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The present study aimed to clarify if stroking stimulation of the skin produces positive emotion in rats. 50-kHz ultrasonic vocalizations (USVs) were recorded as an index of the positive emotion. Stroking stimulation was applied to the ventral, dorsal, or head region of the body while the rat was in a vertical holding condition. Rats emit abundant 50-kHz USVs in response to stroking, and the number of the USVs was not different among these three stimulated regions. Other stimulations, such as light touching of the abdominal area, swinging of the body back and forth, or stroking of the external genitalia under vertical holding condition, produced significantly less 50-kHz USVs. Furthermore, different call subtypes were observed during and after stroking of the ventral region. In particular, “Trill” calls, a representative index of positive emotion, were dominant after stimulation. These results suggest that stroking of the skin induces positive emotional states.

Noxious cutaneous stimulation increases, whereas innocuous cutaneous stimulation decreases serotonin (5-HT) release in the central nucleus of the amygdala (CeA) in anesthetized rats. In the present study, we investigated the contribution of corticotropin releasing factor (CRF) receptors and gamma-aminobutyric acid (GABA) receptors in the dorsal raphe nucleus (DRN) to those responses. Release of 5-HT in the CeA was monitored by microdialysis before and after 10-min stimulation by pinching or stroking. Increased 5-HT release in the CeA in response to pinching was abolished by CRF2 receptor antagonism in the DRN. Decreased 5-HT release in the CeA in response to stroking was abolished by either CRF1 receptor antagonism or GABAA receptor antagonism in the DRN. These results suggest that opposite responses of 5-HT release in the CeA to noxious versus innocuous stimulation of the skin are due to separate contributions of CRF2, CRF1 and GABAA receptors in the DRN.

The effects of electro-acupuncture (EA) on plasma concentration of glucose and on responsiveness to insulin were examined in an animal model of diabetes, the streptozotocin-treated rat. Two weeks after treatment with streptozotocin, rats were anesthetized with urethane-chloralose and subjected to the EA for 10 min delivered to the tibialis anterior muscle of one side. The stimulation produced no significant changes in plasma glucose concentration. In contrast, EA increased the response of plasma glucose to insulin (0.2 U kg(-1)). The effect of EA on the responsiveness to insulin was abolished by section of both sciatic and femoral nerves ipsilateral to the side of the EA. These results show that EA in diabetic rats has no effect on plasma glucose concentration while it augments the responsiveness to insulin, and we show that this occurs via a mechanism that involves the somatic afferent nerves.

In urethane-anesthetized, artificially ventilated rats, alterations in dorsal spinal cord blood flow (SCBF) at the L4-6 level were measured with laser Doppler flowmetry in response to noxious mechanical cutaneous stimulation (pinching) of either a forepaw or a hindpaw. The stimulation was delivered ipsilaterally or contralaterally to the site of blood flow measurement. Pinching of the forepaw or the hindpaw on either side increased mean arterial pressure (MAP) to the same degree. However, the SCBF response to pinching of the ipsilateral hindpaw was significantly greater than that to other stimulations. These responses were not influenced by denervation of the baroreceptors. The responses of SCBF to pinching of the ipsilateral hindpaw persisted both after treatment with phenoxybenzamine and after spinalization at the C1-2 level, whereas the responses to pinching at other sites disappeared. The responses of MAP to stimulation at all four sites became negligible after treatment with phenoxybenzamine and after spinalization at the C1-2 level. These results indicate that noxious mechanical stimulation of the skin produces increases in SCBF via two mechanisms: one is via an elevation of systemic arterial pressure; the other is via a localized spinal mechanism evoked by ipsilateral, segmental inputs.

We investigated the effect of noxious (pinching) and innocuous (stroking) stimulation of skin on serotonin (5-HT) release in the central nucleus of the amygdala (CeA) in anesthetized rats. 5-HT in the CeA was collected by microdialysis methods. Dialysate output from consecutive 10-min periods was injected into a high-performance liquid chromatograph and 5-HT was measured with an electrochemical detector. Bilateral pinching of the back for 10 min increased 5-HT release significantly; 5-HT release was also increased with stimulation of the forelimb or hindlimb. In contrast, stroking of these areas decreased 5-HT release significantly. Furthermore, simultaneous stroking and pinching produced no change in the 5-HT release. In conclusion, the present study demonstrates that 5-HT release in the CeA is regulated by somatic afferent stimulation in a modality-dependent manner, and that innocuous stimulation can dampen the change in 5-HT release that occurs in response to noxious stimulation.

Electroacupuncture (EA) applied to the abdomen and hindlimb modulates the ovarian blood flow (OBF) response. The present study aimed to further elucidate the role of the site and the frequency of short-term EA stimulation and the influence of the estrous cycle on the OBF response using anesthetized rats. EA stimulation was applied to the abdominal or the hindlimb muscles at three different frequencies (2, 10, and 80 Hz) during the estrus or diestrus phase. Involvement of spinal and supraspinal reflexes in OBF responses to EA stimulation was investigated by spinal cord transection. Abdominal EA stimulation at 10 Hz increased the OBF response, whereas hindlimb EA stimulation at 10 Hz and abdominal and hindlimb stimulation at 80 Hz decreased the OBF response; 2-Hz EA caused no OBF response. The OBF response to abdominal EA was more pronounced in the estrus than the diestrus phase. The OBF response to abdominal and hindlimb EA stimulation at both 10 and 80 Hz was almost abolished, both after severance of the sympathetic nerves and after spinal cord transection. In conclusion, the OBF response to both abdominal and hindlimb EA stimulation was mediated as a reflex response via the ovarian sympathetic nerves, and the response was controlled via supraspinal pathways. Furthermore, the OBF response to segmental abdominal EA stimulation was frequency dependent and amplified in the estrous phase.

In urethane-anesthetized, artificially-ventilated rats, alterations in dorsal spinal cord blood flow (SCBF) were measured with a laser Doppler flowmeter in response to innocuous mechanical cutaneous stimulation. SCBF recorded at the T12-L1 level increased with brushing of the ipsilateral, but not contralateral, upper back, lower back or proximal hindlimb. Brushing of the forepaw, proximal forelimb or hindpaw had no effect on T12-L1 SCBF. SCBF recorded at the L4-6 level increased with brushing of the ipsilateral, but not contralateral, proximal hindlimb and hindpaw. Brushing of the forepaw, proximal forelimb, upper back or lower back had no effect on SCBF at the L4-6 level. None of these brushing stimuli produced significant changes in systemic arterial blood pressure or heart rate. Pretreatment with phenoxybenzamine, an alpha adrenoceptor blocking agent, resulted in a small but statistically significant attenuation in the response of SCBF to brushing. However, pretreatment with propranolol, a beta adrenoceptor blocking agent, or atropine, a muscarinic cholinergic receptor blocking agent, produced no such effect. These results indicate that innocuous mechanical cutaneous input can produce a segmentally-organized increase in regional SCBF, which may be mediated in part, by alpha adrenergic receptors.

The purpose of the present study was to investigate changes in ovarian blood flow (OBF) in response to electro-acupuncture (EA) stimulation at different frequencies and intensities in anaesthetized rats. Whether the ovarian sympathetic nerves were involved in OBF responses was elucidated by severance of the ovarian sympathetic nerves. In addition, how changes in the systemic circulation affected OBF was evaluated by continuously recording blood pressure. OBF was measured on the surface of the left ovary using laser Doppler flowmeter. Acupuncture needles with a diameter of 0.3 mm were inserted bilaterally into the abdominal and the hindlimb muscles and connected to an electrical stimulator. Two frequencies-2 Hz (low) and 80 Hz (high)-with three different intensities-1.5, 3, and 6 mA-were applied for 35 s. Both low- and high-frequency EA at 1.5 mA and high-frequency EA at 3 mA had no effect on OBF or mean arterial blood pressure (MAP). Low-frequency EA at 3 and 6 mA elicited significant increases in OBF. In contrast, high-frequency EA with an intensity of 6 mA evoked significant decreases in OBF, followed by decreases in MAP. After severance of the ovarian sympathetic nerves, the increases in the OBF responses to low-frequency EA at 3 and 6 mA were totally abolished, and the responses at 6 mA showed a tendency to decrease, probably because of concomitant decreases in MAP. The decreased OBF and MAP responses to high-frequency EA at 6 mA remained after the ovarian sympathectomy, and the difference in the responses before and after ovarian sympathectomy was nonsignificant. In conclusion, the present study showed that low-frequency EA stimulation increases OBF as a reflex response via the ovarian sympathetic nerves, whereas high-frequency EA stimulation decreases OBF as a passive response following systemic circulatory changes.

Background: Lafutidine, (±)-2-(furfurylsulfinyl)-N-[4-[4-(piperidinomethyl)-2-pyridyl]oxy-(Z)-2 butenyl]acetamide, is a newly synthesized histamine H2 receptor antagonist and possesses a cytoprotective efficacy, which comprises mucin biosynthesis and stimulation of gastric blood flow mediated through capsaicin-sensitive sensory neurons and endogenous calcitonin gene-related peptide (CGRP). In the present study, an effect of lafutidine on hepatic blood flow was investigated in rats that received an intracisternal injection of a subthreshold dose of thyrotropin-releasing hormone (TRH) analog, RX 77368. Methods: Change in hepatic blood flow was determined by laser Doppler flowmetry. Male Wistar rats were anesthetized with urethane (1.5 g/kg, i.p.), and positioned on a stereotaxic apparatus. An abdominal incision was made, and a probe of laser Doppler flowmeter was placed on the surface of the liver. After a 60-min stabilization, basal hepatic blood flow was measured for 30 min, and lafutidine (0.5, 1, 3, 5 or 10 mg/kg) or vehicle was injected into the portal vein and a subthreshold dose (1.5 ng) of RX 77368 was injected intracisternally. Hepatic blood flow was monitored for 120 min postinjection. To investigate a role of capsaicin-sensitive sensory neurons and endogenous CGRP, systemic capsaicin treatment (125 mg/kg, s.c., 10–14 days before) and intravenous infusion of a CGRP receptor antagonist, human CGRP-(8-37) (15 µg/kg as a bolus, followed by infusion at 3 µg/kg/h) were performed, respectively. Results: Intracisternal injection of RX 77368 (1.5 ng) or intraportal lafutidine (10 mg/kg) by itself did not affect hepatic blood flow, but co-injection of intracisternal RX 77368 (1.5 ng) and intraportal lafutidine (5 mg/kg) increased it with peak response at 30 min postinjection. The effect of lafutidine on hepatic blood flow in rats given RX 77368 was dose-related over the range 1–5 mg/kg. By contrast, intracisternal injection of RX 77368 (1.5 ng) did not change hepatic blood flow in rats injected with another histamine H2 receptor antagonist, famotidine (5 mg/kg), intraportally. The stimulatory effect of co-injection of TRH analog and lafutidine was abolished by systemic capsaicin-treatment and CGRP antagonist. Conclusion: These data suggest that lafutidine increases hepatic blood flow by sensitizing the liver to the action of central TRH via both capsaicin-sensitive sensory neurons and endogenous CGRP in urethane-anesthetized rats.

Massage-like stroking induces acute antinociceptive effects that can be reversed by an oxytocin antagonist, indicating activation of oxytocin on endogenous pain controlling systems. We now demonstrate an increase in hindpaw withdrawal latencies (HWLs), in response to thermal and mechanical stimuli, which was present after six treatments of massage-like stroking every other day and which continued to increase through the remaining seven treatments. Repeated massage-like stroking also resulted in increased oxytocin-like immunoreactivity (oxytocin-LI) levels in plasma and periaquaductal grey matter (PAG). Furthermore, increases in HWLs were also present after injections of oxytocin into the PAG (0.1, 0.5 and 1.0 nmol). Intra-PAG oxytocin injection of 1 nmol followed by 1 or 20 nmol of naloxone attenuated the increments in HWL. Also, there was a dose-dependent attenuation of the oxytocin-induced antinociceptive effects following intra-PAG injection of the m-opioid antagonist bfunaltrexamine (b-FNA) and the k-opioid antagonist nor-binaltorphimine (nor-BNI) but not the d-antagonist naltrindole. The longterm antinociceptive effects of massage-like stroking may be attributed, at least partly, to the oxytocinergic system and its interaction with the opioid system, especially the m- and the k-receptors in the PAG.

Radiotherapy for malignant tumours often elicits anorexia or loss of appetite as an adverse effect. However, the mechanism for this is poorly understood. The present study was undertaken to investigate if visceral afferents are responsible for reduction of food intake following X-ray irradiation. Rats were exposed bilaterally to X-ray (10 MV) irradiation with total doses of 1.5, 3 and 6 Gy, using a high-energy electron linear accelerator at a dose rate of 4.9 Gy min−1. X-ray irradiation of the whole body, abdomen or head with doses of 1.5, 3 and 6 Gy reduced food intake in a dose-dependent manner. The reduction of food intake after X-ray irradiation of the whole body or abdomen was significantly greater than when only the head was irradiated. Reduction of food intake was observed for the first 4 days after 6 Gy X-ray irradiation of the abdomen, while it was observed only on the first day after the same 6-Gy irradiation of the abdomen in animals whose small-diameter afferents were ablated by capsaicin pre-treatment. These results suggested that the abdominal afferent nerves at least contribute to the reduction of food intake observed on second to fourth days after 6-Gy abdominal irradiation. Taken together, the present evidence suggests that the reduction of food intake following X-ray irradiation of the whole body or the abdomen is partly mediated via abdominal afferent nerves. Moreover, the results of X-ray irradiation to the head suggest that X-ray irradiation directly influences the central nervous system to reduce food intake.

Since Pavlov! first demonstrated that the central nervous system (CNS) was involved in the regulation of gastric function, and Selye2 established the concept of the stress theory which demonstrated that physicopsychiatric stress altered physiological function? the use of electrical stimulation or lesion of specific brain sites has made it possible to identify specific areas in the hypothalamus, limbic system, and medulla that influence gastrointestinal function, A plethora of peptides have been characterized in the brain using chemical, immunohistochemical, or molecular biological techniques,4 The development of retrograde tracing techniques combined with immunohistochemistry showed these peptides in nerve terminals or cell bodies of hypothalamic and medullary nuclei, which are important sites for autonomic nervous outflow to the gastrointestinal tract,5,6 From these anatomical and electrophysiological studies, Tache et aU,8 first reported the effect of central neuropeptides in regulating gastric function. Since then, about 50 peptides have been tested, and it is well established that many neuropeptides, such as thyrotropinreleasing hormone (TRH) , corticotropin-releasing factor (CRF), neuropeptide Y (NPY), bombesin, and somatostatin, mediate a CNS-induced stimulation or inhibition of gastrointestinal function.9,10 On the other hand, the liver is also densely innervated,1l,12 and retrograde tracing has revealed that the liver is innervated via a vagal pathway originating in the medulla,13 where abundant neuropeptides exist. A role of central neuropeptides in the regulation of hepatic

Interleukin-1beta (IL-1beta) is an important mediator of fever and illness. Recent studies have demonstrated that IL-1beta (2 microg kg(-1)) increases gastric vagal afferent activity. The peripheral mechanisms of the action of lower doses were studied by recording the mass efferent and afferent activity of the gastric branch of the ventral vagal nerve in anesthetized rats. Twenty min after i.v. administration of IL-1beta (1 microg kg(-1)) the efferent activity of the vagal nerve was decreased to 62+/-6% in totally but not in partly vagotomized rats. Preadministration of indomethacin (5 mg kg(-1)) 30 min before IL-1beta blocked this reduction. Administration of 1 microg kg(-1) of IL-1beta had no effect on the afferent activity of the gastric branch of the vagal nerve. The present results suggest that the subdiaphragmatic vagal afferents modulate the parasympathetic efferent outflow in response to IL-1beta partly through prostaglandin dependent mechanisms and that supradiaphragmatic afferents or central sites are more sensitive to the low doses of IL-1beta which becomes evident after elimination of the subdiaphragmatic vagal input.

We have shown that systemic administration of interleukin-1beta (IL-1beta) excites gastric vagal afferent activity in part via stimulation of type A cholecystokinin (CCK-A) receptors in rats. The present study was undertaken to determine whether the response of the gastric vagal afferent nerve to systemic IL-1beta is altered in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, which lack CCK-A receptors. The response was compared with that of the control strain, Long-Evans Tokushima Otsuka (LETO) rats. All animals were anesthetized with pentobarbital and artificially ventilated. Intravenous administration of 4 microg/kg of IL-1beta increased gastric vagal afferent activity in both LETO and OLETF rats, whereas a smaller dose of 2 microg/kg of IL-1beta increased activity only in the OLETF rats. The present results demonstrate that the response of the gastric vagal afferent activity in CCK-A receptor deficient OLETF rats was more sensitive to intravenous administration of IL-1beta than was in control LETO rats.

It has been proposed that the vagus nerve plays a role in mediating cholecystokinin-8 (CCK-8) effect on such gastric functions as motility, emptying and gastric acid secretion. To examine the contribution of the efferent pathways in realizing these effects, efferent mass activity in the ventral gastric vagal nerve in Sprague-Dawley rats was recorded. Intravenous infusion of CCK-8 (0.1-1 nmol) suppressed the efferent activity. The effect of CCK-8 was significantly reduced in animals with total subdiaphragmatic vagotomy in comparison to those with partial vagotomy. Intravenous infusion of CCK(A) receptor antagonist L-364,718 (1-100x10(-6) g) blocked the response of vagal efferent activity to 0.1 nmol CCK-8, but the CCK(B) receptor antagonist L-365,260 (1-100x10(-6) g) did not in the conditions of either partial or total vagotomy. Intracisternal infusion of L-364,718 (1x10(-6) g) blocked the response of vagal efferent activity to 0.1 nmol CCK-8 i.v. Infusion of exogenous CCK-8 did not affect the activity of supradiaphragmatic vagal afferents. The results suggest that the effect of systemically administered CCK-8 on vagal efferent activity is mediated by both peripherally (subdiaphragmatically) and centrally localized CCK(A) receptors.

痛みは組織を損傷するような侵害性の刺激によって起こり，身体を脅かす危険な信号を知らせるという重要な役割を果たしている。侵害性の刺激によって興奮する侵害受容器は特殊な受容器構造を有しておらず，AδやC線維の一次求心性神経自由終末であると考えられている。一次求心性線維は，脊髄後角でグルタミン酸やサブスタンスPなどの伝達物質を分泌して侵害受容二次ニューロンに興奮を伝える。侵害性情報はさらに脊髄内を上行し，視床の特殊核或いは非特殊核に投射した後，大脳皮質感覚野，大脳辺縁系に投射して，痛みの感覚や情動反応，自律反応，防御反応を引き起こす。生体内にはまた，痛みに対する抑制機構(鎮痛機構)も存在する。

A systemic administration of cholecystokinin (CCK) increases gastric vagal afferent activity via type A CCK receptors (CCKAR). In the present study, the response of gastric vagal afferent activity to an intravenous administration of CCK was investigated in Otsuka Long–Evans Tokushima Fatty (OLETF) rats, which lack CCKAR, and compared with its control strain, Long–Evans Tokushima Otsuka (LETO) rats. The intravenous administration of 300 pmol kg −1 and 3 nmol kg −1 of CCK elicited dose-dependent increases in the gastric vagal afferent activity in LETO rats. The responses were not influenced by the pretreatment with L-365,260, a type B CCK receptor (CCKBR) antagonist, while they were significantly diminished by pretreatment with MK-329, a CCKAR antagonist. After pretreatment with MK-329, 3 nmol kg −1 (but not 300 pmol kg −1 ) of CCK still elicited a small but significant increase in the activity. In the OLETF rats, both 300 pmol kg −1 and 3 nmol kg −1 of CCK produced small increases in the vagal afferent activity, and the responses were not influenced by pretreatment with either L-365,260 or MK-329. In addition, the systemic administration of CCK did not change gastric motility in the OLETF rats, indicating that the response of the vagal afferent activity in OLETF rats was independent of the gastric motility change. These results demonstrate that neither CCKAR nor CCKBR contributes to the response of the afferent activity of the gastric vagal nerve to a systemic administration of CCK in OLETF rats, suggesting an involvement of novel (non-A, non-B) CCK receptors.

Intravenous administration of interleukin-1 (IL-1) activates central autonomic neuronal circuitries originating in the nucleus of the solitary tract (NTS). The mechanism(s) by which blood-borne IL-1 regulates brain functions, whether by operating across the blood–brain barrier and/or by activating peripheral sensory afferents, remains to be characterized. It has been proposed that vagal afferents originating in the periphery may monitor circulating IL-1 levels, because neurons within the NTS are primary recipients of sensory information from the vagus nerve and also exhibit exquisite sensitivity to blood-borne IL-1. In this study, we present evidence that viscerosensory afferents of the vagus nerve respond to intravenously administered IL-1β. Specific labeling for mRNAs encoding the type 1 IL-1 receptor and the EP3 subtype of the prostaglandin E2 receptor was detectedin situover neuronal cell bodies in the rat nodose ganglion. Moreover, intravenously applied IL-1 increased the number of sensory neurons in the nodose ganglion that express the cellular activation markerc-Fos, which was matched by an increase in discharge activity of vagal afferents arising from gastric compartments. This response to IL-1 administration was attenuated in animals pretreated with the cyclooxygenase inhibitor indomethacin, suggesting partial mediation by prostaglandins. In conclusion, these results demonstrate that somata and/or fibers of sensory neurons of the vagus nerve express receptors to IL-1 and prostaglandin E2 and that circulating IL-1 stimulates vagal sensory activity via both prostaglandin-dependent and -independent mechanisms.

The aim of this study was to elucidate whether an intracerebroventricular (icv) administration of oxytocin would affect the somatosensory system in anesthetized rats or not. The effect was evaluated by recording cortical somatosensory evoked potentials (SEPs) in pentobarbital-anesthetized rats. The effect was also compared with that of morphine. The SEPs were recorded from the primary sensory cortex with skull screw electrodes. The electrical stimulation of the forelimb elicited four components, a primary positive wave (P1), a primary negative wave (N1), a secondary positive wave (P2) and a secondary negative wave (N2) in the contralateral sensory cortex. The icv administration of oxytocin (0.05-5 μg) had no effect on the peak latency of the P1, N1, P2 or N2 wave, or on the peak-to-peak amplitudes of P1N1 and P2N2. In contrast, the icv administration of morphine (5 μg) prolonged the peak latencies of all four components and reduced the amplitudes of both P1N1 and P2N2. These actions of morphine were antagonized by a subsequent icv administration of naloxone (5 μg). The present results suggest that oxytocin does not influence the somatosensory system in anesthetized rats, while morphine inhibits the system via opioid receptors.

Interleukin-1beta (IL-1beta) and cholecystokinin (CCK) are important mediators in the development of anorexic response during disease. The role of IL-1beta and CCK in the peripheral mechanisms of anorexia was studied by recording the mass afferent activity of the gastric vagal nerve in anesthetized rats. The i.v. administration of CCK (1 nmol) increased the activity of the vagal nerve, and this response was raised by 55-72% 2 h after i.v. injection of IL-1beta. It is proposed that IL-1beta-induced anorexia is mediated via the sensitization of type A CCK receptors in the periphery.

インスリン作用不足に基づく多様な代謝異常症候群をまとめて糖尿病と呼ぶ。本稿では，インスリンの生理作用を中心に血糖調節について述べ，糖尿病の分類とその成因について解説した。そして，糖尿病の診断で用いられる臨床検査法を紹介すると共に，糖尿病に伴う主な合併症や，その臨床検査法についても触れた。

The response of mass activity of the gastric vagal afferent nerve to intravenous administration of interleukin-1 beta (IL-1 beta) and the involvement of cholecystokinin (CCK) in the response were investigated in pentobarbital-anesthetized rats. Intravenous administration of 2 micrograms.kg-1 of IL-1 beta caused an increase in the afferent activity, which reached 150% of control activity by 30 min after administration and persisted for more than 80 min. The increase in the nerve activity was significantly reduced in animals pretreated with a type A CCK receptor antagonist. IL-1 beta also significantly increased the CCK concentration in systemic blood. Furthermore, it was confirmed that intravenous administration of CCK produced an increase in the nerve activity via the type A CCK receptor. These findings suggest that systemically applied IL-1 beta increases CCK concentration in systemic blood secreted from mucosal endocrine cells of the small intestine, and that in turn CCK in the gastric blood flow augments or partly participates in the IL-1 beta-induced excitation of the gastric vagal afferent nerve via stimulation of the type A CCK receptor in the stomach. A possible involvement of IL-1-related excitation of the gastric vagal afferent nerve in IL-1-induced anorexia is discussed.

種々の原因により神経系に障害がおこると，各種運動障害，感覚障害，自律機能障害がおこる。本稿では中枢神経系並びに末梢神経系の機能の評価法一般を紹介すると共に，代表的な中枢神経系疾患として脳卒中とパーキンソン病，末梢神経系疾患としてニューロパチーと重症筋無力症を取り上げ，機能検査に現れる異常について概説した。

血液の液体成分（血漿，血清）中の蛋白（酵素を含む），非蛋白性窒素，脂質について，それらの生化学的検査値とその異常を示す疾患を概説した。血中の蛋白については，9割以上を占めるアルブミンとグロブリンについて説明した。酵素については，内臓疾患の指標になり得る代表的な酵素を4つ挙げ（トランスアミナーゼ，乳酸脱水素酵素，アルカリフォスファターゼ，クレアチンキナーゼ），それらのアイソザイムについても触れながら概説した。非蛋白性窒素については，血中尿素窒素と血中クレアチニンを，脂質については，コレステロールとトリグリセリドを説明した。

臨床検査値とその意味を理解することは，理学療法を実施するにあたり，リスク管理上，重要である。本講座では，数回にわたり，主な臨床検査値について，その生理学的意味，疾病との関係，理学療法との関係などについて概説していく。今回は，血液一般検査，特に各血液成分のうち細胞成分に関する臨床検査一般（赤血球数，ヘモグロビン濃度，ヘマトクリット値，白血球数，血沈，血小板数）とそれらの異常を示す疾患について概説する。

心筋を栄養する冠状動脈に著しい狭窄や閉塞が起こると，心筋が壊死を起こし，いわゆる心筋梗塞と呼ばれる状態になる。そして心筋の壊死に伴い，心電図，心エコー図，心筋シンチグラフィ，血液生化学検査などにおいて独特の変化が現れてくる。本稿では，循環器系に対する臨床検査法として心筋梗塞を例にとりあげ，その診断上重要な臨床検査法について概説した。

Systemic administration of nicotine suppresses food intake. Since gastric vagal afferents convey satiation signals to the hypothalamus in response to cholecystokinin, we investigated the possibility that nicotine increases afferent activity of the gastric vagal nerves by stimulating release of cholecystokinin. Furthermore, involvement of prostaglandins in the responses of gastric vagal afferents to nicotine was also investigated because prostaglandins stimulate gastric vagal afferent activity. Experiments were performed in urethane-anesthetized rats. Intravenous administration of 300 μg/kg but not 3 or 30 μg/kg nicotine produced biphasic increases in afferent activity. The maximum of the first increase was reached within 1 min, while that of the second increase was reached 10–15 min after nicotine injection. Pretreatment with MK-329, a type A cholecystokinin receptor antagonist, significantly reduced the first increase, without influencing the second increase. Pretreatment with indomethacin, a cyclooxygenase inhibitor, further reduced the first increase and abolished the second increase. These results suggest that nicotine can exert its anorexic effect via an increase in gastric vagal afferent activity which is caused by enhanced release of both cholecystokinin and prostaglandins.

Adolescent rats emit 50 kHz ultrasonic vocalizations, a marker of positive emotion, during rough-and-tumble play or on tickling stimulation. The emission of 50 kHz ultrasonic vocalizations in response to tickling is suggested to be mediated by dopamine release in the nucleus accumbens; however, there is no direct evidence supporting this hypothesis. The present study aimed to elucidate whether play behavior (tickling) in adolescent rats can trigger dopamine release in the nucleus accumbens with hedonic 50 kHz ultrasonic vocalizations. The effect of tickling stimulation was compared with light-touch stimulation, as a discernible stimulus. We examined 35-40-day-old rats, which corresponds to the period of midadolescence. Tickling stimulation for 5 min significantly increased dopamine release in the nucleus accumbens (118±7% of the prestimulus control value). Conversely, light-touch stimulation for 5 min did not significantly change dopamine release. In addition, 50 kHz ultrasonic vocalizations were emitted during tickling stimulation but not during light-touch stimulation. Further, tickling-induced 50 kHz ultrasonic vocalizations were significantly blocked by the direct application of SCH23390 (D1 receptor antagonist) and raclopride (D2/D3 receptor antagonist) into the nucleus accumbens. Our study demonstrates that tickling stimulation in adolescent rats increases dopamine release in the nucleus accumbens, leading to the generation of 50 kHz ultrasonic vocalizations.

The aim of this study was to determine how massage-like stroking of the abdomen in rats influences arterial blood pressure. The participation of oxytocinergic mechanisms in this effect was also investigated. The ventral and/or lateral sides of the abdomen were stroked at a speed of 20 cm/s with a frequency of 0.017-0.67 Hz in pentobarbital anesthetized, artificially ventilated rats. Arterial blood pressure was recorded with a pressure transducer via a catheter in the carotid artery. Stroking of the ventral, or both ventral and lateral sides of the abdomen for 1 min with a frequency of 0.67 Hz caused a marked decrease in arterial blood pressure (approx. 50 mmHg). After cessation of the stimulation blood pressure returned to the control level within 1 min. The maximum decrease in blood pressure was achieved at frequencies of 0.083 Hz or more. Stroking only the lateral sides of the abdomen elicited a significantly smaller decrease in blood pressure (approx. 30 mmHg decrease) than stroking the ventral side. The decrease in blood pressure caused by stroking was not altered by s.c. administration of an oxytocin antagonist (1-deamino-2-D-Tyr-(Oet)-4-Thr-8-Orn-oxytocin, 1 mg/kg) directed against the uterine receptor. In contrast, the administration of 0.1 mg/kg of oxytocin diminished the effect, which was antagonized by a simultaneous injection of the oxytocin antagonist. These results indicate that the massage-like stroking of the abdomen decreases blood pressure in anesthetized rats. This effect does not involve intrinsic oxytocinergic transmission. However, since exogenously applied oxytocin was found to diminish the effect of stroking, oxytocin may exert an inhibitory modulatory effect on this reflex arc.

The parietal dura mater encephali of the rat was shown by immunohistochemistry to be densely innervated by calcitonin gene related peptide (CGRP) immunoreactive nerve fibers spreading around the medial meningeal artery and its branches. Electrical stimulation of the dural surface (10–20 V, 5–10 Hz, 10–30 min) caused a depletion of CGRP-immunopositive fibers, suggesting a release of CGRP. The dural blood flow around branches of the medial meningeal artery was also monitored with a laser Doppler flowmeter. Short periods (30 s) of electrical stimulation with parameters that presumably released CGRP from nerve fibers caused a repeatable and constant increase of the blood flow for 1–2 min. This evoked increase could dose dependently be inhibited by topical application of the CGRP antagonist hCGRP8–37. Accordingly, administration of hCGRP increased the basal blood flow. We conclude that stimulation of trigeminal afferents innervating the dura mater releases CGRP from peptidergic afferent terminals, thereby causing vasodilatation and increasing the meningeal blood flow, an important element of neurogenic inflammation.Key words: dura mater encephali, afferent nerve fibers, calcitonin gene related peptide, immunohistochemistry, laser Doppler flowmetry.

1. The dura mater encephali of the rat was exposed and the blood flow around branches of the medial meningeal artery was monitored with a laser Doppler flowmeter. Changes in the meningeal blood flow (MBF) following electrical stimulation of the dura mater at a parasagittal site were registered. The effects of human calcitonin gene-related peptide (h-alpha CGRP) and the CGRP antagonist (h-alpha CGRP8-37) on the MBF were tested. 2. Electrical stimulation with rectangular pulses of 0.5 ms, 10-20 V, 5-10 Hz and a duration of 30 s caused an increase of the MBF in 14 out of 16 rats tested. The increases were dependent on stimulus strength and frequency. 3. The increase in MBF was inhibited in a dose-dependent manner by topical application of 0.1 ml of h-alpha CGRP8-37 at concentrations of 10(-7) - 10(-5) M. The highest dose abolished the increase in MBF. 4. Topical administration of 0.1 ml of h-alpha CGRP at a concentration of 10(-4) M increased the basal MBF by 15% on average. 5. It is suggested that the increase in MBF following electrical stimulation of the dura mater is mediated by the release of CGRP. The contribution of the dural afferent and sympathetic and parasympathetic efferent nerve fibres to this response are discussed.

Therapeutic chaperone effect of a valienamine derivative N-octyl 4-epi-β-valienamine (NOEV) was studied in G(M1)-gangliosidosis model mice. Phamacokinetic analysis revealed rapid intestinal absorption and renal excretion after oral administration. Intracellular accumulation was not observed after continuous treatment. NOEV was delivered to the central nervous system through the blood-brain barrier to induce high expression of the apparently deficient β-galactosidase activity. NOEV treatment starting at the early stage of disease resulted in remarkable arrest of neurological progression within a few months. Survival time was significantly prolonged. This result suggests that NOEV chaperone therapy will be clinically effective for prevention of neuronal damage if started early in life hopefully also in human patients with G(M1)-gangliosidosis.

We examined the neural mechanisms of the effect of noxious and innocuous mechanical stimulation of various segmental skin areas on the plasma glucagon concentration. Experiments were performed using chloralose- and urethane-anesthetized rats, ventilated artificially. The cutaneous stimuli of two different modalities, noxious and innocuous mechanical stimuli by pinching and brushing, were delivered to various segmental areas including the face, forelimb for forepaw, abdomen, and hindlimb or hindpaw. Blood samples were collected from the femoral artery, and plasma glucagon was measured by radioimmunoassay. Cutaneous pinching for 3.5 min of the face, forepaw, abdomen, or hindpaw increased the plasma immunoreactive glucagon (IRG), and the increase was larger following pinching of the abdmen or hindpaw than pinching of the face or forepaw. Brushing for 3.5 min of the face, forelimb, abdomen, or hindlimb did not significantly affect the plasma IRG. The increase in plasma IRG following skin pinching was abolished when both parasympathetic vagal and sympathetic nerves to the pancreas were bilaterally severed. The increase in plasma IRG was not abolished after bilateral severance of either the parasympathetic vagal or sympathetic nerves alone. These findings indicate that excitation of cutaneous nociceptive afferent information from the various spinal segments can regulate glucagon secretion from the pancreas as a reflex response, whose efferent limb is dually composed of both sympathetic and parasympathetic nerves.

We investigated the effect of mild (non-noxious) tactile stimulation (stroking) of skin on dopamine (DA) release in the nucleus accumbens (NAc) of rats. A coaxial microdialysis probe was stereotaxically implanted in the NAc and perfused with modified Ringer’s solution. Dialysate output from consecutive 5-min periods was injected into a high-performance liquid chromatograph and DA was measured using an electrochemical detector. Bilateral tactile stimulation of the back for 5 min significantly increased DA release in conscious and anesthetized animals. Increased DA release was observed by stimulation of the contralateral, but not ipsilateral, back. DA secretion was also increased with stimulation of the forelimb, hindlimb, and abdomen. These effects were abolished after lesioning the ventral tegmental area (VTA). In contrast, noxious stimulation (pinching) of these areas had no effect on DA secretion. In conclusion, innocuous mechanical stimulation of the skin increases DA release in the contralateral NAc via the VTA.

喀痰検診要精検例 (D, E判定) に対して, 気管支鏡検査と併せてCT, 口腔耳鼻科診察を行った.その結果, 肺癌30例と口腔-咽喉頭の癌8例を発見した.上気道の診断において, 口腔耳鼻科的診察を行うことは有効であった.発見肺癌30例のうち23例が胸部X線無所見であったが, うち12例がCTで所見を有していた.喀痰検診要精検症例に対する単純写真の意義は粗大病変のスクリーニング程度と認識しておくべきであり, CTの併用が必要と思われた.特に, CTは気管支鏡観察範囲より末梢の病変の診断に効果があった.以上のような一連の精検で局在不明であった中から経過観察中に3例の癌を発見した.初回検査で癌が証明されない場合は厳重な経過観察が必要と思われた

Effects of pinching and brushing of the various segmental skin areas (face, ear, neck, forelimb, chest, abdomen, hindlimb) on the activities of the sympathetic efferent nerve innervating the interscapular brown adipose tissue (IBAT) and contributing to its thermogenesis were examined in anesthetized rats. Pinching the face, ear, neck, or forelimb produced significant reflex increases in the efferent nerve activities, whereas pinching the chest, abdomen, or hindlimb did not produce any significant responses. In the case of brushing stimulation, only the stimulation of the ear produced significant increases. These results demonstrated that cutaneous mechanical stimulations at cranial, cervical, and upper thoracic segments were effective in producing reflex increases in the activities of the IBAT sympathetic nerve and that noxious stimulation was more dominant for eliciting the reflex responses.

Certain low-molecular-weight substrate analogs act both as in vitro competitive inhibitors of lysosomal hydrolases and as intracellular enhancers (chemical chaperones) by stabilization of mutant proteins. In this study, we performed oral administration of a chaperone compound N-octyl-4-epi-beta-valienamine to G(M1)-gangliosidosis model mice expressing R201C mutant human beta-galactosidase. A newly developed neurological scoring system was used for clinical assessment. N-Octyl-4-epi-beta-valienamine was delivered rapidly to the brain, increased beta-galactosidase activity, decreased ganglioside G(M1), and prevented neurological deterioration within a few months. No adverse effect was observed during this experiment. N-Octyl-4-epi-beta-valienamine will be useful for chemical chaperone therapy of human G(M1)-gangliosidosis.

Responses of dorsal spinal cord blood flow (SCBF) to innocuous mechanical cutaneous stimulation were investigated in anesthetized central nervous system intact (CNS-intact) and C2 spinalized rats. SCBF was recorded at the L4-L6 level with a laser Doppler flowmeter. SCBF increased with brushing of the ipsilateral proximal hindlimb and hindpaw, and there were no significant differences in the magnitudes of the responses in CNS-intact and spinalized animals. Brushing of the lower back had no effect on SCBF at the L4-L6 level in either cohort. Brushing stimulation produced no significant changes in systemic arterial blood pressure. The responses of SCBF to brushing in CNS-intact animals were diminished by pretreatment with phenoxybenzamine, an alpha-adrenoceptor blocking agent, but no such effects were seen in spinalized animals. These results indicate that innocuous mechanical cutaneous input can produce a segmentally-organized increase in regional SCBF, and that the responses are modulated, in part at least, by alpha-adrenergic receptors via supraspinal structures.

A large number of genetic disease model mice have been produced by genetic engineering. However, phenotypic analysis is not sufficient, particularly for brain dysfunction in neurogenetic diseases. We tried to develop a new assessment system mainly for motor and reflex functions in G M1 -gangliosidosis model mice. Two genetically engineered model mouse strains were used for this study: the β-galactosidase-deficient knockout mouse representing infantile G M1 -gangliosidosis (severe form), and transgenic mouse representing juvenile G M1 -gangliosidosis (mild form). We modified human child neurology techniques, and selected eleven tests for motor assessment and reflex testing. The test results were scored in four grades: 0 (normal), 1 (slightly abnormal), 2 (moderately abnormal), and 3 (severely abnormal). Both disease model mouse strains showed high scores even at the apparently pre-symptomatic stage of the disease, particularly with abnormal tail and hind limb postures. Individual and total test scores were well correlated with the progression of the disease. This method is simple, quick, and reproducible. The testing is sensitive enough to detect early neurological abnormalities, and will be useful for monitoring the natural clinical course and effect of therapeutic experiments in various neurogenetic disease model mice, such as chemical chaperone therapy for G M1 -gangliosidosis model mice.

Ghrelin, a novel growth-hormone releasing peptide, was originally isolated from rat and human stomach. Immunohistochemical analyses revealed that ghrelin-immunoreactive neurons were localized in the hypothalamic arcuate nucleus. The function of the digestive organs is controlled from the central nervous system, and the vagus nerve plays an important role. Intracerebroventricular and intravenous administration of ghrelin significantly increased gastric acid secretion, and its effect was abolished by vagotomy. In the present study, the effect of centrally injected ghrelin on pancreatic exocrine secretion was examined in conscious rats. Moreover, an electrophysiologic study was conducted in anesthetized rats to examine whether the excitation of vagal efferent nerve could be induced by ghrelin. To determine the pancreatic exocrine secretion, rats were prepared with cannulae draining bile and pancreatic juice separately. The experiments were conducted in conscious rats on day 4 or 5 after the operation. To exclude the involvement of gastric acid, a proton pump inhibitor omeprazole (5 micromol/kg) was administered into the duodenum 1 h before ghrelin injection. An intracerebroventricular administration of ghrelin (12, 60, and 300 pmol/10 microl) significantly increased pancreatic fluid and protein output in a dose-dependent manner. Pretreatment with the ganglion blocker hexamethonium and with atropine completely abolished the stimulatory effect of central ghrelin. In contrast, an intravenous injection of ghrelin (300 pmol/10 microl) had no effect. Centrally administered ghrelin stimulated the vagal efferent nerve in anesthetized rats. In conclusion, centrally administered ghrelin stimulates pancreatic exocrine secretion through the vagal efferent nerve, and the stimulatory action is independent of gastric acid secretion.

Responses of hepatic glucose output (HGO) to electro-acupuncture (EA) stimulation of the hindlimb were investigated in anaesthetized rats, focusing on involvement of the somatic afferent and autonomic efferent nerves. HGO was measured with a microdialysis probe implanted into the left lateral lobe of the liver. Stainless steel needles with a diameter of 0.25 mm were inserted into the right tibialis anterior muscle and connected to an electrical stimulator. The EA stimulation was delivered for 10 min at 10 mA, 20 Hz. Atropine was injected in order to block the action of the parasympathetic nerves, whereas phentolamine and propranolol were injected in order to block the action of the sympathetic nerves. Furthermore, adrenal sympathetic nerves were crushed bilaterally to block the reflex secretion of adrenal medullary hormones. The EA stimulation significantly increased HGO for 20 min after the onset of stimulation. The increases of HGO were abolished by severing the femoral and sciatic nerves, demonstrating that the responses are elicited via activation of somatic afferent nerves. Furthermore, the increases were diminished after severance of the adrenal sympathetic nerves, which regulate catecholamine secretion from the adrenal medulla. The increases were totally abolished after pretreatment with phentolamine, an alpha-adrenergic blocker, and propranolol, a beta-adrenergic blocker. On the other hand, the increases of HGO in response to the EA stimulation were augmented after pretreatment with atropine, a muscarinic cholinergic blocker. The present results demonstrate that EA stimulation to a hindlimb can reflexly increase HGO via activation of somatic afferents and, thereby, sympathetic efferents, including sympathetic efferents to the adrenal medulla. The present results further show that the increases of HGO in responses to EA stimulation are simultaneously reflexly inhibited via the parasympathetic nerves.

Smoking has been demonstrated to aggravate liver injury. Nicotine, a major pharmacological component of tobacco smoke, affects a multitude of functions. Smoking and nicotine induce synthesis of endothelin (ET)-1. The effect of intraportal infusion of nicotine on hepatic circulation and an involvement of ET-1 and ET receptor in the action of nicotine were investigated in rats. Nicotine (0-100 microg/kg/h) was infused into the portal vein of urethane-anesthetized rats, and changes of hepatic blood flow were evaluated. Intraportal infusion of nicotine dose-dependently decreased hepatic blood flow and increased portal pressure without any alteration of heart rate or arterial blood pressure. This action of intraportal nicotine was completely abolished by pretreatment of ET-1 antibody. Either BQ485 (ET(A) receptor antagonist) or BQ788 (ET(B) receptor antagonist) partially reversed the effect of nicotine, and combination of BQ788 and BQ485 completely abolished it. These findings suggest that nicotine inhibits hepatic circulation through ET-1, and ET(A) and ET(B) receptor.

Responses of hepatic glucose output (HGO) to noxious mechanical stimulation of different skin areas were investigated in anaesthetised rats with central nervous system intact or acutely spinalized at the thoracic 1-2 (T1-T2) level by focusing on the involvement of the sympathetic and parasympathetic nerves in the responses of HGO. We measured HGO with a microdialysis probe implanted into the left lateral lobe of the liver. Pinching was applied to bilateral skin areas of the abdomen and hindlimb for 10 min. Atropine was injected in order to block the action of the parasympathetic nerves, whereas phentolamine and propranolol were injected in order to block the action of the sympathetic nerves. The HGO started to increase immediately after the cessation of pinching of the abdomen and the hindlimb, and lasted for 30 min. The increase of HGO was observed during stimulus period in animals pretreated with atropine, and totally abolished in animals pretreated with phentolamine and propranolol. The responses of HGO to abdominal pinching, but not to hindlimb pinching, remained after spinal cord transection at the T1-T2 level. The present results suggest that HGO is regulated as a reflex response via both sympathetic and parasympathetic nerves by noxious mechanical stimulation of the skin. Furthermore, it was shown that relative contribution of the spinal and supraspinal organization to the somato-HGO responses was dependent on the skin areas stimulated.