Possible Participation of Nitric Oxide/Cyclic Guanosine Monophosphate/Protein Kinase C/ATP-Sensitive K+ Channels Pathway in the Systemic Antinociception of Flavokawin B

Abstract

The possible mechanisms of action in the antinociceptive activity induced by systemic administration (intraperitoneal, i.p.) of flavokawin B (FKB) were analysed using chemical models of nociception in mice. It was demonstrated that i.p. administration of FKB to the mice at 0.3, 1.0, 3.0 and 10 mg ⁄ kg produced significant dose-related reduction in the number of abdominal constrictions. The antinociception induced by FKB in the acetic acid test was significantly attenuated by i.p. pretreatment of mice with L-arginine, the substrate for nitric oxide synthase or glibenclamide, the ATP-sensitive K + channel inhibitor, but was enhanced by methylene blue, the non-specific guanylyl cyclase inhibitor. FKB also produced dose-dependent inhibition of licking response caused by intraplantar injection of phorbol 12-myristate 13-acetate, a protein kinase C activator (PKC). Together, these data indicate that the NO ⁄ cyclic guanosine monophosphate ⁄ PKC ⁄ ATP-sensitive K + channel pathway possibly participated in the antinociceptive action induced by FKB.Chalcones or 1,3-diaryl-2-propen-1-ones are a well-known class of flavonoids that have been reported to possess both in vitro and in vivo biological activities including antimicrobial, anticancer, antiprotozoal, antiplatelet, antinociceptive and anti-inflammatory [1][2][3][4][5][6]. It has been reported elsewhere that chalcones and their derivatives inhibited the synthesis of nitric oxide (NO), lipoxygenase as well as cyclo-oxygenase activities which constitute the major pro-inflammatory pathways and remain most targeted for anti-inflammatory and antinociceptive drug development [7][8][9][10].In attempts to obtain active derivatives from chalcone that possesses anti-inflammatory and antinociceptive activities, our group previously isolated 6¢-hydroxy-2¢,4¢-dimethoxychalcone or flavokawin B (FKB) from Alpinia nutans Rosc. along with other chalcones such as cardamonin (6), 5,6-dehydrokawain, (-)-pinocembrin, (-)-pinostrobin and 2¢,3¢,4¢,6¢-tetrahydroxychalcone [11]. Recently, we chemically synthesized FKB and demonstrated that systemic administration of FKB exerted potent dose-dependent antinociceptive activity when assessed in the chemical and thermal models of nociception in mice, indicating involvement of the peripheral and central antinociceptive activities [12]. Moreover, in the same study, we demonstrated that the central antinociceptive activity of FKB was not mediated by the activation of opioid receptors. Besides, we also demonstrated that FKB produced marked inhibition of the nociceptive response caused by intraplantar injection of glutamate into mouse hind paw in the glutamate-induced nociception test and perhaps the inhibition of peripheral N-Methyl-D-aspartic acid (NMDA) receptors contributes to the antinociceptive effect of FKB [12]. As activation of the NO cascade is known to take place secondary to NMDA receptor activation and a great deal of evidence has demonstrated the role of NO in various models of nociception [13][14][15][16], this has led to the ...

New pyrazole derivative 5‐[1‐(4‐fluorophenyl)‐1H‐pyrazol‐4‐yl]‐2H‐tetrazole: synthesis and assessment of some biological activities

“…l ‐arginine is a substrate that NOS uses to produce NO, which subsequently activates guanylate cyclase, thereby stimulating the synthesis of cGMP that can interact with K + channels and promote its opening. The opening of K + channels leads to the hyperpolarization of the cell membrane and prevents the generation of nociceptive stimuli . It has been reported that the blockade of K + channels can moreover reduce the analgesic effect …”

Antinociceptive Activity of a Synthetic Curcuminoid Analogue, 2,6‐bis‐(4‐hydroxy‐3‐methoxybenzylidene)cyclohexanone, on Nociception‐induced Models in Mice

“…Numerous studies have indicated that capsaicin mediates the release of several neuropeptides, excitatory amino acids (glutamate and aspartate), NO and pro‐inflammatory mediators from the peripheral and central terminal of primary sensory neurons that critically contribute to nociceptive processing [42,44,45]. A substantial number of scientific reports have implicated the roles of NO as well as both NMDA and non‐NMDA receptors in the nociceptive response induced by the administration of acetic acid, formalin, glutamate and capsaicin [8,40,46,47]. Thus, the antinociceptive activity of BHMC in the acetic acid‐, formalin‐, glutamate‐ and capsaicin‐induced nociceptive tests could be due to both the inhibition of NO and the blockade of NMDA receptors.…”

Antinociceptive effect of methanol extract of Dalbergia sissoo leaves in mice

“…The possible contribution of K + channels in the antinociceptive effect of MEDS was evaluated by using the method described by Mohamad et al with slide modification [46]. The mice were pre-treated with glibenclamide (10 mg/kg), an ATP-sensitive K + channel inhibitor, intraperitoneally 15 min before the administration of either diclofenac sodium or MEDS (100, 200 and 400 mg/kg, p.o.).…”