Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：公益社団法人 日本薬学会  

<bibitem lang="en">  The anti-influenza virus drug oseltamivir has been reported to have several pharmacological actions including blocking of nicotinic acetylcholine receptor channels and activation of the dopaminergic system. These pharmacological actions highly overlap those of amantadine, another anti-influenza virus drug authorized in Japan, and ester-type local anesthetics. Moreover, oseltamivir and amantadine can clinically induce similar adverse neuropsychiatric reactions. In the present study, from the database of the Pharmaceuticals and Medical Devices Agency (PMDA), we surveyed 2,576 drugs for which neuropsychiatric side effects similar to those of oseltamivir, amantadine and local anesthetics (abnormal behavior, confusion, consciousness disturbance, convulsion, delirium, delusion, hallucination, myoclonus, tremor) are listed as “clinically significant adverse reactions”, and found 327 that had at least one of these adverse reactions. Other neuraminidase inhibitors (laninamivir, peramivir and zanamivir) did not elicit such adverse reactions. By discussing the pharmacological effects of drugs that elicit these adverse reactions, we propose that the similarity of adverse neuropsychiatric reactions between oseltamivir and amantadine is possibly attributable to their common pharmacological effects.<br>

DOI： 10.1248/yakushi.18-00022

PubMed

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japanese Pharmacological Society  

Oseltamivir has a hypothermic effect in mice when injected intraperitoneally (i.p.) and intracerebroventricularly (i.c.v.). Here we show that the hypothermia evoked by i.c.v.-oseltamivir is inhibited by non-selective dopamine receptor antagonists (sulpiride and haloperidol) and the D2-selective antagonist L-741,626, but not by D1/D5-selective and D3-selective antagonists (SCH-23390 and SB-277011-A, respectively). The hypothermic effect of i.p.-administered oseltamivir was not inhibited by sulpiride, haloperidol, L-741,626 and SCH-23390. In addition, neither sulpiride, haloperidol nor SCH-23390 blocked hypothermia evoked by i.c.v.-administered oseltamivir carboxylate (a hydrolyzed metabolite of oseltamivir). These results suggest that oseltamivir in the brain induces hypothermia through activation of dopamine D2 receptors.

DOI： 10.1016/j.jphs.2017.12.005

Web of Science

Scopus

PubMed

Other Link： http://orcid.org/0000-0003-4465-7445

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

The transient receptor potential vanilloid type 1 (TRPV1) is a thermosensitive cation channel that triggers heat pain in the periphery. Long-term desensitization of TRPV1, which can be induced by excess amounts of agonists, has been a method for investigating the physiological relevance of TRPV1 containing neuronal circuits, and desensitization induced by various routes of administration, including systemic, intrathecal and intraganglionic, has been demonstrated in rodents. In the present study, we examined the effect of intracerebroventricular (i.c.v.) treatment with an ultrapotent TRPV1 agonist, resiniferatoxin (RTX), on nociception and the analgesic effect of acetaminophen, which is known to mediate the activation of central TRPV1. I.c.v. administration of RTX a week before the test did not affect the licking/biting response to intraplantar injection of RTX (RTX test), suggesting that such i.c.v. treatment spares the function of TRPV1 at the hindpaw. Mice that had been i.c.v.-administered RTX also exhibited normal nociceptive responses in the formalin test and the tail pressure test, but acetaminophen failed to induce analgesia in those mice in any of the tests. These results suggest that i.c.v. administration of RTX leads to brain-selective TRPV1 desensitization in mice.

DOI： 10.1038/s41598-017-12717-5

Web of Science

PubMed

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：PHARMACEUTICAL SOC JAPAN  

Acetaminophen (AcAP), a widely-used antipyretic and analgesic drug, has been considered to exert its effects via central mechanisms, and many studies have demonstrated that the analgesic action of AcAP involves activation of the serotonergic system. Although the serotonergic system also plays an important role in thermoregulation, the contribution of serotonergic activity to the hypothermic effect of AcAP has remained unclear. In the present study, we examined whether the serotonergic system is involved in AcAP-induced hypothermia. In normal mice, AcAP (300 mg/kg, intraperitoneally (i.p.)) induced marked hypothermia (ca. -4 degrees C). The same dose of AcAP reduced pain response behavior in the formalin test. Pretreatment with the serotonin synthesis inhibitor DL-p-chlorophenylalanine (PCPA, 300 mg/kg/d, i.p., 5 consecutive days) substantially decreased serotonin in the brain by 70% and significantly inhibited the analgesic, but not the hypothermic action of AcAP. The same PCPA treatment significantly inhibited the hypothermia induced by the selective serotonin reuptake inhibitor fluoxetine hydrochloride (20mg/kg, i.p.) and the serotonin 5-HT2 receptor antagonist cyproheptadine hydrochloride (3 mg/kg, i.p.). The lower doses of fluoxetine hydrochloride (3 mg/kg, i.p.) and cyproheptadine hydrochloride (0.3 mg/kg, i.p.) did not affect the AcAP-induced hypothermia. These results suggest that, in comparison with its analgesic effect, the hypothermic effect of AcAP is not mediated by the serotonergic system.

DOI： 10.1248/bpb.b16-00728

Web of Science

Scopus

PubMed

Other Link： http://orcid.org/0000-0003-4465-7445

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.ejphar.2015.06.004

Event date： 2022.12

Language：Japanese   Presentation type：Symposium, workshop panel (nominated)  

Event date： 2022.2

Language：English   Presentation type：Oral presentation (general)  

Event date： 2021.3

Language：English   Presentation type：Symposium, workshop panel (nominated)  

Venue：Web  

Endothermic animals maintain their core body temperature by controlling skin vasomotion and brown adipose tissue (BAT) thermogenesis. These thermoregulatory organs are regulated by sympathetic inputs from the hypothalamo-medullary-spinal central pathway. Oxytocin (OXT), a hypothalamic neuropeptide, contributes to a variety of behaviors and stress responses. Impairment of the oxytocinergic (OXTergic) neural system leads to metabolic hypofunction. However, the neuronal pathway underpinning the link between OXT and metabolism has not been determined. To elucidate the mechanism, we performed neural tract tracing and in vivo BAT sympathetic recording in combination with optogenetic stimulation of a specific OXTergic neural pathway, and found that (i) OXT neurons in a dorsocaudal part of the paraventricular hypothalamic nucleus innervate sympathetic premotor neurons in the rostral medullary raphe region (rMR); (ii) the OXTergic input to the rMR stimulates BAT thermogenesis by potentiating glutamatergic transmission onto sympathetic premotor neurons. This OXTergic pathway may underlie etiologies of metabolic disorders, such as Prader-Willi syndrome, and be relevant to emotional responses.

Event date： 2021.3

Language：English   Presentation type：Symposium, workshop panel (nominated)  

Venue：Web  

Emotions strongly impact thermogenic and cardiovascular functions by affecting the central sympathetic regulatory system. We have discovered a central neural pathway that mediates psychological stress signaling by connecting the corticolimbic emotion circuit to the hypothalamomedullary autonomic regulatory system. This is a master psychosomatic pathway that drives a variety of sympathetic and behavioral stress responses, such as brown adipose tissue (BAT) thermogenesis, tachycardia, and pressor response. Recently, we have also identified a central circuit mechanism by which the oxytocin nervous system, which is stimulated by emotional cues, impacts metabolic and cardiac functions. In vivo optogenetic and physiological studies revealed that oxytocinergic inputs from the hypothalamus to medullary sympathetic premotor neurons stimulate BAT thermogenic and cardiac responses by potentiating glutamatergic sympathoexcitatory efferent transmission. Based on these findings, we will discuss central psychosomatic circuit mechanisms that underlie a variety of phenomena due to “mind?body” relationship in health and disease.

Event date： 2020.10

Language：English   Presentation type：Poster presentation  

Venue：Web  

Event date： 2020.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：Web  

Event date： 2020.8

Presentation type：Oral presentation (general)  

Venue：Web  

Event date： 2020.3

Language：English   Presentation type：Poster presentation  

Event date： 2020.3

Presentation type：Oral presentation (general)  

Event date： 2019.11

Presentation type：Public lecture, seminar, tutorial, course, or other speech  

Event date： 2019.9

Language：English   Presentation type：Poster presentation  

Event date： 2019.4

Language：English   Presentation type：Poster presentation  

Venue：Orlando, USA   Country：United States  

Hypothalamic neurons in the paraventricular nucleus (PVN) produce several neuropeptides, including oxytocin and vasopressin, and send their axons to various brain regions. These PVN neurons have been considered to serve neuroendocrine and autonomic functions, and many studies have demonstrated the involvement of oxytocin in social and emotional behaviors (e.g. maternal and sexual behaviors, and stress responses). Although these behaviors are accompanied with autonomic responses, it is unclear how oxytocin modulates the activities of the autonomic nervous system. To investigate the roles of PVN oxytocinergic neurons in the central regulation of autonomic function, in this study, we first performed neural tract tracing in rats from PVN oxytocinergic neurons to the rostral medullary raphe region (rMR), which contains sympathetic premotor neurons controlling brown adipose tissue (BAT) thermogenesis. In the rMR, oxytocin‐immunoreactive fibers, but not vasopressin‐immunoreactive fibers, were distributed, and oxytocin‐containing terminals were apposed to tryptophan hydroxylase‐expressing (i.e., serotonergic) neurons, potentially BAT sympathetic premotor neurons. Retrograde tracing from the rMR with cholera toxin b‐subunit (CTb) labeled a portion of oxytocinergic neurons in the caudal PVN, but not in the supraoptic nucleus, suggesting that the PVN is a major source of oxytocinergic fibers in the rMR. Then, we performed in vivo BAT sympathetic nerve recording combining optogenetic stimulation of the PVN‐derived oxytocinergic axon terminals in the rMR. Recombinant adeno‐associated viral vectors were injected into the PVN to express the engineered channel rhodopsin variant, ChIEF, under the oxytocin promoter. We confirmed that most of PVN neurons expressing ChIEF‐mCherry contained oxytocin and that their axon fibers were densely distributed in the rMR. Optogenetic stimulation of these fibers evoked BAT sympathetic nerve activities as well as increased expired CO2 and heart rate. Similar thermogenic and cardiac responses were elicited by nanoinjection of oxytocin into the rMR, and these responses were blocked by prior injection of the oxytocin receptor antagonist, L‐368,899 into the rMR. In addition, oxytocin injection into the rMR also potentiated NMDA‐evoked BAT sympathetic nerve activities. These findings indicate that PVN oxytocinergic neurons stimulate thermogenic sympathetic outflow to BAT through activation of rMR neurons. This oxytocinergic pathway may play an important role in emotion‐related autonomic responses.

Event date： 2019.3

Language：English   Presentation type：Poster presentation  

Venue：Kobe Convention Center  

Event date： 2018.12

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：⽇本光電⼯業株式会社本社ビル  

Event date： 2018.11

Language：Japanese   Presentation type：Poster presentation  

Event date： 2017.3

Language：Japanese   Presentation type：Poster presentation  

Venue：仙台国際センター   Country：Japan  

Event date： 2016

Language：English   Presentation type：Poster presentation  

Country：Japan  

Event date： 2016

Language：English   Presentation type：Poster presentation  

Country：Japan  

Event date： 2016

Language：English   Presentation type：Poster presentation  

Country：Japan  

Event date： 2015

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2015

Language：English   Presentation type：Poster presentation  

Country：Japan  

Event date： 2015

Language：Japanese   Presentation type：Poster presentation  

Country：Japan  

Event date： 2008

Language：English   Presentation type：Poster presentation  

Country：Japan  

Event date： 2008

Language：English   Presentation type：Poster presentation  

Country：Japan  

実習項目２「骨格筋の収縮特性」

実習項目２「骨格筋の収縮特性」

実習項目２「骨格筋の収縮特性」