Involvement of Descending Serotonergic and Noradrenergic Systems and their Spinal Receptor Subtypes in the Antinociceptive Effect of Dipyrone

Abstract

The antinociceptive effect of dipyrone is partly due to its action upon pain-related central nervous system structures. Despite intensive research, the precise mechanisms mediating its analgesic effects remain unclear. Here, we aimed to determine whether neurotoxic destruction of descending inhibitory pathways affect dipyrone-induced antinociception and whether various spinal serotonergic and adrenergic receptors are involved in this antinociception. The nociceptive response was assessed by the tail-flick test. Mice injected with dipyrone (150, 300, 600 mg/kg, i.p.) elicited dose-related antinociception. The neurotoxins 5,7-dihydroxytryptamine (50 μg/mouse) and 6-hydroxydopamine (20 μg/mouse) are applied intrathecally to deplete serotonin and noradrenaline in the spinal cord. 3 days after neurotoxin injections, a significant reduction in the antinociceptive effect of dipyrone was observed. Intrathecal administration of monoaminergic antagonists (10 μg/mouse), the 5-HT2a antagonist ketanserin, the 5-HT3 antagonist ondansetron, the 5-HT7 antagonist SB-258719, α1-adrenoceptor antagonist prazosin, α2-adrenoceptor antagonist yohimbine, and the β-adrenoceptor antagonist propranolol also attenuated dipyrone antinociception. We propose that descending serotonergic and noradrenergic pathways play pivotal role in dipyrone-induced antinociception and spinal 5-HT2a, 5-HT3, and 5-HT7-serotonergic and α1, α2, and β-adrenergic receptors mediate this effect.

Antinociceptive Activity of Methanolic Extract ofClinacanthus nutansLeaves: Possible Mechanisms of Action Involved

“…Similarly, yohimbine also inhibited the antinociceptive activity of MECN when assessed using the same assay, hence suggesting that the antinociceptive activity of MECN is partly mediated via the α 2 adrenergic receptor activation. Meanwhile, previous studies have also reported on the participation of activated β -adrenergic receptors in central and peripheral nociceptive transmission [ 58 , 59 ]. In the present study, MECN-exerted antinociceptive activity was inhibited by pindolol, thus suggesting the modulation of MECN antinociceptive activity occurs partly via the activation of β- adrenergic receptors.…”

Differential innervation of superficial versus deep laminae of the dorsal horn by bulbo-spinal serotonergic pathways in the rat

“…In spite of such a large body of studies devoted to unveil the actual role of bulbo-spinal serotonergic pathways in the control of pain signaling, the situation is still confused to date. Thus, some authors ( Suzuki et al., 2004 , Rahman et al., 2006 , Wei et al., 2010 , Guo et al., 2014 ) concluded that these pathways are implicated in pain promoting mechanisms whereas others ( Yamazaki et al., 1999 , Hung et al., 2003 , Gencer et al., 2015 , Lee et al., 2015 ) reached the opposite conclusion, i.e. these pathways exerting an inhibitory influence on pain signaling.…”

Antiallodynic Effects of Intrathecal Areca Nut for Spinal Nerve-Ligated and Chemotherapy-Induced Neuropathic Pain in Rats

“…Furthermore, the spasmogenic effects of areca nut can be blocked by atropine [29], which suggests that other systems, including muscarinic receptors, are also involved in the effects of areca nut. In addition, other types of 5-HT receptor and α1 adrenoceptors are involved in nociceptive modulation, and may play roles in the activity of areca nut [30,31]. Therefore, although the antiallodynic effects of areca nut have been validated by the current study, further research should be undertaken to investigate its detailed mechanisms of action and its influence on monoamines.…”