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

Abstract

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.

The antipsychotic aripiprazole induces peripheral antinociceptive effects through PI3Kγ/NO/cGMP/KATP pathway activation

“…The nonselective NOS inhibitor, L‐NOarg, dose‐dependently reversed the antinociceptive effect of the highest dose of aripiprazole. This finding is in accordance with other works that demonstrated a role for NOS enzymes in antinociception (Costa et al, 2014; De Carvalho Veloso et al, 2015; Ghorbanzadeh et al, 2019; Gong et al, 2016; Ortiz et al, 2020). To better understand which isoform of NOS could be involved in this process, it was evaluated iNOS, eNOS and nNOS participation with the selective inhibitors L‐NIL, L‐NIO and L‐NPA, respectively.…”

“…It is interesting to notice that other molecular mediators such as noradrenaline (Romero et al, 2012) and N‐palmitoyl‐ethanolamine (Romero & Duarte, 2012), may also activate a similar intracellular pathway to produce antinociception, both, also only through K ATP channel activation. Moreover, exogenous substances such as Tingenone (De Carvalho Veloso et al, 2015), Carbamazepine (Ghorbanzadeh et al, 2019) and Nalbuphine (Ortiz et al, 2020) also have the ability to activate K ATP channels in hyperalgesic models induced by PGE 2 and formalin. Overall the PI3Kγ/NOS/cGMP/K ATP pathway is recruited on central and peripheral tissues to cause analgesia regulation, in the last instance the excitability of the neuronal cell, once the potassium efflux causes hyperpolarization and inhibition of nociception through inhibition of afference of noxious stimuli (Madishetti et al, 2014).…”

“…All drugs were injected on mice's footpad to maximize drug delivery to the nerve endings and nociceptors present in the paw. The protocols concerning dose and time of injection of each drug used in this study were obtained through literature data (Amarante & Duarte, 2002; De Carvalho Veloso et al, 2015; Freitas et al, 2017; Petrocchi et al, 2019; Romero et al, 2009, 2013). To reduce stress, mice were habituated to the apparatus, 2 days before the experiments.…”

cGMP signalling in dorsal root ganglia and the spinal cord: Various functions in development and adulthood

“…Furthermore, the lack of NO‐GC in sensory neurons challenges the conclusion of earlier studies that a NO‐GC/cGMP/PKG1 signalling pathway leading to activation of ATP‐sensitive potassium channels is functional in sensory neurons (Alves et al, 2013; Costa et al, 2014; de Carvalho Veloso et al, 2015; Sachs et al, 2004; Spiller et al, 2019). In these studies, inhibitors of NOS (such as L‐NAME, NOArg or L‐NPA), NO‐GC (such as ODQ or methylene blue), PKG1 (such as KT5823) or ATP sensitive potassium channels (such as glibenclamide) inhibited the pain behaviour or reversed the antinociceptive effects of other drugs in rodents.…”

“…Carvalho Veloso, Rodrigues et al, 2015;Costa, Galdino et al, 2014;Sachs, Cunha et al, 2004;Spiller, Oliveira Formiga et al, 2019). In these studies, inhibitors of NOS (such as L-NAME, NOArg or L-NPA), NO-GC (such as ODQ or methylene blue), PKG1 (such as KT5823) or ATP sensitive potassium channels (such as glibenclamide) inhibited the pain behaviour or reversed the antinociceptive effects of other drugs in rodents.…”