Abstract. The neuronal pathways involved in the muscle relaxant effect of tizanidine were examined by measurement of spinal reflexes in rats. Tizanidine (i.v. and intra-4th ventricular injection) decreased the mono-and disynaptic (the fastest polysynaptic) reflexes (MSR and DSR, respectively) in non-spinalized rats. Depletion of central noradrenaline by 6-hydroxydopamine abolished the depressant effect of tizanidine on the MSR almost completely and attenuated the effect on the DSR. Co-depletion of serotonin by 5,6-dihydroxytryptamine and noradrenaline resulted in more prominent attenuation of tizanidine-induced inhibition of the DSR. Supraspinal receptors were then studied using yohimbine-and some imidazoline-receptor ligands containing an imidazoline moiety. Idazoxan (I 1 , I 2 , I 3 , and α 2 ), efaroxan (I 1 , I 3 , and α 2 ), and RX821002 (I 3 and α 2 ), but not yohimbine, an α 2 -adrenergic receptor antagonist with no affinity for I receptors, antagonized the inhibitory effects of tizanidine. Thus, supraspinal I receptors (most likely I 3 ) and descending monoaminergic influences are necessary for tizanidine-induced inhibition of spinal segmental reflexes.
Imidazoline receptors are expressed widely in the CNS. In the present study, whole-cell patch-clamp recordings were made from medium spiny neurons in dorsal striatum slices from the rat brain, and the roles of I 1 -imidazoline receptors in the modulation of synaptic transmission were studied. Moxonidine, an I 1 -imidazoline receptor agonist, decreased the GABA A receptor-mediated IPSCs in a concentration-dependent manner. However, glutamate-mediated EPSCs were hardly affected. The depression of IPSCs by moxonidine was antagonized by either idazoxan or efaroxan, which are both imidazoline receptor antagonists containing an imidazoline moiety. In contrast, yohimbine and SKF86466 (6-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine), which are ␣2-adrenergic receptor antagonists with no affinity for imidazoline receptors, did not affect the moxonidine-induced inhibition of IPSCs. Moxonidine increased the paired-pulse ratio and reduced the frequency of miniature IPSCs without affecting their amplitude, indicating that this agent inhibits IPSCs via presynaptic mechanisms. Moreover, the sulfhydryl alkylating agent N-ethylmaleimide (NEM) significantly reduced the moxonidine-induced inhibition of IPSCs. Thus, the activation of presynaptic I 1 -imidazoline receptors decreases GABA-mediated inhibition of medium spiny neurons in the striatum, in which NEM-sensitive proteins such as G i/o -type G-proteins play an essential role. The adenylate cyclase activator forskolin partly opposed IPSC inhibition elicited by subsequently applied moxonidine. Furthermore, the protein kinase C (PKC) activator phorbol 12,13-dibutyrate attenuated and the PKC inhibitor chelerythrine potentiated the moxonidineinduced inhibition of IPSCs. These results suggest that IPSC inhibition via presynaptic I 1 -imidazoline receptors involves intracellular adenylate cyclase activity and is influenced by static PKC activity in the striatum.
Peripheral postischemic dysesthesia was examined behaviorally in mice and we investigated the underlying molecular mechanism with a focus on oxidative stress. Hind-paw ischemia was induced by tight compression of the ankle with a rubber band, and reperfusion was achieved by cutting the rubber tourniquet. We found that reperfusion after ischemia markedly provoked licking of the reperfused hind paw, which was significantly inhibited by systemic administration of the antioxidant N-acetyl-L-cysteine and the transient receptor potential (TRP) A1 channel blocker HC-030031 [2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)-N-(4-isopropylphenyl)acetamide]. Postischemic licking was also significantly inhibited by an intraplantar injection of another antioxidant, phenyl-N-tert-butylnitrone. The TRPV1 channel blocker BCTC [N-(4-tert-butylphenyl)-4-(3-chloropyridin-2-yl) tetrahydropyrazine-1(2H)-carboxamide] did not inhibit postischemiclicking. An intraplantar injection of hydrogen peroxide elicited hind-paw licking, which was inhibited by N-acetyl-L-cysteine, phenyl-N-tert-butylnitrone, and HC-030031. Postischemic licking was not affected by chemical depletion of sensory C-fibers, but it was inhibited by morphine, which has been shown to inhibit the C-and Ad-fiber-evoked responses of dorsal horn neurons. Interestingly, postischemic licking was not inhibited by gabapentin and pregabalin, which have been shown to inhibit the C-fiberbut not Ad-fiber-evoked response. The present results suggest that ischemia-reperfusion induces oxidative stress, which activates TRPA1 channels to provoke postischemic licking. It has been suggested that this behavior is mediated by myelinated (probably Ad-type) afferent fibers. Oxidative stress and TRPA1 channels may be potential targets to treat peripheral ischemiaassociated dysesthesia.
Several of the drugs currently available for the treatment of premature ejaculation (PE) (e.g., local anesthetics or antidepressants) are associated with numerous safety concerns and exhibit weak efficacy. To date, no therapeutics for PE have been approved in the United States, highlighting the need to develop novel agents with sufficient efficacy and fewer side effects. In this study, we focused on the histamine H3 receptor (H3R) as a potential target for the treatment of PE and evaluated the effects of imetit (an H3R/H4R agonist), ciproxifan (an H3R antagonist), and JNJ-7777120 (an H4R antagonist) in vivo. Our in vivo electrophysiological experiments revealed that imetit reduced mechanical stimuli-evoked neuronal firing in anesthetized rats. This effect was inhibited by ciproxifan but not by JNJ-7777120. Subsequently, we evaluated the effect of imetit using a copulatory behavior test to assess ejaculation latency (EL) in rats. Imetit prolonged EL, although this effect was inhibited by ciproxifan. These findings indicate that H3R stimulation suppresses mechanical stimuli-evoked neuronal firing in the spinal–penile neurotransmission system, thereby resulting in prolonged EL. To our knowledge, this is the first report to describe the relationship between H3R and PE. Thus, H3R agonists may represent a novel treatment option for PE.
Sexual dysfunction can be caused by impaired neurotransmission from the peripheral to the central nervous system. Therefore, it is important to evaluate the input of sensory information from the peripheral genital area and investigate the control mechanisms in the spinal cord to clarify the pathological basis of sensory abnormalities in the genital area. However, an in vivo evaluation system for the spinal cord–penile neurotransmission mechanism has not yet been developed. Here, urethane-anesthetized rats were used to evaluate neuronal firing induced by innocuous or nociceptive stimulation of the penis using extracellular recording or patch-clamp techniques in the lumbosacral spinal dorsal horn and electrophysiological evaluation in the peripheral pelvic nerves. As a result, innocuous and nociceptive stimuli-evoked neuronal firing was successfully recorded in the deep and superficial spinal dorsal horns, respectively. The innocuous stimuli-evoked nerve firing was also recorded in the pelvic nerve. These firings were suppressed by lidocaine. To the best of our knowledge, this is the first report of a successful quantitative evaluation of penile stimuli-evoked neuronal firing. This method is not only useful for analyzing the pathological basis of spinal cord–penile neurotransmission in sexual dysfunction but also provides a useful evaluation system in the search for new treatments.
In 2017 Mitsubishi Tanabe Pharma established the Future Design Department. The Future Design Department is advancing a transformation to a data-driven company with a view to the use of Big Data, AI, IoT, Digital Medicine and other digital technologies with the objective of fostering "disruptive innovation" in the pharmaceutical business. We are working to create new methods that transcend the pharmaceutical industry's conventional pharmaceutical categories. Mitsubishi Tanabe Pharma is promoting open innovation with some universities and companies of different industries about issues with impact within the drug discovery value chain. For example, Mitsubishi Tanabe Pharma and Hitachi have initiated collaborative creation for improving the efficiency of clinical trials using Hitachi's advanced digital technology such as AI. In another example, in 2018, we will start an accelerator program. With the key words of "creating the future of healthcare" we will build a business model that transcends the conventional pharmaceutical business framework and strive to contribute to the happiness and health of patients and those around them. In order to expand our business "around the pill" and "beyond the pill", we are working on the challenge of creating new value in the fields of medicine and healthcare through cross-industry collaboration with cutting edge technologies and different industries. In this presentation, we would like to introduce the above contents along the case of Future Design Department in Mitsubishi Tanabe Pharma.
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