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

BACKGROUND: Acute application of decanoic acid (DA) in vivo suppresses the excitability of spinal trigeminal nucleus caudalis (SpVc) wide dynamic range (WDR) neurons associated with the short-term mechanical hypoalgesia via muscarinic M2 receptor signaling; however, the effect of DA on nociceptive trigeminal ganglion (TG) and SpVc nociceptive-specific (NS) neuronal excitability under in vivo conditions remains to be determined. The present study investigated whether this effect could be observed in naive rats. RESULTS: Extracellular single-unit recordings were made from TG and SpVc NS neurons of pentobarbital-anesthetized rats in response to orofacial noxious mechanical stimuli. DA inhibited the mean firing frequency of both TG and SpVc NS neurons, reaching a maximum inhibition of discharge frequency within 1-5 minutes and reversing after approximately 10-minutes; however, this DA-induced suppression of SpVc NS neuronal firing frequency did not occur in rats administered with methoctramine intravenously prior to stimulation. CONCLUSION: This in vivo study indicated that firing of TG and SpVc NS neurons induced by mechanical hypoalgesia through peripheral M2 receptors could be inhibited by acutely administered DA, implicating the potential of DA in the future treatment of trigeminal pain. PERSPECTIVE: This article presents that the acute DA application suppresses the excitability of TG and SpVc NS neurons associated with mechanical hypoalgesia via peripheral M2 receptor signaling, supporting DA as a potential therapeutic agent in complementary and alternative medicine for the attenuation of nociception.

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

Background: Although 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. Results: After 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 1­5 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. Conclusion: These 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.

Inhibitory effect of ß-hydroxybutyric acid on L-type Ca(2+) current under ß-adrenergic stimulation in guinea pig cardiac ventricular myocytes.

Severe ketoacidosis induces heart failure and cardiac arrest, but its mechanism is unknown. Recently, hydroxy-carboxylic acid receptor 2 (HCA(2)) was found to be a receptor for a ketone body, ß-hydroxybutyric acid (BHB), and is coupled with Gi-GTP binding protein. HCA(2) expression was reported in the guinea pig heart. Therefore, using guinea pig cardiac myocytes, we investigated effects of BHB on L-type Ca(2+) current pre-augmented with ß-adrenoceptor agonist, isoproterenol under the whole-cell voltage clamp. BHB significantly reduced the Ca(2+) current pre-augmented with isoproterenol. The effect of BHB was concentration dependent with IC(50) of 1.1 mM. Nicotinic acid (NA), another ligand for HCA(2), also exerted an effect on the Ca(2+) current similar to that of BHB. The effects of BHB and NA were reduced by a specific Gi inhibitor, pertussis toxin in the pipette solution. Our results suggest that BHB activates Gi-coupled signal transduction pathway via HCA(2) in guinea pig cardiac myocytes. The HCA(2)-mediated signal transduction may be associated with ketoacidosis-induced cardiac suppression.