Autonomic Neuroscience:Basic and Clinical 185 (2014)29-35 Contents lists available at ScienceDirect Autonomic Neuroscience:Basic and Clinical ELSEVIER journal homepage:www.elsevier.com/locate/autneu Review Olfactory stimulatory with grapefruit and lavender oils change CrossMark autonomic nerve activity and physiological function Katsuya Nagai*,Akira Niijima,Yuko Horii,Jiao Shenb,Mamoru Tanidab ANBAS Corporation,4-12-17 Toyosaki.Kita-Ku,Osaka 531-0072.Japan Institute for Protein Research,Osaka University.Japan Niigata University.Japan Kanazawa Medical University.Japan ARTICLE INFO ABSTRACT Article history: This review summarizes the effects of olfactory stimulation with grapefruit and lavender oils on autonomic nerve Received 17 April 2013 activity and physiological function.Olfactory stimulation with the scent of grapefruit oil (GFO)increases the ac- Received in revised form 3 June 2014 tivity of sympathetic nerves that innervate white and brown adipose tissues,the adrenal glands,and the kidneys, Accepted 16 June 2014 decreases the activity of the gastric vagal nerve in rats and mice.This results in an increase in lipolysis,thermo- Keyword达： genesis,and blood pressure,and a decrease in food intake.Olfactory stimulation with the scent of lavender oil Autonomic neurotransmission (LVO)elicits the opposite changes in nerve activity and physiological variables.Olfactory stimulation with Sympathetic scent of limonene,a component of GFO,and linalool,a component of LVO,has similar effects to stimulation Parasympathetic with GFO and LVO,respectively.The histamine H1-receptor antagonist,diphenhydramine,abolishes all GFO- Limonene induced changes in nerve activity and physiological variables,and the hitstamine H3-receptor antagonist. Linalool thioperamide,eliminates all LVO-induced changes.Lesions to the hypothalamic suprachiasmatic nucleus and an- Circadian clock osmic treatment with ZnSO4 also abolish all GFO-and LVO-induced changes.These findings indicate that limo- Suprachiasmatic nucleus nene and linalool might be the active substances in GFO and LVO,and suggest that the suprachiasmatic Histamine nucleus and histamine are involved in mediating the GFO-and LVO-induced changes in nerve activity and phys- Rat Mice iological variables. Aromatherapy 2014 Elsevier B.V.All rights reserved. White adipose tissue Brown adipose tissue Adrenal glands Kidney Stomach Lipolysis Thermogenesis Body temperature Blood pressure Appetite Contents 1. Introduction······ 2. Effects of GFO on autonomic neurotransmission and physiological phenomena... 30 2.1. Effects on the sympathetic nerve that innervates WAT and on lipolysis........................... 22. Effects on the sympathetic nerve that innervates BAT and on thermogenesis... 23 Effects on the sympathetic nerves that innervate the adrenal glands and kidneys and on blood pressure....... 30 2.4. Effects on the vagal nerve innervating the stomach and appetite.................................... Abbreviations:ASNA,adrenal sympathetic nerve activity:BAT.brown adipose tissue:BAT-SNA,brown adipose tissue-sympathetic nerve activity:BP.blood pressure:BT,body temper- ature:2DG.2-deoxy-D-glucose:FFA,free fatty acid:GFO.grapefruit oil:GVNA.gastric vagal nerve activity:IP.intraperitoneal:LVO.lavender oil:RSNA,renal sympathetic nerve activity SCN,suprachiasmatic nucleus:TMN,tuberomammillary nucleus:UCP.uncoupling protein:WAT.white adipose tissue:WAT-SNA.white adipose tissue-sympathetic nerve activity. Corresponding author.TeL:+81 6 6486 1080:fax:+81 6 6486 1081. E-mail address:knagai@anbas.co.jp (K.Nagai). http://dx.doi.org/10.1016/j.autneu.2014.06.005 1566-0702/2014 Elsevier B.V.All rights reserved
Review Olfactory stimulatory with grapefruit and lavender oils change autonomic nerve activity and physiological function Katsuya Nagai a,b, ⁎, Akira Niijima c , Yuko Horii a,b , Jiao Shen b , Mamoru Tanida b,d a ANBAS Corporation, 4-12-17 Toyosaki, Kita-Ku, Osaka 531-0072, Japan b Institute for Protein Research, Osaka University, Japan c Niigata University, Japan d Kanazawa Medical University, Japan article info abstract Article history: Received 17 April 2013 Received in revised form 3 June 2014 Accepted 16 June 2014 Keywords: Autonomic neurotransmission Sympathetic Parasympathetic Limonene Linalool Circadian clock Suprachiasmatic nucleus Histamine Rat Mice Aromatherapy White adipose tissue Brown adipose tissue Adrenal glands Kidney Stomach Lipolysis Thermogenesis Body temperature Blood pressure Appetite This review summarizes the effects of olfactory stimulation with grapefruit and lavender oils on autonomic nerve activity and physiological function. Olfactory stimulation with the scent of grapefruit oil (GFO) increases the activity of sympathetic nerves that innervate white and brown adipose tissues, the adrenal glands, and the kidneys, decreases the activity of the gastric vagal nerve in rats and mice. This results in an increase in lipolysis, thermogenesis, and blood pressure, and a decrease in food intake. Olfactory stimulation with the scent of lavender oil (LVO) elicits the opposite changes in nerve activity and physiological variables. Olfactory stimulation with scent of limonene, a component of GFO, and linalool, a component of LVO, has similar effects to stimulation with GFO and LVO, respectively. The histamine H1-receptor antagonist, diphenhydramine, abolishes all GFOinduced changes in nerve activity and physiological variables, and the hitstamine H3-receptor antagonist, thioperamide, eliminates all LVO-induced changes. Lesions to the hypothalamic suprachiasmatic nucleus and anosmic treatment with ZnSO4 also abolish all GFO- and LVO-induced changes. These findings indicate that limonene and linalool might be the active substances in GFO and LVO, and suggest that the suprachiasmatic nucleus and histamine are involved in mediating the GFO- and LVO-induced changes in nerve activity and physiological variables. © 2014 Elsevier B.V. All rights reserved. Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 2. Effects of GFO on autonomic neurotransmission and physiological phenomena . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 2.1. Effects on the sympathetic nerve that innervates WAT and on lipolysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 2.2. Effects on the sympathetic nerve that innervates BAT and on thermogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 2.3. Effects on the sympathetic nerves that innervate the adrenal glands and kidneys and on blood pressure . . . . . . . . . . . . . . . . . . 30 2.4. Effects on the vagal nerve innervating the stomach and appetite . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 Autonomic Neuroscience: Basic and Clinical 185 (2014) 29–35 Abbreviations: ASNA, adrenal sympathetic nerve activity; BAT, brown adipose tissue; BAT-SNA, brown adipose tissue-sympathetic nerve activity: BP, blood pressure; BT, body temperature; 2DG, 2-deoxy-D-glucose; FFA, free fatty acid; GFO, grapefruit oil; GVNA, gastric vagal nerve activity; IP, intraperitoneal; LVO, lavender oil; RSNA, renal sympathetic nerve activity; SCN, suprachiasmatic nucleus; TMN, tuberomammillary nucleus; UCP, uncoupling protein; WAT, white adipose tissue; WAT-SNA, white adipose tissue-sympathetic nerve activity. ⁎ Corresponding author. Tel.: +81 6 6486 1080; fax: +81 6 6486 1081. E-mail address: knagai@anbas.co.jp (K. Nagai). http://dx.doi.org/10.1016/j.autneu.2014.06.005 1566-0702/© 2014 Elsevier B.V. All rights reserved. Contents lists available at ScienceDirect Autonomic Neuroscience: Basic and Clinical journal homepage: www.elsevier.com/locate/autneu
30 K Nagai et al.Autonomic Neuroscience:Basic and Clinical 185(2014)29-35 Effects of the LVO on autonomic neurotransmission and physiological phenomena 32 3.1. Effects on the sympathetic nerve innervating the white adipose tissue and lipolysis 32 32. Effects on the sympathetic nerve innervating BAT and thermogenesis 的 33. Effects on the sympathetic nerves innervating the adrenal glands and kidney and blood pressure 32 3.4 Effects on the vagal nerve innervating the stomach and appetite . 32 4. Role of histamine in changes in autonomic neurotransmission and physiological phenomena due to GFO and LVO ... 32 5. Roles of circadian clock mechanism in changes in autonomic neurotransmission and physiological phenomena due to GFO and LVO 33 6. Concluding remarks 34 Conflict of interest 35 35 References 35 1.Introduction The increase in WAT-SNA caused triacylglycerol hydrolysis(lipoly- sis)through the activation of hormone-sensitive lipase (Shimazu, In mice,the inhalation of the lavender oil (LVO)reduces motility, 1981:Ganong.2005).In addition,olfactory stimulation with the scent suggesting a sedative effect (Buchbauer et al.,1991).In humans,3 min of 0.01%water-suspension of GFO increased plasma glycerol concentra- of aromatherapy with either lavender or rosemary aroma positively af- tion,a marker of lipolysis,in unanesthetized rats(Shen et al.,2007) fected mood and electroencephalographic patterns of alertness(Diego These findings suggest that the GFO-induced increase in WAT-SNA en- et al.,1998),the inhalation of essential oil of fragrances such as pepper hances lipolysis.Moreover,olfactory stimulation with the scent of 1% or grapefruit oils caused an increase in relative cardiac sympathetic water-suspension of R-(+)-limonene (Sigma-Aldrich Co.LLC,U.S.A.) nerve activity (Haze et al.,2002),and odors elicited changes in the auto- increased WAT-SNA in urethane-anesthetized rats (Shen et al.unpub- nomic nervous system that were indicative of emotional responses lished observations)and olfactory stimulation with the scent of 0.02% (Alaoui-Ismali et al.,1997;Vermet-Maury et al.,1999).These findings water-suspension of R-(+)-limonene increased the plasma glycerol suggest that olfactory stimulation with scents of essential oils such as concentration in unanesthetized rats(Shen et al,2005a),suggesting grapefruit oil (GFO)and LVO can alter the activity of autonomic nerves that limonene is one of the active substances in GFO that causes an in- that innervate organs and tissues,and thus cause physiological changes crease in lipolysis through its effects on WAT-SNA. in mammals.In this regard,we observed that oral administration of 4G- o-glucopyranosyl hesperidin excited the efferent brown adipose tissue 2.2.Effects on the sympathetic nerve that innervates BAT and sympathetic nerve but inhibited the efferent cutaneous arterial sympa- on thermogenesis thetic nerve in rats(Shen et al,2009).These facts suggest that activities of sympathetic nerves do not change to the same direction under the al- Olfactory stimulation with the scent of 1%water-suspension of GFO teration of internal and external environments.In other words,in some increased BAT sympathetic nerve activity (BAT-SNA)in urethane- circumstances a sympathetic nerve innervating an organ/tissue may be anesthetized rats and mice (Fig.1;Shen et al.,2005a;Tanida et al. excited but a sympathetic nerve innervating another organ/tissue may 2007b;2008b).This effect of GFO was abolished by anosmic treatment be suppressed.Therefore,we have examined the effects of olfactory with either xylocaine or ZnSO4(Shen et al.,2005a).These findings sug- stimulation with the scent of GFO(Citrus paradisi,Pranarom Interna- gest that olfactory stimulation with the scent of GFO increases BAT-SNA tional s.a.,Bergium;major components:limonene 95.98%;beta- BAT functions as a thermogenic tissue through uncoupling protein-1 myrcen 1.97%)and LVO (Lavandula angustifolia,Pranarom International and uses free fatty acids as its primary energy source(Ganong.2005). s.a.;major components:linalool 42.19%;linalyl acetate 40.0%)on the Thermogenesis in this tissue is evoked through the B3 adrenergic recep- sympathetic nerves that innervate epididymal white adipose tissue tor by the excitation of the BAT sympathetic nerve secondary to com- (WAT),interscapular brown adipose tissue(BAT),the adrenal glands mands from the autonomic center in the hypothalamus (Morrison, and the kidneys and on the parasympathetic nerve that innervates the 2004).Olfactory stimulation with the scent of 0.01%water-suspension stomach in rats.We have found that GFO and LVO have opposite effects of GFO increased body temperature (BT)in unanesthetized rats on these autonomic nerves and opposite effects on lipolysis,thermo- (Tanida et al.,2008b)and olfactory stimulation with the scent of either genesis,blood pressure(BP),and appetite (Niijima and Nagai,2003: 0.01%water-suspension of GFO or 0.1%water-suspension of R-(+)-lim- Shen et al.,2005a,b:Tanida et al.,2005b,2006,2007a).The details of onene increased BT in unanesthetized mice (Shen et al,2005a).These these effects and the results of other reports on the effects of essential findings suggest that GFO-induced increase in BAT-SNA elevates ther- oils on the autonomic nervous system and physiological functions are mogenesis,and therefore BT and that limonene is one of the active sub- discussed in this article. stances in GFO that causes these changes. The GFO-induced change in BT is time dependent.Elevation of rat BT 2.Effects of GFO on autonomic neurotransmission and physiological after GFO stimulation was observed in the light period (resting period) phenomena but not in the dark period (active period)of a 12-h light and 12-h dark cycle (Tanida et al,2008b).These findings indicate that the effect of ol- 2.1.Effects on the sympathetic nerve that innervates WAT and on lipolysis factory stimulation with the scent of GFO may be time dependent in rats,and may be observed only in periods of rest. Olfactory stimulation with the scent of 1%water-suspension of GFO increased WAT sympathetic nerve activity (WAT-SNA)in urethane- 2.3.Effects on the sympathetic nerves that innervate the adrenal glands and anesthetized rats,but olfactory stimulation with the scent of 0.1% kidneys and on blood pressure water-suspension of GFO did not (Fig.1:Niijima and Nagai,2003; Shen et al.,2005a).This effect of GFO was abolished by anosmic treat- Olfactory stimulation with the scent of 1%water-suspension of GFO ment with nasal application of ZnSO4 solution (Kolune and Stern, increased the adrenal sympathetic nerve activity(ASNA;Fig.1;Niijima 1995)and by nasal xylocaine-anesthesia (Shen et al.,2005a).These and Nagai,2003;Shen et al.,2005a)and renal sympathetic nerve activ- findings suggest that olfactory stimulation with the scent of a certain ity (RSNA;Fig.1;Shen et al.,2005b:Tanida et al.,2006)in urethane- amount of GFO increases WAT-SNA. anesthetized rats.These effects of GFO were abolished by anosmic
3. Effects of the LVO on autonomic neurotransmission and physiological phenomena . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 3.1. Effects on the sympathetic nerve innervating the white adipose tissue and lipolysis . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 3.2. Effects on the sympathetic nerve innervating BAT and thermogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 3.3. Effects on the sympathetic nerves innervating the adrenal glands and kidney and blood pressure . . . . . . . . . . . . . . . . . . . . . 32 3.4. Effects on the vagal nerve innervating the stomach and appetite . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 4. Role of histamine in changes in autonomic neurotransmission and physiological phenomena due to GFO and LVO . . . . . . . . . . . . . . . . . 32 5. Roles of circadian clock mechanism in changes in autonomic neurotransmission and physiological phenomena due to GFO and LVO . . . . . . . . . 33 6. Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 1. Introduction In mice, the inhalation of the lavender oil (LVO) reduces motility, suggesting a sedative effect (Buchbauer et al., 1991). In humans, 3 min of aromatherapy with either lavender or rosemary aroma positively affected mood and electroencephalographic patterns of alertness (Diego et al., 1998), the inhalation of essential oil of fragrances such as pepper or grapefruit oils caused an increase in relative cardiac sympathetic nerve activity (Haze et al., 2002), and odors elicited changes in the autonomic nervous system that were indicative of emotional responses (Alaoui-Ismali et al., 1997; Vermet-Maury et al., 1999). These findings suggest that olfactory stimulation with scents of essential oils such as grapefruit oil (GFO) and LVO can alter the activity of autonomic nerves that innervate organs and tissues, and thus cause physiological changes in mammals. In this regard, we observed that oral administration of 4G- α-glucopyranosyl hesperidin excited the efferent brown adipose tissue sympathetic nerve but inhibited the efferent cutaneous arterial sympathetic nerve in rats (Shen et al., 2009). These facts suggest that activities of sympathetic nerves do not change to the same direction under the alteration of internal and external environments. In other words, in some circumstances a sympathetic nerve innervating an organ/tissue may be excited but a sympathetic nerve innervating another organ/tissue may be suppressed. Therefore, we have examined the effects of olfactory stimulation with the scent of GFO (Citrus paradisi, Pranarom International s.a., Bergium; major components: limonene 95.98%; betamyrcen 1.97%) and LVO (Lavandula angustifolia, Pranarom International s.a.; major components: linalool 42.19%; linalyl acetate 40.0%) on the sympathetic nerves that innervate epididymal white adipose tissue (WAT), interscapular brown adipose tissue (BAT), the adrenal glands and the kidneys and on the parasympathetic nerve that innervates the stomach in rats. We have found that GFO and LVO have opposite effects on these autonomic nerves and opposite effects on lipolysis, thermogenesis, blood pressure (BP), and appetite (Niijima and Nagai, 2003; Shen et al., 2005a,b; Tanida et al., 2005b, 2006, 2007a). The details of these effects and the results of other reports on the effects of essential oils on the autonomic nervous system and physiological functions are discussed in this article. 2. Effects of GFO on autonomic neurotransmission and physiological phenomena 2.1. Effects on the sympathetic nerve that innervates WAT and on lipolysis Olfactory stimulation with the scent of 1% water-suspension of GFO increased WAT sympathetic nerve activity (WAT-SNA) in urethaneanesthetized rats, but olfactory stimulation with the scent of 0.1% water-suspension of GFO did not (Fig. 1; Niijima and Nagai, 2003; Shen et al., 2005a). This effect of GFO was abolished by anosmic treatment with nasal application of ZnSO4 solution (Kolune and Stern, 1995) and by nasal xylocaine-anesthesia (Shen et al., 2005a). These findings suggest that olfactory stimulation with the scent of a certain amount of GFO increases WAT-SNA. The increase in WAT-SNA caused triacylglycerol hydrolysis (lipolysis) through the activation of hormone-sensitive lipase (Shimazu, 1981; Ganong, 2005). In addition, olfactory stimulation with the scent of 0.01% water-suspension of GFO increased plasma glycerol concentration, a marker of lipolysis, in unanesthetized rats (Shen et al., 2007). These findings suggest that the GFO-induced increase in WAT-SNA enhances lipolysis. Moreover, olfactory stimulation with the scent of 1% water-suspension of R-(+)-limonene (Sigma–Aldrich Co. LLC, U.S.A.) increased WAT-SNA in urethane-anesthetized rats (Shen et al. unpublished observations) and olfactory stimulation with the scent of 0.02% water-suspension of R-(+)-limonene increased the plasma glycerol concentration in unanesthetized rats (Shen et al., 2005a), suggesting that limonene is one of the active substances in GFO that causes an increase in lipolysis through its effects on WAT-SNA. 2.2. Effects on the sympathetic nerve that innervates BAT and on thermogenesis Olfactory stimulation with the scent of 1% water-suspension of GFO increased BAT sympathetic nerve activity (BAT-SNA) in urethaneanesthetized rats and mice (Fig. 1; Shen et al., 2005a; Tanida et al., 2007b; 2008b). This effect of GFO was abolished by anosmic treatment with either xylocaine or ZnSO4 (Shen et al., 2005a). These findings suggest that olfactory stimulation with the scent of GFO increases BAT-SNA. BAT functions as a thermogenic tissue through uncoupling protein-1 and uses free fatty acids as its primary energy source (Ganong, 2005). Thermogenesis in this tissue is evoked through the β3 adrenergic receptor by the excitation of the BAT sympathetic nerve secondary to commands from the autonomic center in the hypothalamus (Morrison, 2004). Olfactory stimulation with the scent of 0.01% water-suspension of GFO increased body temperature (BT) in unanesthetized rats (Tanida et al., 2008b) and olfactory stimulation with the scent of either 0.01% water-suspension of GFO or 0.1% water-suspension of R-(+)-limonene increased BT in unanesthetized mice (Shen et al., 2005a). These findings suggest that GFO-induced increase in BAT-SNA elevates thermogenesis, and therefore BT and that limonene is one of the active substances in GFO that causes these changes. The GFO-induced change in BT is time dependent. Elevation of rat BT after GFO stimulation was observed in the light period (resting period) but not in the dark period (active period) of a 12-h light and 12-h dark cycle (Tanida et al., 2008b). These findings indicate that the effect of olfactory stimulation with the scent of GFO may be time dependent in rats, and may be observed only in periods of rest. 2.3. Effects on the sympathetic nerves that innervate the adrenal glands and kidneys and on blood pressure Olfactory stimulation with the scent of 1% water-suspension of GFO increased the adrenal sympathetic nerve activity (ASNA; Fig. 1; Niijima and Nagai, 2003; Shen et al., 2005a) and renal sympathetic nerve activity (RSNA; Fig. 1; Shen et al., 2005b; Tanida et al., 2006) in urethaneanesthetized rats. These effects of GFO were abolished by anosmic 30 K. Nagai et al. / Autonomic Neuroscience: Basic and Clinical 185 (2014) 29–35
K Nagai et aL Autonomic Neuroscience:Basic and Clinical 185 (2014)29-35 今 Stimulation with GFO Stimulation with LVO WAT-SNA BAT-SNA ASNA RSNA GVNA Fig.1.Effects of olfactory stimulation with scent of grapefruit oil(GPO)and lavender oil(LVO)on the activities of sympathetic nerves innervating the white adipose tissue(WAT-SNA) (Shen et al 2005a.b),brown adipose tissue(BAT-SNA)(Tanida et aL 2008b).adrenal gland (ASNA)(Shen et al 2005a:Shen et aL,2005b)and renal sympathetic nerve(RSNA)(Tanida et al.,2005b.2006)and the activity of the parasympathetic nerve innervating the stomach(GVNA)(Shen et al,2005a.b).Representative trace data from recordings of autonomic nerve activities before and after olfactory stimulation with the grapefruit oil(GFO)and lavender oil (LVO)scents for 10 min.The upper bars indicate the 10-min stimulation period,the lower bars indicate 20 min and the vertical bars indicate electrical activity of 200 spikes/5 s. treatment with xylocaine or ZnSO4(Niijima and Nagai,2003:Shen et al.. of GFO was abolished by anosmic treatment with either xylocaine or 2005a:Tanida et al,2005b).These findings suggest that the scent of ZnSO(Tanida et al,2005b).These findings suggest that olfactory stim- GFO increases ASNA and RSNA. ulation with the scent of GFO suppresses GVNA. Increased ASNA enhances adrenaline secretion in mammals The suppressions of the efferent vagal nerves innervating the stom- (Ganong.2005).which elevates BP(Ganong,2005).The renal sympa- ach and intestine cause the inhibition of gut movements(peristaltic thetic nerve or post-ganglionic sympathetic nerve fibers that innervate movements),digestion and absorption(Ganong,2005).Therefore,it the renal vascular bed(Dibona,1982)are under the control of the med- was possible that the scent of GFO might reduce the appetite.Thus, ullary sympathetic premotoneurons in the central nervous system and the effect of GFO scent on appetite was examined in un-anesthetized also play an important role in modulating BP(Guynet et al.,1996;Sly rats.In this study,the scent stimulation of 0.01%water-suspension of et al.,1999).Olfactory stimulation with the scent of 1%water- GFO for 15 min a day 3 times per week for 6 weeks reduced food intake suspension of GFO increased BP in urethane-anesthetized rats (Tanida and body weight(Shen et al,2005a). et al,2005b),suggesting that the GFO-induced increase in ASNA and These findings suggest that the scent of a certain amount of GFO re- RSNA elevates BP.Moreover,olfactory stimulation with the scent of duces appetite and body weight through the decrease in GVNA and prob- 1%water-suspension of R-(+)-limonene increased ASNA(Shen et al. ably that in intestinal vagal nerve activity.With respect to this issue,it has 2005a)and RSNA (Tanida et al.,2005b)in urethane-anesthetized rats been reported that fresh grapefruit,grapefruit capsules or grapefruit juice and consistent with these results,olfactory stimulation with the scent are effective for reducing body weight in humans(Fujioka et al,2006) of 1%water-suspension of R-(+)-limonene increased BP in urethane Whether this weight reduction was caused by the loss of appetite and/ anesthetized rats(Tanidaet al.2005b).These findings suggest that lim- or metabolic changes,such as the enhancement of lipid degradation and onene is one of the active substances in GFO that causes an increase in utilization,due to olfactory stimulation with the scent of grapefruit or BP through its effects on ASNA and RSNA. other mechanisms must be examined in the future. Moreover,the authors examined the effect of olfactory stimulation 2.4.Effects on the vagal nerve innervating the stomach and appetite with the R-(+)-limonene on GVNA in urethane-anesthetized rats and found that the scent of 1%water-suspension of R-(+)-limonene sup- Olfactory stimulation with the scent of 1%water-suspension of pressed GVNA(Shen et al.,2005a;Tanida et al,2005a;)This result sug- GFO suppressed gastric vagal nerve activity (GVNA)in urethane- gests that limonene is at least one of the effective substances in GFO for anesthetized rats (Shen et al.,2005a;Tanida et al.,2005b).This effect its lowering action of GVNA
treatment with xylocaine or ZnSO4 (Niijima and Nagai, 2003; Shen et al., 2005a; Tanida et al., 2005b). These findings suggest that the scent of GFO increases ASNA and RSNA. Increased ASNA enhances adrenaline secretion in mammals (Ganong, 2005), which elevates BP (Ganong, 2005). The renal sympathetic nerve or post-ganglionic sympathetic nerve fibers that innervate the renal vascular bed (Dibona, 1982) are under the control of the medullary sympathetic premotoneurons in the central nervous system and also play an important role in modulating BP (Guynet et al., 1996; Sly et al., 1999). Olfactory stimulation with the scent of 1% watersuspension of GFO increased BP in urethane-anesthetized rats (Tanida et al., 2005b), suggesting that the GFO-induced increase in ASNA and RSNA elevates BP. Moreover, olfactory stimulation with the scent of 1% water-suspension of R-(+)-limonene increased ASNA (Shen et al., 2005a) and RSNA (Tanida et al., 2005b) in urethane-anesthetized rats and consistent with these results, olfactory stimulation with the scent of 1% water-suspension of R-(+)-limonene increased BP in urethaneanesthetized rats (Tanida et al., 2005b). These findings suggest that limonene is one of the active substances in GFO that causes an increase in BP through its effects on ASNA and RSNA. 2.4. Effects on the vagal nerve innervating the stomach and appetite Olfactory stimulation with the scent of 1% water-suspension of GFO suppressed gastric vagal nerve activity (GVNA) in urethaneanesthetized rats (Shen et al., 2005a; Tanida et al., 2005b). This effect of GFO was abolished by anosmic treatment with either xylocaine or ZnSO4 (Tanida et al., 2005b). These findings suggest that olfactory stimulation with the scent of GFO suppresses GVNA. The suppressions of the efferent vagal nerves innervating the stomach and intestine cause the inhibition of gut movements (peristaltic movements), digestion and absorption (Ganong, 2005). Therefore, it was possible that the scent of GFO might reduce the appetite. Thus, the effect of GFO scent on appetite was examined in un-anesthetized rats. In this study, the scent stimulation of 0.01% water-suspension of GFO for 15 min a day 3 times per week for 6 weeks reduced food intake and body weight (Shen et al., 2005a). These findings suggest that the scent of a certain amount of GFO reduces appetite and body weight through the decrease in GVNA and probably that in intestinal vagal nerve activity. With respect to this issue, it has been reported that fresh grapefruit, grapefruit capsules or grapefruit juice are effective for reducing body weight in humans (Fujioka et al., 2006). Whether this weight reduction was caused by the loss of appetite and/ or metabolic changes, such as the enhancement of lipid degradation and utilization, due to olfactory stimulation with the scent of grapefruit or other mechanisms must be examined in the future. Moreover, the authors examined the effect of olfactory stimulation with the R-(+)-limonene on GVNA in urethane-anesthetized rats and found that the scent of 1% water-suspension of R-(+)-limonene suppressed GVNA (Shen et al., 2005a; Tanida et al., 2005a;). This result suggests that limonene is at least one of the effective substances in GFO for its lowering action of GVNA. Stimulation with GFO Stimulation with LVO WAT-SNA BAT-SNA ASNA RSNA GVNA Fig. 1. Effects of olfactory stimulation with scent of grapefruit oil (GFO) and lavender oil (LVO) on the activities of sympathetic nerves innervating the white adipose tissue (WAT-SNA) (Shen et al., 2005a,b), brown adipose tissue (BAT-SNA) (Tanida et al., 2008b), adrenal gland (ASNA) (Shen et al., 2005a: Shen et al., 2005b) and renal sympathetic nerve (RSNA) (Tanida et al., 2005b, 2006) and the activity of the parasympathetic nerve innervating the stomach (GVNA) (Shen et al., 2005a,b). Representative trace data from recordings of autonomic nerve activities before and after olfactory stimulation with the grapefruit oil (GFO) and lavender oil (LVO) scents for 10 min. The upper bars indicate the 10-min stimulation period, the lower bars indicate 20 min and the vertical bars indicate electrical activity of 200 spikes/5 s. K. Nagai et al. / Autonomic Neuroscience: Basic and Clinical 185 (2014) 29–35 31
32 K Nagai et al.Autonomic Neuroscience:Basic and Clinical 185 (2014)29-35 3.Effects of the LVO on autonomic neurotransmission and Moreover,olfactory stimulation with the scent of 1%water- physiological phenomena suspension of (+)-linalool decreased ASNA(Shen et al.,2005b)and RSNA(Tanida et al.,2006)and lowered BP in urethane-anesthetized 3.1.Effects on the sympathetic nerve innervating the white adipose tissue rats (Tanida et al.,2006).These findings suggest that linalool is at least and lipolysis one of the effective substances of LVO which lowers BP through the de- crease in ASNA and RSNA. In authors'studies,it was found that olfactory stimulation with the scent of 1%water-suspension of LVO depressed WAT-SNA in 3.4.Effects on the vagal nerve innervating the stomach and appetite urethane-anesthetized rats (Fig.1;Shen et al.,2005b).This effect of LVO was also abolished by anosmic treatment with either xylocaine or It was found that the scent of 1%water-suspension of LVO increased ZnSO4(Shen et al,2005b).These findings suggest that olfactory stimu- GVNA in urethane-anesthetized rats(Shen et al.,2005b;Tanida et al., lation with the scent of LVO suppresses WAT-SNA. 2006).The effects of LVO on GVNA were obliterated by anosmic treat- Furthermore,it was observed that the scent of 0.001%water- ment with ZnSO(Tanida et al,2006).These findings suggest that olfac- suspension of LVO reduced the plasma glycerol concentration in un- tory stimulation with the scent of a certain amount of LVO enhances anesthetized rats (Shen et al.,2005b).These findings suggest that olfac- GVNA.Furthermore,the scent of 0.001%water-suspension of LVO for tory stimulation with the scent of a certain amount of LVO reduces 15 min a day 3 times per week for 5 weeks increased food intake and lipolysis through the decrease in WAT-SNA. body weight (Shen et al,2005b).These findings suggest that olfactory Moreover,it was observed that the scent of 1%water-suspension of stimulation with the scent of a certain amount of LVO increases appetite ()-linalool decreased WAT-SNA (Shen et al.,unpublished observation). and body weight through increase in GVNA and,probably,that in intes- Consistent with this,the scent of 0.02%water-suspension of ()-linalool tinal vagal nerve activity. lowered the plasma glycerol concentration in unanesthetized rats(Shen Olfactory stimulation with the scent of 1%water-suspension of () et al.,2005b).These findings suggest that linalool is at least one of the ef- linalool increased GVNA (Shen et al.,2005b;Tanida et al.,2006).This fective substances of LVO in its anti-lipolytic action,and that it acts fact suggests that linalool is at least one of the effective substances in through the change in WAT-SNA. LVO that are effective for its increasing action of GVNA. 3.2.Effects on the sympathetic nerve innervating BAT and thermogenesis 4.Role of histamine in changes in autonomic neurotransmission and physiological phenomena due to GFO and LVO It was observed that olfactory stimulation with the scent of 1%water- Our previous study found that diphenhydramine,a histamine H1 suspension of LVO suppressed BAT-SNA in urethane-anesthetized rats (Fig.1:Shen et al,2005b:Tanida et al.,2008b).This effect of LVO was receptor-antagonist,inhibited hyperglycemia induced by intracranial also abolished by anosmic treatment with ZnSO4(Shen et al.,2005b). injection of 2-deoxy-D-glucose(2DG)through the excitation of sympa thetic nerves(Nagai et al,2003)and GFO caused lipolysis through the These findings suggest that olfactory stimulation with the scent of cer- increase in WAT-SNA(Shen et al.,2005a).Thus,the effect of diphenhy- tain amount of LVO suppresses BAT-SNA. In this relation,it was observed that olfactory stimulation with the dramine on the lipolytic action of GFO was also examined.Consequent- ly,it was found that intraperitoneal (IP)injection of diphenhydramine scent of 0.001%water-suspension of LVO decreased BT in unanesthe- abolished the increase in the plasma glycerol concentration due to tized rats (Shen et al.,2005b;Tanida et al.,2008b).Furthermore,it was found that the scent of 0.02%water-suspension of ()-linalool de- GFO scent in unanesthetized rats(Shen et al.,2005a).In order to exam- creased BT in unanesthetized rats (Shen et al.,2005b).Consistent with ine the specificity of the effect of diphenhydramine,the effects of other autonomic blockers on the lipolytic action of GFO were examined.Pro- these findings,it was observed in urethane-anesthetized mice that the scent of 1%water-suspension of LVO reduced BAT-SNA (Tanida et al. pranolol eliminated the GFO-mediated increase in the plasma glycerol concentration,but atropine did not (Shen et al.,2007).Furthermore, 2008b).In accordance with these findings,it was reported that the inha- lation of 1%and 3%linalool caused the suppression of the body temper- our previous study showed that thioperamide,a histamine H3- ature in mice (Linck et al.,2009). receptor antagonist,inhibited the suppressive effect of L-camosine on These findings suggest that olfactory stimulation with the scent of a the hyperglycemia induced by 2DG (Yamano et al,2001;Nagai et al, certain amount of LVO decreases thermogenesis and BT through the de- 2012).Therefore,the authors examined the effect of thioperamide on crease in BAT-SNA in rats and mice.In this case linalool might be the ef the suppressive action of lipolysis elicited by LVO,and it was observed that thioperamide eliminated the LVO-mediated decrease in the plasma fective substance in LVO.However,the reduction in the rat BT by LVO was time-dependent and it was observed in the light period(resting pe- glycerol concentration in rats(Shen et al.,2005b).In order to study the riod)but not in the dark period under the 12-h light and 12-h dark cy- specificity of the effect of thioperamide,the effects of other autonomic blockers on the plasma glycerol level were examined.In this study,atro- cles (Tanida et al..2008b). pine but not propranolol abolished the LVO-mediated decrease in plas- ma glycerol concentration (Shen et al.,2007). 3.3.Effects on the sympathetic nerves innervating the adrenal glands and These findings suggest that either the histamine H1-receptor or B- kidney and blood pressure adrenergic-receptor is involved in the mechanisms underlying the GFO-mediated increase in the plasma glycerol level,thus in the lipolytic It was found that olfactory stimulation with the scent of 1%water- action of GFO,and that either the histamine H-3 receptor or the musca- suspension of LVO depressed either ASNA(Fig.1:Shen et al.,2005b) rinic receptor is involved in the mechanisms underlying the LVO- or RSNA (Fig.1:Tanida et al,2006)in urethane-anesthetized rats.The mediated decrease in the plasma glycerol level,thus in the mechanisms effect of LVO on RSNA was also eliminated by anosmic treatment with underlying the anti-lipolytic action of LVO.This is consistent with the in- ZnSO4(Tanida et al.,2006).These findings suggest that olfactory stimu- volvement of the B3 adrenergic receptor in the facilitation of lipolysis in lation with the scent of a certain amount of LVO suppressed ASNA and WAT due to the stimulation ofthe WAT-SNA and noradrenaline(Kumar RSNA. etal.2007). Olfactory stimulation with the scent of 1%water-suspension of LVO Furthermore,the following things were observed:1)diphenhydra- suppressed BP in urethane-anesthetized rats(Tanida et al,2006).These mine eliminated the increasing actions of either GFO or R-(+)-limo- findings suggest that olfactory stimulation with the scent of a certain nene on RSNA and BP (Tanida et al.,2005b).2)thioperamide amount of LVO decreases BP though decreases in ASNA and RSNA. abolished the suppressive actions of either LVO or (+)-linalool on
3. Effects of the LVO on autonomic neurotransmission and physiological phenomena 3.1. Effects on the sympathetic nerve innervating the white adipose tissue and lipolysis In authors' studies, it was found that olfactory stimulation with the scent of 1% water-suspension of LVO depressed WAT-SNA in urethane-anesthetized rats (Fig. 1; Shen et al., 2005b). This effect of LVO was also abolished by anosmic treatment with either xylocaine or ZnSO4 (Shen et al., 2005b). These findings suggest that olfactory stimulation with the scent of LVO suppresses WAT-SNA. Furthermore, it was observed that the scent of 0.001% watersuspension of LVO reduced the plasma glycerol concentration in unanesthetized rats (Shen et al., 2005b). These findings suggest that olfactory stimulation with the scent of a certain amount of LVO reduces lipolysis through the decrease in WAT-SNA. Moreover, it was observed that the scent of 1% water-suspension of (±)-linalool decreased WAT-SNA (Shen et al.,unpublished observation). Consistent with this, the scent of 0.02% water-suspension of (±)-linalool lowered the plasma glycerol concentration in unanesthetized rats (Shen et al., 2005b). These findings suggest that linalool is at least one of the effective substances of LVO in its anti-lipolytic action, and that it acts through the change in WAT-SNA. 3.2. Effects on the sympathetic nerve innervating BAT and thermogenesis It was observed that olfactory stimulation with the scent of 1% watersuspension of LVO suppressed BAT-SNA in urethane-anesthetized rats (Fig. 1; Shen et al., 2005b; Tanida et al., 2008b). This effect of LVO was also abolished by anosmic treatment with ZnSO4 (Shen et al., 2005b). These findings suggest that olfactory stimulation with the scent of certain amount of LVO suppresses BAT-SNA. In this relation, it was observed that olfactory stimulation with the scent of 0.001% water-suspension of LVO decreased BT in unanesthetized rats (Shen et al., 2005b; Tanida et al., 2008b). Furthermore, it was found that the scent of 0.02% water-suspension of (±)-linalool decreased BT in unanesthetized rats (Shen et al., 2005b). Consistent with these findings, it was observed in urethane-anesthetized mice that the scent of 1% water-suspension of LVO reduced BAT-SNA (Tanida et al., 2008b). In accordance with these findings, it was reported that the inhalation of 1% and 3% linalool caused the suppression of the body temperature in mice (Linck et al., 2009). These findings suggest that olfactory stimulation with the scent of a certain amount of LVO decreases thermogenesis and BT through the decrease in BAT-SNA in rats and mice. In this case linalool might be the effective substance in LVO. However, the reduction in the rat BT by LVO was time-dependent and it was observed in the light period (resting period) but not in the dark period under the 12-h light and 12-h dark cycles (Tanida et al., 2008b). 3.3. Effects on the sympathetic nerves innervating the adrenal glands and kidney and blood pressure It was found that olfactory stimulation with the scent of 1% watersuspension of LVO depressed either ASNA (Fig. 1; Shen et al., 2005b) or RSNA (Fig. 1; Tanida et al., 2006) in urethane-anesthetized rats. The effect of LVO on RSNA was also eliminated by anosmic treatment with ZnSO4 (Tanida et al., 2006). These findings suggest that olfactory stimulation with the scent of a certain amount of LVO suppressed ASNA and RSNA. Olfactory stimulation with the scent of 1% water-suspension of LVO suppressed BP in urethane-anesthetized rats (Tanida et al., 2006). These findings suggest that olfactory stimulation with the scent of a certain amount of LVO decreases BP though decreases in ASNA and RSNA. Moreover, olfactory stimulation with the scent of 1% watersuspension of (±)-linalool decreased ASNA (Shen et al., 2005b) and RSNA (Tanida et al., 2006) and lowered BP in urethane-anesthetized rats (Tanida et al., 2006). These findings suggest that linalool is at least one of the effective substances of LVO which lowers BP through the decrease in ASNA and RSNA. 3.4. Effects on the vagal nerve innervating the stomach and appetite It was found that the scent of 1% water-suspension of LVO increased GVNA in urethane-anesthetized rats (Shen et al., 2005b; Tanida et al., 2006). The effects of LVO on GVNA were obliterated by anosmic treatment with ZnSO4 (Tanida et al., 2006). These findings suggest that olfactory stimulation with the scent of a certain amount of LVO enhances GVNA. Furthermore, the scent of 0.001% water-suspension of LVO for 15 min a day 3 times per week for 5 weeks increased food intake and body weight (Shen et al., 2005b). These findings suggest that olfactory stimulation with the scent of a certain amount of LVO increases appetite and body weight through increase in GVNA and, probably, that in intestinal vagal nerve activity. Olfactory stimulation with the scent of 1% water-suspension of (±)- linalool increased GVNA (Shen et al., 2005b; Tanida et al., 2006). This fact suggests that linalool is at least one of the effective substances in LVO that are effective for its increasing action of GVNA. 4. Role of histamine in changes in autonomic neurotransmission and physiological phenomena due to GFO and LVO Our previous study found that diphenhydramine, a histamine H1 receptor-antagonist, inhibited hyperglycemia induced by intracranial injection of 2-deoxy-D-glucose (2DG) through the excitation of sympathetic nerves (Nagai et al., 2003) and GFO caused lipolysis through the increase in WAT-SNA (Shen et al., 2005a). Thus, the effect of diphenhydramine on the lipolytic action of GFO was also examined. Consequently, it was found that intraperitoneal (IP) injection of diphenhydramine abolished the increase in the plasma glycerol concentration due to GFO scent in unanesthetized rats (Shen et al., 2005a). In order to examine the specificity of the effect of diphenhydramine, the effects of other autonomic blockers on the lipolytic action of GFO were examined. Propranolol eliminated the GFO-mediated increase in the plasma glycerol concentration, but atropine did not (Shen et al., 2007). Furthermore, our previous study showed that thioperamide, a histamine H3- receptor antagonist, inhibited the suppressive effect of L-carnosine on the hyperglycemia induced by 2DG (Yamano et al., 2001; Nagai et al., 2012). Therefore, the authors examined the effect of thioperamide on the suppressive action of lipolysis elicited by LVO, and it was observed that thioperamide eliminated the LVO-mediated decrease in the plasma glycerol concentration in rats (Shen et al., 2005b). In order to study the specificity of the effect of thioperamide, the effects of other autonomic blockers on the plasma glycerol level were examined. In this study, atropine but not propranolol abolished the LVO-mediated decrease in plasma glycerol concentration (Shen et al., 2007). These findings suggest that either the histamine H1-receptor or β- adrenergic-receptor is involved in the mechanisms underlying the GFO-mediated increase in the plasma glycerol level, thus in the lipolytic action of GFO, and that either the histamine H-3 receptor or the muscarinic receptor is involved in the mechanisms underlying the LVOmediated decrease in the plasma glycerol level, thus in the mechanisms underlying the anti-lipolytic action of LVO. This is consistent with the involvement of the β3 adrenergic receptor in the facilitation of lipolysis in WAT due to the stimulation of the WAT-SNA and noradrenaline (Kumar et al., 2007). Furthermore, the following things were observed: 1) diphenhydramine eliminated the increasing actions of either GFO or R-(+)-limonene on RSNA and BP (Tanida et al., 2005b), 2) thioperamide abolished the suppressive actions of either LVO or (±)-linalool on 32 K. Nagai et al. / Autonomic Neuroscience: Basic and Clinical 185 (2014) 29–35
K Nagai et al Autonomic Neuroscience:Basic and Clinical 185 (2014)29-35 33 RSNA and BP(Tanida et al,2006),3)intracranial administration of di- olfactory stimulation with GFO and LVO scents.Consequently,the fol- phenhydramine eliminated the suppressing actions of either GFO or lowing results were observed:1)bilateral lesions of the SCN abolished R-(+)-limonene on GVNA(Tanida et al.,2005b),and 4)intracranial in- changes in the plasma glycerol concentration induced by olfactory stim- jection of thioperamide abolished the enhancing actions of either LVO ulation with either GFO or LVO scents in rats (Shen et al.,2007),2)bilat- or ()-linalool on GVNA (Tanida et al,2006). eral lesions of the SCN eliminated the changes in RSNA,BP and GVNA These findings suggest the following things:1)the histamine H1 re- elicited by olfactory stimulation with either GFO or LVO scents in rats ceptor is implicated in the mechanisms underlying the GFO-mediated (Tanida et al.,2005b,2006).and 3)bilateral lesions of the SCN abolished increase in RSNA and BP.2)the histamine H3 receptor is involved in the changes in BAT-SNA and BT caused by olfactory stimulation with ei- the mechanisms underlying LVO-mediated decrease in RSNA and ther GFO or LVO scents in rats(Tanida et al,2008b). BP,3).the histamine H1 receptor in the mechanisms underlying the These findings suggest that the SCN is implicated in the changes in GFO-mediated decrease in GVNA,and 4)the histamine H3 receptor in autonomic neurotransmission and physiological phenomena that the mechanisms underlying the LVO-mediated increase in GVNA. were caused by olfactory stimulation with either GFO or LVO scents. These findings suggest that olfactory stimulation with the GFO scent The findings described above implicate the SCN in the changes in au- increases BP and decreases appetite through the histamine H1 receptor tonomic neurotransmission and body functions induced by olfactory via the elevation in RSNA and the reduction in GVNA and other efferent stimulation with GFO and LVO scents.However,when electrolytic le- vagal nerves innervating the gut,and that olfactory stimulation with the sions of the SCN are made,the neural fibers pass through the lesioned LVO scent lowers BP and increases appetite through the histamine H3 area are also cut,and this denervation might be responsible for the dis- receptor via the suppression in RSNA and stimulation of GVNA and appearances of the autonomic and physiological responses to GFO and other efferent vagal nerves innervating the gut. LVO.In consideration of this possibility,we tried to examine the changes in autonomic neurotransmission and physiological phenomena that 5.Roles of circadian clock mechanism in changes in autonomic were due to olfactory stimulation with GFO and LVO scents in mice lack- neurotransmission and physiological phenomena due to GFO and LVO ing the ability to form circadian rhythms due to genetic manipulation. We used gene-knockout(KO)mice including the chryptochrome 1 In mammals,the hypothalamic suprachiasmatic nucleus(SCN)func- (Cry1)and chryptochrome 2(Cry2)double KO mice and Clock-mutant tions as a master circadian clock that forms circadian rhythms in phys- mice,which have no electrolytic brain lesions.Before starting this iological phenomena and behaviors (Lowrey and Takahashi,2004).The study,the authors confirmed the changes in the autonomic neurotrans- authors observed that the hyperglycemia induced by the intracranial mission and BP induced by olfactory stimulation with GFO and LVO administration of 2DG,an inhibitor of glucose utilization,is associated scents in intact control mice and obtained changes that were similar with the excitation of the sympathetic nerves innervating the pancreas. to those found in rats (Tanida et al.,2007a).That is,in urethane- liver and adrenal glands,a reduction in the blood insulin level and ele- anesthetized mice,olfactory stimulation with the GFO scent enhanced vations in the blood glucagon and adrenaline levels in rats (Nagai the activities of the sympathetic nerves innervating the adrenal glands et al.,1996a).Because a daily rhythm was observed in the hyperglyce- (ASNA).kidney (RSNA)and brown adipose tissue(BAT-SNA)and sup- mia induced by 2DG (Nagai et al.,1982),the effects of bilateral electro- pressed GVNA,and olfactory stimulation with the LVO scent reduced lytic lesions of the SCN on the 2DG-hyperglycemia were examined. ASNA,RSNA and BAT-SNA and increased GVNA (Tanida et al.,2007a). Consequently,it was found that SCN lesions eliminated the hyperglyce- Olfactory stimulation with GFO and LVO scents increased and lowered mia (Yamamoto et al.,1984;Nagai et al.,1996a),autonomic changes BP,respectively,in urethane-anesthetized mice (Tanida et al.,2007a) (Nagai et al.,1996b)and endocrine changes (Nagai et al.,1996a)due Furthermore,it was observed that bilateral electrolytic lesions of the to 2DG. SCN eliminated all changes in RSNA,GVNA and BP that were elicited Because of this background,the authors examined the effects of bi- by olfactory stimulation with either GFO or LVO scents in urethane- lateral electrolytic lesions of the SCN on the changes induced by anesthetized mice (Tanida et al.,2007a).After confirming these WAT-SNA&Lipolysis个 BAT-SNA BT Scent of 个 GFO ASNA BP 个 HI receptor RSNA BP 个 Oifactory Hypothalamic Hypothalamic GVNA Appetite epithelium TMN SCN H3 receptor WAT-SNA&Lipolysis↓ Scent of LVO BAT-SNA BT ASNA BP RSNA BP GVNA Appetite 个 Fig.2.Schematic figure summarizing the contents of the review.Scent stimulation of grapefruit oil(GFO)and lavender oil (LVO)are sensed by the olfactory epithelium,and the informa- tion of the olfactory epithelium send signals probably through limbic system to the hypothalamic tuberomammillary nucleus (TMN).Then,this signal is sent to the hypothalamic supra- chiasmatic nucleus(SCN).Finally,these information elicits changes in autonomic nerve activities(WAT-SNA.BAT-SNA.ASNA.RSNA and GVNA)and these changes caused alteration of physiological phenomena such as lipolysis,the body temperature(BT).blood pressure (BP)and appetite
RSNA and BP (Tanida et al., 2006), 3) intracranial administration of diphenhydramine eliminated the suppressing actions of either GFO or R-(+)-limonene on GVNA (Tanida et al., 2005b), and 4) intracranial injection of thioperamide abolished the enhancing actions of either LVO or (±)-linalool on GVNA (Tanida et al., 2006). These findings suggest the following things: 1) the histamine H1 receptor is implicated in the mechanisms underlying the GFO-mediated increase in RSNA and BP, 2) the histamine H3 receptor is involved in the mechanisms underlying LVO-mediated decrease in RSNA and BP, 3) .the histamine H1 receptor in the mechanisms underlying the GFO-mediated decrease in GVNA, and 4) the histamine H3 receptor in the mechanisms underlying the LVO-mediated increase in GVNA. These findings suggest that olfactory stimulation with the GFO scent increases BP and decreases appetite through the histamine H1 receptor via the elevation in RSNA and the reduction in GVNA and other efferent vagal nerves innervating the gut, and that olfactory stimulation with the LVO scent lowers BP and increases appetite through the histamine H3 receptor via the suppression in RSNA and stimulation of GVNA and other efferent vagal nerves innervating the gut. 5. Roles of circadian clock mechanism in changes in autonomic neurotransmission and physiological phenomena due to GFO and LVO In mammals, the hypothalamic suprachiasmatic nucleus (SCN) functions as a master circadian clock that forms circadian rhythms in physiological phenomena and behaviors (Lowrey and Takahashi, 2004). The authors observed that the hyperglycemia induced by the intracranial administration of 2DG, an inhibitor of glucose utilization, is associated with the excitation of the sympathetic nerves innervating the pancreas, liver and adrenal glands, a reduction in the blood insulin level and elevations in the blood glucagon and adrenaline levels in rats (Nagai et al., 1996a). Because a daily rhythm was observed in the hyperglycemia induced by 2DG (Nagai et al., 1982), the effects of bilateral electrolytic lesions of the SCN on the 2DG-hyperglycemia were examined. Consequently, it was found that SCN lesions eliminated the hyperglycemia (Yamamoto et al., 1984; Nagai et al., 1996a), autonomic changes (Nagai et al., 1996b) and endocrine changes (Nagai et al., 1996a) due to 2DG. Because of this background, the authors examined the effects of bilateral electrolytic lesions of the SCN on the changes induced by olfactory stimulation with GFO and LVO scents. Consequently, the following results were observed: 1) bilateral lesions of the SCN abolished changes in the plasma glycerol concentration induced by olfactory stimulation with either GFO or LVO scents in rats (Shen et al., 2007), 2) bilateral lesions of the SCN eliminated the changes in RSNA, BP and GVNA elicited by olfactory stimulation with either GFO or LVO scents in rats (Tanida et al., 2005b, 2006), and 3) bilateral lesions of the SCN abolished the changes in BAT-SNA and BT caused by olfactory stimulation with either GFO or LVO scents in rats (Tanida et al., 2008b). These findings suggest that the SCN is implicated in the changes in autonomic neurotransmission and physiological phenomena that were caused by olfactory stimulation with either GFO or LVO scents. The findings described above implicate the SCN in the changes in autonomic neurotransmission and body functions induced by olfactory stimulation with GFO and LVO scents. However, when electrolytic lesions of the SCN are made, the neural fibers pass through the lesioned area are also cut, and this denervation might be responsible for the disappearances of the autonomic and physiological responses to GFO and LVO. In consideration of this possibility, we tried to examine the changes in autonomic neurotransmission and physiological phenomena that were due to olfactory stimulation with GFO and LVO scents in mice lacking the ability to form circadian rhythms due to genetic manipulation. We used gene-knockout (KO) mice including the chryptochrome 1 (Cry1) and chryptochrome 2 (Cry2) double KO mice and Clock-mutant mice, which have no electrolytic brain lesions. Before starting this study, the authors confirmed the changes in the autonomic neurotransmission and BP induced by olfactory stimulation with GFO and LVO scents in intact control mice and obtained changes that were similar to those found in rats (Tanida et al., 2007a). That is, in urethaneanesthetized mice, olfactory stimulation with the GFO scent enhanced the activities of the sympathetic nerves innervating the adrenal glands (ASNA), kidney (RSNA) and brown adipose tissue (BAT-SNA) and suppressed GVNA, and olfactory stimulation with the LVO scent reduced ASNA, RSNA and BAT-SNA and increased GVNA (Tanida et al., 2007a). Olfactory stimulation with GFO and LVO scents increased and lowered BP, respectively, in urethane-anesthetized mice (Tanida et al., 2007a). Furthermore, it was observed that bilateral electrolytic lesions of the SCN eliminated all changes in RSNA, GVNA and BP that were elicited by olfactory stimulation with either GFO or LVO scents in urethaneanesthetized mice (Tanida et al., 2007a). After confirming these Fig. 2. Schematic figure summarizing the contents of the review. Scent stimulation of grapefruit oil (GFO) and lavender oil (LVO) are sensed by the olfactory epithelium, and the information of the olfactory epithelium send signals probably through limbic system to the hypothalamic tuberomammillary nucleus (TMN). Then, this signal is sent to the hypothalamic suprachiasmatic nucleus (SCN). Finally, these information elicits changes in autonomic nerve activities (WAT-SNA, BAT-SNA, ASNA, RSNA and GVNA) and these changes caused alteration of physiological phenomena such as lipolysis, the body temperature (BT), blood pressure (BP) and appetite. K. Nagai et al. / Autonomic Neuroscience: Basic and Clinical 185 (2014) 29–35 33
34 K Nagai et al.Autonomic Neuroscience:Basic and Clinical 185 (2014)29-35 Table 1 Effects of olfactory stimulation with the scent of grapefruit oil on autonomic neurotransmission and physiological function in rats. Nerve Changes innerve activity Changes in physiological phenomena Reference White adipose tissue sympathetic nerve Facilitation Increase in lipolysis Niijima and Nagai,2003 Shen et aL,2005a Brown adipose tissue Facilitation Increase in thermogenesis Shen et aL,2005a Sympathetic nerve Increase in BT Tanida et al,2008a Adrenal sympathetic nerve Facilitation Increase in adrenaline Shen et al,2005a Secretion,increase in BP Tanida et al,2005b Renal sympathetic nerve Facilitation Increase in BP Tanida et aL,2005b Gastric vagal nerve Suppression Decrease in appetite Shen et aL,2005a BT.body temperature:BP.blood pressure findings,the authors examined the changes in autonomic neurotrans- 6.Concluding remarks mission and a physiological phenomenon(i.e.,BP)elicited by GFO and LVO in Cryl and Cry2 double KO mice and Clock-mutant mice. This review described that olfactory stimulation with GFO and LVO In this study.it was found that GFO-induced increases in RSNA and scents affect physiological functions in association with changes in auto- BP and the LVO-induced increase in GVNA were not observed in Cryl nomic neurotransmission in rats (Tables 1 and 2).That is,olfactory and Cry2 double KO mice,which lack circadian rhythm of locomotive stimulation with the GFO scent increases lipolysis,thermogenesis activity under constant dark condition (Tanida et al.,2007a).However. (BT),and BP,and suppresses appetite in association with increases in GFO-induced increases in RSNA and BP were not observed in Clock- WAT-SNA,BAT-SNA,ASNA and RSNA and a decrease in GVNA in rats. mutant mice,but LVO-induced suppressions of RSNA and BP were ob- However,olfactory stimulation with the LVO scent represses lipolysis, served (Tanida et al.,2008a).These findings suggest that the molecular thermogenesis(BT)and BP,and facilitates appetite in association with clock mechanisms in the SCN,which involve the Cry1,Cry2 and Clock decreases in WAT-SNA,BAT-SNA,ASNA and RSNA and an increase in genes,are partially involved in mediating these autonomic and cardio- GVNA in rats.Because olfactory stimulation with the scent of R-(+)- vascular actions of GFO and LVO. limonene causes similar changes in physiological phenomena and auto- Using the pseudorabies virus,which is retrogradely and nomic functions after olfactory stimulation as does the GFO scent(Shen multisynaptically transported in nerves,we(Buijs et al.,2001,2003) et al..2005a:Tanida et al,2005b),limonene may be at least one of the and others (Bamshad et al.,1999.;Sly et al.,1999;Bartness et al. effective substances in GFO.In contrast,()-linalool resulted in similar 2001)have found evidence that the SCN sends sympathetic and para- changes in physiological phenomena and autonomic functions after ol- sympathetic neuronal projections to peripheral organs and tissues in- factory stimulation as does the LVO scent (Shen et al.,2005b;Tanida cluding the pancreas,liver,kidney,adrenal glands,and white and et al.,2006).Thus,linalool may be at least one of the effective substances brown adipose tissues.This represents the neural transmission route in LVO.Furthermore,evidence suggesting the involvement of the mas- from the SCN to peripheral organs.In this respect,we presented evi- ter circadian clock,the SCN,circadian clock mechanisms,and histamine dence that sympathetic preautonomic neurons and parasympathetic mechanisms in the changes in autonomic neurotransmission and phys- preautonomic neurons are different at the level of the SCN(Buijs et al. iological phenomena induced by stimulations with GFO and LVO were 2003).With regard to the relationship between histamine neurons in described in this review. the hypothalamic tuberomammillary nucleus(TMN)and the SCN,it With respect to the effects of olfactory stimulation with the scents of has been suggested that histaminergic neurons in the TMN project to essential oils in human beings,it has been described that psychosensory the SCN neurons (Michelsen et al.,2005).Therefore,the signals of the effects that are derived from individual experience and events are im- GFO and LVO scents that are responsible for the changes in neurotrans- portant in the effects of essential oils(Bureau,2012).Therefore,how mission and thus in the physiological phenomena described above much innate functional changes due to essential oils observed in animal might be transmitted from olfactory receptors in the nose to the SCN experiments are detected in human beings must be examined in the fu- through histamine neurons in the TMN.Then,this signal might be trans- ture.It was reported that an increase in the parasympathetic tone, mitted from the SCN down to the peripheral organs/tissues,and in this which was determined by the power spectral analysis of human heart way,the effects of olfactory stimulation with GFO,LVO and other essen- rate variability,were observed after the lavender fragrance (Duan tial oils on physiological functions might be realized (Fig.2). et al.,2007),and that blood norepinephrine levels following the cold Table 2 Effects of olfactory simulation with the scent of lavender oil on autonomic neurotransmission and physiological functions in rats Nerve Changes in nerve activity Changes in physiological phenomena Reference White adipose tissue Suppression Decrease in lipolysis Shen et al..2005b Sympathetic nerve Brown adipose tissue Suppression Decrease in thermogenesis Shen et al 2005b Sympathetic nerve Decrease in BT Tanida et al.2008a Adrenal sympathetic Suppression Decrease in adrenaline Shen et al.,2005b nerve Secretion,decrease in BP Tanida et al 2006 Renal sympathetic Suppression Decrease in BP Tanida et al.2006 nerve Gastric vagal Facilitation Increase in appetite Shen et al.,2005b nerve BT.body temperature:BP.blood pressure
findings, the authors examined the changes in autonomic neurotransmission and a physiological phenomenon (i.e., BP) elicited by GFO and LVO in Cry1 and Cry2 double KO mice and Clock-mutant mice. In this study, it was found that GFO-induced increases in RSNA and BP and the LVO-induced increase in GVNA were not observed in Cry1 and Cry2 double KO mice, which lack circadian rhythm of locomotive activity under constant dark condition (Tanida et al., 2007a). However, GFO-induced increases in RSNA and BP were not observed in Clockmutant mice, but LVO-induced suppressions of RSNA and BP were observed (Tanida et al., 2008a). These findings suggest that the molecular clock mechanisms in the SCN, which involve the Cry1, Cry2 and Clock genes, are partially involved in mediating these autonomic and cardiovascular actions of GFO and LVO. Using the pseudorabies virus, which is retrogradely and multisynaptically transported in nerves, we (Buijs et al., 2001, 2003) and others (Bamshad et al., 1999,; Sly et al., 1999; Bartness et al., 2001) have found evidence that the SCN sends sympathetic and parasympathetic neuronal projections to peripheral organs and tissues including the pancreas, liver, kidney, adrenal glands, and white and brown adipose tissues. This represents the neural transmission route from the SCN to peripheral organs. In this respect, we presented evidence that sympathetic preautonomic neurons and parasympathetic preautonomic neurons are different at the level of the SCN (Buijs et al., 2003). With regard to the relationship between histamine neurons in the hypothalamic tuberomammillary nucleus (TMN) and the SCN, it has been suggested that histaminergic neurons in the TMN project to the SCN neurons (Michelsen et al., 2005). Therefore, the signals of the GFO and LVO scents that are responsible for the changes in neurotransmission and thus in the physiological phenomena described above might be transmitted from olfactory receptors in the nose to the SCN through histamine neurons in the TMN. Then, this signal might be transmitted from the SCN down to the peripheral organs/tissues, and in this way, the effects of olfactory stimulation with GFO, LVO and other essential oils on physiological functions might be realized (Fig. 2). 6. Concluding remarks This review described that olfactory stimulation with GFO and LVO scents affect physiological functions in association with changes in autonomic neurotransmission in rats (Tables 1 and 2). That is, olfactory stimulation with the GFO scent increases lipolysis, thermogenesis (BT), and BP, and suppresses appetite in association with increases in WAT-SNA, BAT-SNA, ASNA and RSNA and a decrease in GVNA in rats. However, olfactory stimulation with the LVO scent represses lipolysis, thermogenesis (BT) and BP, and facilitates appetite in association with decreases in WAT-SNA, BAT-SNA, ASNA and RSNA and an increase in GVNA in rats. Because olfactory stimulation with the scent of R-(+)- limonene causes similar changes in physiological phenomena and autonomic functions after olfactory stimulation as does the GFO scent (Shen et al., 2005a; Tanida et al., 2005b), limonene may be at least one of the effective substances in GFO. In contrast, (±)-linalool resulted in similar changes in physiological phenomena and autonomic functions after olfactory stimulation as does the LVO scent (Shen et al., 2005b; Tanida et al., 2006). Thus, linalool may be at least one of the effective substances in LVO. Furthermore, evidence suggesting the involvement of the master circadian clock, the SCN, circadian clock mechanisms, and histamine mechanisms in the changes in autonomic neurotransmission and physiological phenomena induced by stimulations with GFO and LVO were described in this review. With respect to the effects of olfactory stimulation with the scents of essential oils in human beings, it has been described that psychosensory effects that are derived from individual experience and events are important in the effects of essential oils (Bureau, 2012). Therefore, how much innate functional changes due to essential oils observed in animal experiments are detected in human beings must be examined in the future. It was reported that an increase in the parasympathetic tone, which was determined by the power spectral analysis of human heart rate variability, were observed after the lavender fragrance (Duan et al., 2007), and that blood norepinephrine levels following the cold Table 2 Effects of olfactory simulation with the scent of lavender oil on autonomic neurotransmission and physiological functions in rats. Nerve Changes in nerve activity Changes in physiological phenomena Reference White adipose tissue Suppression Decrease in lipolysis Shen et al., 2005b Sympathetic nerve Brown adipose tissue Suppression Decrease in thermogenesis Shen et al., 2005b Sympathetic nerve Decrease in BT Tanida et al., 2008a Adrenal sympathetic nerve Suppression Decrease in adrenaline Shen et al., 2005b Secretion, decrease in BP Tanida et al., 2006 Renal sympathetic nerve Suppression Decrease in BP Tanida et al., 2006 Gastric vagal nerve Facilitation Increase in appetite Shen et al., 2005b BT, body temperature; BP, blood pressure. Table 1 Effects of olfactory stimulation with the scent of grapefruit oil on autonomic neurotransmission and physiological function in rats. Nerve Changes innerve activity Changes in physiological phenomena Reference White adipose tissue sympathetic nerve Facilitation Increase in lipolysis Niijima and Nagai, 2003 Shen et al., 2005a Brown adipose tissue Facilitation Increase in thermogenesis Shen et al., 2005a Sympathetic nerve Increase in BT Tanida et al., 2008a Adrenal sympathetic nerve Facilitation Increase in adrenaline Shen et al., 2005a Secretion, increase in BP Tanida et al., 2005b Renal sympathetic nerve Facilitation Increase in BP Tanida et al., 2005b Gastric vagal nerve Suppression Decrease in appetite Shen et al., 2005a BT, body temperature; BP, blood pressure. 34 K. Nagai et al. / Autonomic Neuroscience: Basic and Clinical 185 (2014) 29–35
K Nagai et aL Autonomic Neuroscience:Basic and Clinical 185 (2014)29-35 35 stress remained elevated when subjects smelled lemon odor compared Linck,V.M.,da Silva,A.L.Figueiro,M.,Piato.A.L.Herrmann,A.P.,Dupont,Birck F.. Caramao.E.B.Nunes.D.S..Moreno.P.R..Elisabetsky.E..2009.Inhaled linalool- when subjects smelled lavender odor (Kiecolt-Glaser et al.,2008) induced sedation in mice.Phytomedicine 16,303-307 Therefore,it is reasonable to speculate that autonomic neurotransmis- Lowrey.P.L.Takahashi.J.S..2004.Mammalian circadian biology:elucidating genome- sion and thus physiological phenomena can be innately modulated by wide levels of temporal organization.Annu.Rev.Genomics Hum.Genet.5.407-441 sensory olfactory signals in humans.Whether these effects that have Michelsen.K.A..Lozada.A.Kaslin.J.Karlstedt,K..Kukko-Lukjanov,T.K.Holopainen.L.. Ohtsu,H.,Panula,P 2005.Histamine-immunoreactive neurons in the mouse and been observed in the animal experiments described above will be ob- rat suprachiasmatic nucleus.Eur.J.Neurosci 22.1997-2004 served in human beings is the next target investigation of this line of Morrison,S.F 2004.Central pathways controlling brown adipose tissue thermogenesis. studies News Physiol.Sci.19,67-74. Nagai,K.Yamamoto,H.Nakagawa.H.1982.Time-dependent hyperglycemic actions of centrally administered 2-deoxy-D-glucose,D-mannitol and D-glucose.Biomed.Res. Conflict of interest 3.288-293. Nagai,K.Nagai,N.,Shimizu,K.,Chun,S.J,Nakagawa,H.,Niijima.A.1996a.SCN output drives the autonomic nervous system:with special reference to the autonomic func- All of the results mentioned in this review were obtained in the au- tion related to the regulation of glucose metabolism.Prog.Brain Res.111.253-272. thors'study in Osaka University.From the text-book style results ob- Nagai,K.Niijima,A.Nagai,N.Hibino,H.Chun,S..Shimizu,K.Nakagawa.H.1996b.Bi- tained in this study made the first author of this review confident lateral lesions of the hypothalamic suprachiasmatic nucleus eliminated sympathetic response to intracranial injection of 2-deoxy-D-glucose and VIP rescued this response. with the relationship between changes in autonomic neurotransmis- Brain Res.BulL 39,293-297. sion and those in physiological functions.The first author thinks that Nagai,K.Niijima,A..Yamano,T.,Otani,H.Okumura.N.,Tsuruoka,N.Nakai,M..Kiso,Y.. these relationships must be important and worthwhile to make the re- 2003.Possible role of L-carnosine in the regulation of blood glucose through control- ling autonomic nerves.Exp.Biol.Med.(Maywood)228,1138-1145. view for the understanding of the readers.Thus,this review does not Nagai,K,Tanida,M.,Niijima,A.,Tsuruoka,N.Kiso,Y..Horii,Y..Shen,J Okumura,N. have any conflict of interest. 2012.Role of L-carnosine in the control of blood glucose,blood pressure,thermogen- esis and lipolysis by autonomic nerves in rats:involvement of the circadian clock and Acknowledgments histamine.Amino Acids 43,97-109. Niijima,A.Nagai,K,2003.Effect of olfactory stimulation with flavor of grapefruit oil and lemon oil on the activity of sympathetic branch in the white adipose tissue of the ep- We would like to express our deep gratitude to the contributors of ididymis.Exp.Biol.Med.(Maywood)228.1190-1192. this research in the Institute for Protein Research,Osaka University, Shen,Niijima,A..Tanida,M..Horii,Y..Maeda.K.Nagai,K.2005a.Olfactory stimulation with scent of grapefruit oil affects autonomic nerves.lipolysis and appetite in rats. Japan. Neurosci.Lett.380.289-294. Shen.L Niijima.A.Tanida.M..Horii,Y..Maeda.K..Nagai.K..2005b.Olfactory stimulation References with scent of lavender oil affects autonomic nerves,lipolysis and appetite in rats. Neurosci.Lett.383.188-193. 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stress remained elevated when subjects smelled lemon odor compared when subjects smelled lavender odor (Kiecolt-Glaser et al., 2008). Therefore, it is reasonable to speculate that autonomic neurotransmission and thus physiological phenomena can be innately modulated by sensory olfactory signals in humans. Whether these effects that have been observed in the animal experiments described above will be observed in human beings is the next target investigation of this line of studies. Conflict of interest All of the results mentioned in this review were obtained in the authors' study in Osaka University. From the text-book style results obtained in this study made the first author of this review confident with the relationship between changes in autonomic neurotransmission and those in physiological functions. The first author thinks that these relationships must be important and worthwhile to make the review for the understanding of the readers. 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