Expression of oxytocin in hypothalamus and reduction of nociceptive stress following administration of Kamikihi-to in female rats

Hypothalamo-neurohypophysial oxytocin (OXT) plays an essential role in reproduction and in several socio-physiological functions, including stress reduction, anxiety relief, feeding suppression, social recognition, and trust building. Recent studies suggest that the central OXT system is also involved in antinociceptive and anti-inflammatory functions. Kamikihi-to (KKT), a Japanese traditional herbal (Kampo) medicine composed of 14 herbal ingredients, is clinically prescribed for patients with psychological symptoms, including anxiety, depression, and insomnia, and it has been associated with OXT expression. We investigated the antinociceptive response and OXT expression according to sex and the effects of KKT pre administration in a rat model. We found that nociceptive responses measured via the hot plate and formalin tests were attenuated following the administration of KKT-enriched feed for 4 weeks. The observation of mRFP1 fluorescence in OXT-mRFP1 transgenic rats revealed that KKT-administered rats showed increased expression of OXT in the magnocellular and parvocellular paraventricular nucleus of the hypothalamus. Food intake in the KKT-pre-administered group significantly decreased after cholecystokinin (CCK)-8 administration. Our results suggest that KKT is involved in the attenuation of nociceptive stress in female rats by enhancing the expression of OXT in the hypothalamus.

[1]  S. Misaka,et al.  Identification of oxytocin receptor activating chemical components from traditional Japanese medicines , 2021, Journal of food and drug analysis.

[2]  X. Lee,et al.  Kamikihito, a traditional Japanese Kampo medicine, increases the secretion of oxytocin in rats with acute stress. , 2021, Journal of ethnopharmacology.

[3]  K. Conzelmann,et al.  Social touch promotes interfemale communication via activation of parvocellular oxytocin neurons , 2020, Nature Neuroscience.

[4]  Toshihiro Endo,et al.  Kamikihito Enhances Cognitive Functions and Reward-Related Behaviors of Aged C57BL/6J Mice in an Automated Behavioral Assay System , 2020, Frontiers in Pharmacology.

[5]  Y. Ueta,et al.  Acute Mono-Arthritis Activates the Neurohypophysial System and Hypothalamo-Pituitary Adrenal Axis in Rats , 2020, Frontiers in Endocrinology.

[6]  A. D. de Kloet,et al.  Endogenous oxytocin inhibits hypothalamic corticotrophin‐releasing hormone neurones following acute hypernatraemia , 2020, Journal of neuroendocrinology.

[7]  Eszter Riethmüller,et al.  Blood-brain barrier permeability study of ginger constituents. , 2020, Journal of pharmaceutical and biomedical analysis.

[8]  Y. Ueta,et al.  Effect of oestrogen-dependent vasopressin on HPA axis in the median eminence of female rats , 2019, Scientific Reports.

[9]  G. Elkins,et al.  Complementary and Alternative Medicine for Menopause , 2019, Journal of evidence-based integrative medicine.

[10]  K. Curtis,et al.  Estrogen effects on oxytocinergic pathways that regulate food intake , 2018, Hormones and Behavior.

[11]  Sung-Soo Yoon,et al.  Efficacy and Safety of the Traditional Herbal Medicine, Gamiguibi-tang, in Patients With Cancer-Related Sleep Disturbance: A Prospective, Randomized, Wait-List-Controlled, Pilot Study , 2017, Integrative cancer therapies.

[12]  E. Lawson.  The effects of oxytocin on eating behaviour and metabolism in humans , 2017, Nature Reviews Endocrinology.

[13]  M. Aoyama,et al.  Impact of sex, fat distribution and initial body weight on oxytocin’s body weight regulation , 2017, Scientific Reports.

[14]  V. Lira,et al.  Ovarian Hormone Deprivation Reduces Oxytocin Expression in Paraventricular Nucleus Preautonomic Neurons and Correlates with Baroreflex Impairment in Rats , 2016, Front. Physiol..

[15]  Y. Ueta,et al.  Effects of peripherally administered cholecystokinin-8 and secretin on feeding/drinking and oxytocin-mRFP1 fluorescence in transgenic rats , 2016, Neuroscience Research.

[16]  Y. Ueta,et al.  Possible Involvement of the Rat Hypothalamo‐Neurohypophysial/‐Spinal Oxytocinergic Pathways in Acute Nociceptive Responses , 2016, Journal of neuroendocrinology.

[17]  A. Meyer-Lindenberg,et al.  Oxytocin Enhances Social Recognition by Modulating Cortical Control of Early Olfactory Processing , 2016, Neuron.

[18]  R. Froemke,et al.  A New Population of Parvocellular Oxytocin Neurons Controlling Magnocellular Neuron Activity and Inflammatory Pain Processing , 2016, Neuron.

[19]  R. Handa,et al.  Oxytocin and Estrogen Receptor β in the Brain: An Overview , 2015, Front. Endocrinol..

[20]  Y. Ueta,et al.  Fluorescent Visualisation of Oxytocin in the Hypothalamo‐neurohypophysial/‐spinal Pathways After Chronic Inflammation in Oxytocin‐Monomeric Red Fluorescent Protein 1 Transgenic Rats , 2015, Journal of neuroendocrinology.

[21]  W. Jung,et al.  Comparing the Effects of Kamikihito in Japan and Kami‐Guibi‐Tang in Korea on Memory Enhancement: Working Towards the Development of a Global Study , 2015, Phytotherapy research : PTR.

[22]  Y. Ueta,et al.  Fluorescent visualization of oxytocin in the hypothalamo-neurohypophysial system , 2014, Front. Neurosci..

[23]  T. Ushiroyama.  The role of traditional Japanese medicine (Kampo) in the practice of psychosomatic medicine: the usefulness of Kampo in the treatment of the stress-related symptoms of women, especially those with peri-menopausal disorder , 2013, BioPsychoSocial Medicine.

[24]  加藤 明子.  Highly visible expression of an oxytocin-monomeric red fluorescent protein 1 fusion gene in the hypothalamus and posterior pituitary of transgenic rats. , 2013 .

[25]  Hong-bin Xiao,et al.  [Analysis of chemical constituents of chuanxiong rhizoma absorbed into rat brain tissues by UPLC-Q-TOF-MS]. , 2012, Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica.

[26]  G. Ibironke,et al.  Pain threshold variations in female rats as a function of the estrus cycle. , 2011, Nigerian journal of physiological sciences : official publication of the Physiological Society of Nigeria.

[27]  G. Leng,et al.  The Involvement of Voltage-Operated Calcium Channels in Somato-Dendritic Oxytocin Release , 2011, PloS one.

[28]  J. Terao,et al.  Accumulation of orally administered quercetin in brain tissue and its antioxidative effects in rats. , 2011, Free radical biology & medicine.

[29]  Y. Ueta,et al.  Highly visible expression of an oxytocin-monomeric red fluorescent protein 1 fusion gene in the hypothalamus and posterior pituitary of transgenic rats. , 2011, Endocrinology.

[30]  Y. Shoyama,et al.  Kamikihi‐to, a Kampo medicine, Ameliorates impairment of spatial memory in rats , 2007, Phytotherapy research : PTR.

[31]  K. J. Parker,et al.  Intranasal oxytocin administration attenuates the ACTH stress response in monkeys , 2005, Psychoneuroendocrinology.

[32]  U. Fischbacher,et al.  Oxytocin increases trust in humans , 2005, Nature.

[33]  I. Neumann,et al.  Brain oxytocin: differential inhibition of neuroendocrine stress responses and anxiety-related behaviour in virgin, pregnant and lactating rats , 1999, Neuroscience.

[34]  G. Leng,et al.  Sex, parturition and motherhood without oxytocin? , 1998, The Journal of endocrinology.

[35]  I. Ebenezer.  Systemic administration of cholecystokinin (CCK) inhibits operant water intake in rats: implications for the CCK-satiety hypothesis , 1996, Proceedings of the Royal Society of London. Series B: Biological Sciences.

[36]  T. Lundeberg,et al.  The antinociceptive effect of non-noxious sensory stimulation is mediated partly through oxytocinergic mechanisms. , 1993, Acta physiologica Scandinavica.

[37]  Z. Seltzer,et al.  A-fibers mediate mechanical hyperesthesia and allodynia and C-fibers mediate thermal hyperalgesia in a new model of causalgiform pain disorders in rats , 1990, Neuroscience Letters.

[38]  M. Sofroniew.  Projections from vasopressin, oxytocin, and neurophysin neurons to neural targets in the rat and human. , 1980, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[39]  L. Swanson,et al.  The distribution of oxytocin‐ and neurophysin‐stained fibers in the spinal cord of the rat and monkey , 1979, The Journal of comparative neurology.

[40]  H. Dale.  On some physiological actions of ergot , 1906, The Journal of physiology.

[41]  U. Fischbacher,et al.  Oxytocin Increases Trust in Humans Nature , 2015 .

[42]  S. Lightman,et al.  Printed in U.S.A. Copyright © 1997 by The Endocrine Society Central Oxytocin Administration Reduces Stress- Induced Corticosterone Release and Anxiety Behavior in Rats* , 2022 .

[43]  A. Yamashita,et al.  [Effects of kamikihi-to on ovariectomy-induced changes in behavior and circulation in rats]. , 1996, Nihon yakurigaku zasshi. Folia pharmacologica Japonica.