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.

Resveratrol attenuates inflammation-induced hyperexcitability of trigeminal spinal nucleus caudalis neurons associated with hyperalgesia in rats.

BACKGROUND: Resveratrol, a component of red wine, has been reported to decrease prostaglandin E2 production by inhibiting the cyclooxygenase-2 cascade and to modulate various voltage-dependent ion channels, suggesting that resveratrol could attenuate inflammatory hyperalgesia. However, the effects of resveratrol on inflammation-induced hyperexcitability of nociceptive neurons in vivo remain to be determined. Thus, the aim of the present study was to determine whether daily systemic administration of resveratrol to rats attenuates the inflammation-induced hyperexcitability of spinal trigeminal nucleus caudalis wide-dynamic range neurons associated with hyperalgesia. RESULTS: Inflammation was induced by injection of complete Freund's adjuvant into the whisker pad. The threshold of escape from mechanical stimulation applied to whisker pad in inflamed rats was significantly lower than in control rats. The decreased mechanical threshold in inflamed rats was restored to control levels by daily systemic administration of resveratrol (2 mg/kg, i.p.). The mean discharge frequency of spinal trigeminal nucleus caudalis wide-dynamic range neurons to both nonnoxious and noxious mechanical stimuli in inflamed rats was significantly decreased after resveratrol administration. In addition, the increased mean spontaneous discharge of spinal trigeminal nucleus caudalis wide-dynamic range neurons in inflamed rats was significantly decreased after resveratrol administration. Similarly, resveratrol significantly diminished noxious pinch-evoked mean after discharge frequency and occurrence in inflamed rats. Finally, resveratrol restored the expanded mean size of the receptive field in inflamed rats to control levels. CONCLUSION: These results suggest that chronic administration of resveratrol attenuates inflammation-induced mechanical inflammatory hyperalgesia and that this effect is due primarily to the suppression of spinal trigeminal nucleus caudalis wide dynamic range neuron hyperexcitability via inhibition of both peripheral and central cyclooxygenase-2 cascade signaling pathways. These findings support the idea of resveratrol as a potential complementary and alternative medicine for the treatment of trigeminal inflammatory hyperalgesia without side effects.