibition by PnPP‐19 and Leu‐enkephalin of NEP enzyme activity was determined spectrofluorimetrically. Key Results PnPP‐19 (5, 10 and 20 μg per paw) induced peripheral antinociception in rats. Specific antagonists of μ opioid receptors (clocinnamox), δ opioid receptors (naltrindole) and CB1 receptors (AM251) partly inhibited the antinociceptive effect of PnPP‐19. Inhibition of fatty acid amide hydrolase by MAFP or of anandamide uptake by VDM11 enhanced PnPP‐19‐induced antinociception. NEP cleaved PnPP‐19 only after a long incubation, and Ki values of 35.6 ± 1.4 and 14.6 ± 0.44 μmol·L−1 were determined for PnPP‐19 and Leu‐enkephalin respectively as inhibitors of NEP activity. Conclusions and Implications Antinociception induced by PnPP‐19 appears to involve the inhibition of NEP and activation of CB1, μ and δ opioid receptors. Our data provide a greater understanding of the antinociceptive effects of PnPP‐19. This peptide could be useful as a new antinociceptive drug candidate.

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Section: Discussionsupporting

confidence: 94%

“…The nociceptive threshold was always measured in the right hind paw. This protocol was assessed in pilot experiments and published data was used to determine the dose and optimal time point for the injection of each substance (Pacheco et al , ; Reis et al , ; Galdino et al , ; Veloso et al , ).…”

Section: Methodsmentioning

confidence: 99%

PnPP‐19, a spider toxin peptide, induces peripheral antinociception through opioid and cannabinoid receptors and inhibition of neutral endopeptidase

Freitas

Pacheco

Machado

et al. 2016

British J Pharmacology

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“…Our data indicated that only δ -opioid antagonist was able to reverse the peripheral antinociception induced by aripiprazole. This result is in agreement with several studies suggesting a role of δ -opioid receptor in peripheral antinociceptive effects [24–26]. Izquierdo and coworkers demonstrated that the peripheral administration of mangiferin produced a reduction of nociception in response to the formalin test, mediated by δ -receptors peripherally [26].…”

Section: Discussionsupporting

confidence: 91%

Peripheral Antinociception Induced by Aripiprazole Is Mediated by the Opioid System

Ferreira

Almeida-Santos

Duarte

et al. 2017

BioMed Research International

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Background Aripiprazole is an antipsychotic drug used to treat schizophrenia and related disorders. Our previous study showed that this compound also induces antinociceptive effects. The present study aimed to assess the participation of the opioid system in this effect. Methods Male Swiss mice were submitted to paw pressure test and hyperalgesia was induced by intraplantar injection of prostaglandin E2 (PGE2, 2 μg). Aripiprazole was injected 10 min before the measurement. Naloxone, clocinnamox, naltrindole, nor-binaltorphimine, and bestatin were given 30 min before aripiprazole. Nociceptive thresholds were measured in the 3rd hour after PGE2 injection. Results Aripiprazole (100 μg/paw) injected locally into the right hind paw induced an antinociceptive effect that was blocked by naloxone (50 μg/paw), a nonselective opioid receptor antagonist. The role of μ-, δ-, and κ-opioid receptors was investigated using the selective antagonists, clocinnamox (40 μg/paw), naltrindole (15, 30, and 60 μg/paw), and nor-binaltorphimine (200 μg/paw), respectively. The data indicated that only the δ-opioid receptor antagonist inhibited the peripheral antinociception induced by aripiprazole. Bestatin (400 μg), an aminopeptidase-N inhibitor, significantly enhanced low-dose (25 μg/paw) aripiprazole-induced peripheral antinociception. Conclusion The results suggest the participation of the opioid system via δ-opioid receptor in the peripheral antinociceptive effect induced by aripiprazole.

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“…In a previous study 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 nonselective antagonist to opioid receptors. Clocinnamox, naltrindole, and nor-binaltorphimine are selective antagonists to m, δ and κ receptors, respectively, that prevented the peripheral antinociception induced by tingenone.…”

Section: Discussionmentioning

confidence: 99%

“…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. Thus, the purpose of this study was to investigate the L-arginine/NO/cGMP pathway and activation of potassium channels in the peripheral antinociceptive mechanism of locally applied tingenone, a pentacyclic triterpene, isolated from the roots of Maytenus imbricata (Rodrigues et al, 2012).…”

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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Tingenone, a Pentacyclic Triterpene, Induces Peripheral Antinociception Due to Opioidergic Activation

Cited by 13 publications

References 33 publications

PnPP‐19, a spider toxin peptide, induces peripheral antinociception through opioid and cannabinoid receptors and inhibition of neutral endopeptidase

PnPP‐19, a spider toxin peptide, induces peripheral antinociception through opioid and cannabinoid receptors and inhibition of neutral endopeptidase

Peripheral Antinociception Induced by Aripiprazole Is Mediated by the Opioid System

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

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