Tingenone, a pentacyclic triterpene, induces peripheral antinociception due to NO/cGMP and ATP-sensitive K(+) channels pathway activation in mice.
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.
Department of Pharmacology, Institute of Biological Sciences, Federal University of Minas Gerais (UFMG), Belo Horizonte, Minas Gerais, Brazil.
Clarice
C
de Carvalho Veloso
Department of Chemistry, Institute of Exact Sciences, UFMG, Belo Horizonte, Minas Gerais, Brazil.
Vanessa Gregório
VG
Rodrigues
Department of Pharmacology, Institute of Biological Sciences, Federal University of Minas Gerais (UFMG), Belo Horizonte, Minas Gerais, Brazil.
Renata Cristina Mendes
RC
Ferreira
Department of Chemistry, Institute of Exact Sciences, UFMG, Belo Horizonte, Minas Gerais, Brazil.
Lucienir Pains
LP
Duarte
Department of Pharmacology, Institute of Biological Sciences, Federal University of Minas Gerais (UFMG), Belo Horizonte, Minas Gerais, Brazil.
Andre
A
Klein
Department of Pharmacology, Institute of Biological Sciences, Federal University of Minas Gerais (UFMG), Belo Horizonte, Minas Gerais, Brazil.
Igor Dimitri
ID
Duarte
Department of Pharmacology, Institute of Biological Sciences, Federal University of Minas Gerais (UFMG), Belo Horizonte, Minas Gerais, Brazil.
Thiago Roberto Lima
TR
Romero
Department of Pharmacology, Institute of Biological Sciences, Federal University of Minas Gerais (UFMG), Belo Horizonte, Minas Gerais, Brazil. Electronic address: acp@icb.ufmg.br.
Andrea
A
de Castro Perez
D000700:Analgesics / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001120:Arginine / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D015232:Dinoprostone; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D054086:KATP Channels / Q000378:metabolism; D008297:Male; D029755:Maytenus; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D018517:Plant Roots / Q000737:chemistry; D015398:Signal Transduction / Q000187:drug effects; D014315:Triterpenes / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D053978:Pentacyclic Triterpenes
D000700:Analgesics; D001120:Arginine; D006152:Cyclic GMP; D015232:Dinoprostone; D054086:KATP Channels; D009569:Nitric Oxide; D014315:Triterpenes; C009492:tingenone; D053978:Pentacyclic Triterpenes
Antinociception; KATP; Nitric oxide; Pain; Tingenone