Neurophysiological Mechanisms Underlying the Attenuation of Nociceptive and Pathological Pain by Phytochemicals: Clinical Application as Therapeutic Agents

Although phytochemicals are plant-derived toxins that are primarily produced by plants as a form of defense against insects or microbes, several lines of studies have demonstrated that phytochemicals (e.g., polyphenols, carotenoids, and amino acids) have several beneficial biological actions for human health, such as anti-oxidative, anti-inflammatory, and cardioprotective effects. Recent studies have demonstrated that phytochemicals can modulate neuronal excitability in the nervous system, including nociceptive sensory transmission, so it is possible that phytochemicals could be complementary alternative medicine candidates; specifically, therapeutic agents against pain. The focus of this review is to elucidate the mechanisms underlying the modulatory effects of phytochemicals on neuronal electrical signals, such as generator potentials, action potentials, and postsynaptic potentials, in the nociceptive pathway neurons resulting in potential local anesthetic effects, intravenous anesthesia and analgesic effects, and inflammatory pain relief effects. In addition, we discuss the contribution of phytochemicals to the relief of nociceptive and/or pathological pain and their potential clinical application on the basis of our recent studies in vivo.journal articl

The Phytochemical, Quercetin, Attenuates Nociceptive and Pathological Pain: Neurophysiological Mechanisms and Therapeutic Potential

Although phytochemicals are plant-derived toxins that are primarily produced as a form of defense against insects or microbes, several lines of study have demonstrated that the phytochemical, quercetin, has several beneficial biological actions for human health, including antioxidant and inflammatory effects without side effects. Quercetin is a flavonoid that is widely found in fruits and vegetables. Since recent studies have demonstrated that quercetin can modulate neuronal excitability in the nervous system, including nociceptive sensory transmission via mechanoreceptors and voltage-gated ion channels, and inhibit the cyclooxygenase-2-cascade, it is possible that quercetin could be a complementary alternative medicine candidate; specifically, a therapeutic agent against nociceptive and pathological pain. The focus of this review is to elucidate the neurophysiological mechanisms underlying the modulatory effects of quercetin on nociceptive neuronal activity under nociceptive and pathological conditions, without inducing side effects. Based on the results of our previous research on trigeminal pain, we have confirmed in vivo that the phytochemical, quercetin, demonstrates (i) a local anesthetic effect on nociceptive pain, (ii) a local anesthetic effect on pain related to acute inflammation, and (iii) an anti-inflammatory effect on chronic pain. In addition, we discuss the contribution of quercetin to the relief of nociceptive and inflammatory pain and its potential clinical application.journal articl

Suppression of the Excitability of Rat Nociceptive Primary Sensory Neurons Following Local Administration of the Phytochemical, Quercetin

Although the modulatory effect of quercetin on voltage-gated Na, K, and Ca channels has been studied in vitro, the in vivo effect of quercetin on the excitability of nociceptive primary neurons remains to be determined. The aim of the present study was to examine whether acute local quercetin administration to rats attenuates the excitability of nociceptive trigeminal ganglion (TG) neurons in response to mechanical stimulation in vivo. Extracellular single unit recordings were made from TG neurons of anesthetized rats in response to orofacial non-noxious and noxious mechanical stimulation. The mean firing frequency of TG neurons in response to both non-noxious and noxious mechanical stimuli was dose-dependently inhibited by quercetin, and maximum inhibition of the discharge frequency of both non-noxious and noxious mechanical stimuli was seen within 10 min. The inhibitory effect of quercetin lasted for 15 minutes and was reversible. The mean magnitude of inhibition on TG neuronal discharge frequency with 10 mM quercetin was almost equal to that of the local anesthetic, 2% lidocaine. These results suggest that local injection of quercetin into the peripheral receptive field suppresses the excitability of nociceptive primary sensory neurons in the TG, possibly via inhibition of voltage-gated Na channels and opening voltage-gated K channels.journal articl

Naringenin Suppresses the Hyperexcitability of Trigeminal Nociceptive Neurons Associated with Inflammatory Hyperalgesia: Replacement of NSAIDs with Phytochemicals

The present study examines whether the systemic application of naringenin (NRG) reduces inflammation-induced hyperexcitability in the spinal trigeminal nucleus caudalis (SpVc) related to hyperalgesia, and compares its impact with that of diclofenac (DIC). To provoke inflammation, the whisker pads of rats were injected with complete Freund’s adjuvant, and subsequently, mechanical stimuli were administered to the orofacial region to determine the escape threshold. Compared to naïve rats, the inflamed rats showed a significantly lower mechanical threshold, and this reduced threshold returned to normal levels two days post-administration of NRG, DIC, and half-dose DIC plus half-dose NRG (1/2 DIC + 1/2 NRG). Using extracellular single-unit recordings, the activity of SpVc wide-dynamic range neurons was measured in response to mechanical stimulation of the orofacial area under anesthesia. The average firing rate of SpVc neurons when exposed to both non-painful and painful mechanical stimuli was significantly reduced in inflamed rats following NRG, DIC, and 1/2 DIC + 1/2 NRG administration. The heightened average spontaneous activity of SpVc neurons in rats with inflammation was significantly reduced following NRG, DIC, and 1/2 DIC + 1/2 NRG administration. The increased average receptive field size observed in inflamed rats reverted to normal levels after either NRG, DIC, or 1/2 DIC + 1/2 NRG treatment. These findings indicate that NRG administration can reduce inflammatory hyperalgesia linked to the heightened excitability of SpVc wide-dynamic range neurons.journal articl

ヴァージニア ウルフ ノ ショジョサク フナデ シロン : ニンゲン ノ コドク ト パーティー ノ イメージ オ メグッテ

application/pdfdepartmental bulletin pape

Negative feedback by IRE1β optimizes mucin production in goblet cells

In mammals, the prototypical endoplasmic reticulum (ER) stress sensor inositol-requiring enzyme 1 (IRE1) has diverged into two paralogs. IRE1α is broadly expressed and mediates the unconventional splicing of X-box binding protein 1 (XBP1) mRNA during ER stress. By contrast, IRE1β is expressed selectively in the digestive tract, and its function remains unclear. Here, we report that IRE1β plays a distinctive role in mucin-secreting goblet cells. In IRE1β-/- mice, aberrant mucin 2 (MUC2) accumulated in the ER of goblet cells, accompanied by ER distension and elevated ER stress signaling such as increased XBP1 mRNA splicing. In contrast, conditional IRE1α-/- mice showed no such ER distension but a marked decrease in spliced XBP1 mRNA. mRNA stability assay revealed that MUC2 mRNA was greatly stabilized in IRE1β-/- mice. These findings suggest that in goblet cells, IRE1β, but not IRE1α, promotes efficient protein folding and secretion in the ER by optimizing the level of mRNA encoding their major secretory product, MUC2.journal articl

Observation of b→dγ and Determination of |Vtd/Vts|

journal articl

千金塞炭坑採炭法計画

東京帝国大学工科大学種別:卒業論文thesi

中性線を有する三相／単相マトリクスコンバータを用いた配電用トランスレスマイクログリッドの構築に関する研究

application/pdf三重大学大学院工学研究科博士前期課程電気電子工学専攻89thesi

十五世紀江南デルタの済農倉をめぐる資料について

1994-03-31departmental bulletin pape