Dietary constituent, decanoic acid suppresses the excitability of nociceptive trigeminal neuronal activity associated with hypoalgesia via muscarinic M₂ receptor signaling

Abstract

BackgroundAlthough decanoic acid (DA) is thought to act as a muscarinic cholinergic agonist, effect of DA on nociceptive behavioral responses and the excitability of nociceptive neuronal activity under in vivo conditions remain to be determined. The aim of the present study, therefore, was to investigate whether in vivo acute administration of ointment containing DA affects the excitability of nociceptive trigeminal spinal nucleus caudalis (SpVc) neurons associated with hypoalgesia in naïve rats.ResultsAfter local application of DA, the threshold of escape from mechanical stimulation applied to the shaved orofacial skin was significantly higher than before DA application. Vehicle treatment (without DA) had no significant effect on the escape threshold from mechanical stimulation. Extracellular single unit recordings were made from SpVc wide-dynamic range (WDR) neurons in response to orofacial non-noxious and noxious mechanical stimuli of pentobarbital-anesthetized rats. The mean firing frequency of SpVc WDR neurons in response to noxious, but not non-noxious, mechanical stimuli was inhibited by local application of DA, and the maximum inhibition of discharge frequency of both non-noxious and noxious mechanical stimuli was seen within 1–5 min. The DA-induced short-term inhibitory effects were reversed after approximately 10 min. Pretreatment intravenously with the muscarinic-specific M2 receptor antagonist, methoctramine, abolished the DA-induced suppression of firing frequency of SpVc WDR neurons in response to noxious stimulation. Fluorogold (FG) labeling was identified as the trigeminal ganglion (TG) neurons innervating orofacial skin. FG-labeled small-diameter TG neurons expressed M2 receptor immunoreactivity.ConclusionThese results suggest that acute DA application induces short-term mechanical hypoalgesia and this effect was mainly due to suppression of the excitability of SpVc WDR neurons via the peripheral M2 receptor signaling pathway in the trigeminal primary afferents. These findings support the idea that DA is a potential therapeutic agent and complementary alternative medicine for the attenuation of trigeminal nociception in the absence of inflammatory/neuropathic conditions.

Modulatory mechanism underlying how dietary constituents attenuate orofacial pain

“…Another study showed membrane hyperpolarization after M 2 mAchRs stimulation via activation of low-threshold, voltage-operated K + channels in nucleus raphe magnus (NRM) neurons [47]. The present authors' recent in vivo electrophysiological and behavioral experiments showed that topical DA reversibly evoked transient mechanical hypoalgesia, presumably via the same mechanism described above in TG neurons [48,49]. Together, these data suggest that DA is a potential therapeutic CAM for treatment of trigeminal nociception (Fig.…”

“…During action potential generation, voltage-gated Na + currents in trigeminal ganglia are inhibited by resveratrol and DHA applied locally (43,45), while voltage-gated K + currents in primary sensory neurons are potentiated by resveratrol and chlorogenic acid (44). Topical application of decanoic acid also induces mechanical hypoalgesia, which in turn suppresses trigeminal ganglia excitability through M2 mAchRs signaling, thereby stimulating membrane hyperpolarization (48,49) and inhibiting action potential firing rates discharged through nociceptive primary afferent fibers to the central terminal and nociceptive neurons in the SpVc. Systemic delivery of LA inhibits Ca 2+ currents in presynaptic terminals, while local administration of resveratrol suppresses glutamatergic-activated neurotransmission of SpVc neurons responding to nociceptive mechanical stimulation via the NMDA receptor.…”

Decanoic acid attenuates the excitability of nociceptive trigeminal primary and secondary neurons associated with hypoalgesia

“…Therefore, we formulated an ointment for in vivo application of DA (Patent number: P2013-139421A, Japan), as described and defined previously. 11 …”

“…Electrophysiological recordings were conducted on 26 adult male Wistar rats weighing 230–310 g (18 rats: SpVc NS neurons; 8 rats: TG neurons), as previously described. 11 In brief, after anesthesia and maintenance with pentobarbital sodium through a cannula into the jugular veins, animals were placed in a stereotaxic apparatus for extracellular activity recordings of single SpVc neurons, according to the coordinates demonstrated by Paxinos and Watson, 16 using a glass micropipette filled with 2% pontamine sky blue and 0.5 M sodium acetate. 11 , 17 For recordings of single TG neurons, the rats underwent a craniotomy and hemispherectomy to expose the trigeminal ganglia, and the activity was recorded from the left side of the neurons, as described for the SpVc units.…”

“… 14 Indeed, we previously showed that DA applied acutely as an ointment induces mechanical hypoalgesia, predominantly by limiting the SpVc WDR neuronal excitability via peripheral acetyl-choline muscarinic 2 (M 2 ) receptors, suggesting a role of this fatty acid in CAM for trigeminal nociceptive pain present without inflammation or neuropathy. 11 Thus, the present study further investigated how a similar acute treatment with DA affects TG and SpVc NS neuronal activities associated with hypoalgesia in naive rats.…”