Involvement of the NO/cGMP/KATP pathway in the antinociceptive effect of the new pyrazole 5-(1-(3-fluorophenyl)-1H-pyrazol-4-yl)-2H-tetrazole (LQFM-021)

Abstract

The pyrazol compounds are known to possess antipyretic, analgesic and anti-inflammatory activities. This study was conducted to investigate the peripheral antinociceptive effect of the pyrazole compound 5-(1-(3-Fluorophenyl)-1H-pyrazol-4-yl)-2H-tetrazole (LQFM-021) and involvement of opioid receptors and of the NO/cGMP/K(ATP) pathway. The oral treatments in mice with LQFM-021 (17, 75 or 300 mg/kg) decreased the number of writhing. In the formalin test, the treatments with LQFM-021 at doses of 15, 30 and 60 mg/kg reduced the licking time at both neurogenic and inflammatory phases of this test. The treatment of the animals with LQFM-021 (30 mg/kg) did not have antinociceptive effects in the tail-flick and hot plate tests. Furthermore, pre-treatment with naloxone (3 mg/kg i.p.), L-name (10 mg/kg i.p.), ODQ (10 mg/kg i.p.) or glibenclamide (3 mg/kg i.p.) antagonized the antinociceptive effect of LQFM-021 in both phases of the formalin test. In addition, it was also demonstrated that the treatments of mice with LQFM-021(15, 30 and 60 mg/kg) did not compromise the motor activity of the animals in the chimney test. Only the highest dose used in the antinociceptive study promoted changes in the open field test and pentobarbital-induced sleep test, thus ruling out possible false positive effects on nociception tests. Our data suggest that the peripheral antinociception effects of the LQFM-021 were mediated through the peripheral opioid receptors with activation of the NO/cGMP/KATP pathway.

Potential anti-inflammatory effect of LQFM-021 in carrageenan-induced inflammation: The role of nitric oxide

“…This fact may contribute to the effect found with the PGE 2 levels in the pleural exudate and their marked anti-inflammatory activity observed in this study, as well as the anti-inflammatory and antinociceptive effects in previous works [24,25].…”

“…In this work, we present a prevailing hypothesis regarding the role of NO on the anti-inflammatory effect of LQFM-021. This hypothesis is based on the previous observation that the maintenance of the production of nitric oxide is very important for the antinociceptive effect of LQFM-021 [24]. Another important fact about this pyrazole compound is that sub-chronic administration induced antinociceptive and anti-inflammatory activities in CFA-induced arthritis, but did not induce alterations in the toxicology and maintenance of the gastric integrity [25].…”

“…Administration of LQFM-021 (15, 30 and 60 mg/kg) induced inhibition of paw edema in a dose-dependent manner after the second hour. This protocol was initially chosen considering the treatment schedule with LQFM-021 used in our previous study [24].…”

“…The mechanisms of action of the antinociceptive activity of LQFM-021 involve the activation of peripheral opioid receptors and the NO/cGMP/K ATP pathway [24]. Furthermore, these effects occurred in the absence of apparent toxic effects, indicating that the pyrazole compound LQFM-021 may be a good prototype for the development of new analgesic/anti-inflammatory drugs.…”

Tabernaemontana catharinensis ethyl acetate fraction presents antinociceptive activity without causing toxicological effects in mice

“…Since Eta has low efficiency in the tail-immersion test, indicating a minor probability of exerts its antinociceptive effects via central nervous system, we investigated the participation of opioid system in the action mechanism of Eta because opioid receptors activation on peripheral terminals of afferent nerves may lead to analgesic effects in the absence of the central adverse effects caused by opioids (Florentino et al, 2015). Eta prevented the spontaneous nociception caused by capsaicin even when administered with naloxone; thus, its antinociceptive activity does not involve the activation of opioid receptors.…”