Tsukasa Nozu

Brainstem control of locomotion and muscle tone with special reference to the role of the mesopontine tegmentum and medullary reticulospinal systems

The lateral part of the mesopontine tegmentum contains functionally important structures involved in the control of posture and gait. Specifically, the mesencephalic locomotor region, which may consist of the cuneiform nucleus and pedunculopontine tegmental nucleus (PPN), occupies the interest with respect to the pathophysiology of posture-gait disorders. The purpose of this article is to review the mechanisms involved in the control of postural muscle tone and locomotion by the mesopontine tegmentum and the pontomedullary reticulospinal system. To make interpretation and discussion more robust, the above issue is considered largely based on our findings in the experiments using decerebrate cat preparations in addition to the results in animal experimentations and clinical investigations in other laboratories. Our investigations revealed the presence of functional topographical organizations with respect to the regulation of postural muscle tone and locomotion in both the mesopontine tegmentum and the pontomedullary reticulospinal system. These organizations were modified by neurotransmitter systems, particularly the cholinergic PPN projection to the pontine reticular formation. Because efferents from the forebrain structures as well as the cerebellum converge to the mesencephalic and pontomedullary reticular formation, changes in these organizations may be involved in the appropriate regulation of posture-gait synergy depending on the behavioral context. On the other hand, abnormal signals from the higher motor centers may produce dysfunction of the mesencephalic-reticulospinal system. Here we highlight the significance of elucidating the mechanisms of the mesencephalic-reticulospinal control of posture and locomotion so that thorough understanding of the pathophysiological mechanisms of posture-gait disorders can be made.

Clinical characteristics of asymptomatic esophagitis

Background. Asymptomatic esophagitis is not rare in gastroesophageal reflux disease. However, little attention has been given to this disease so far. We evaluated the clinical characteristics of patients with asymptomatic esophagitis and determined the factors associated with this disease. Methods. A cross-sectional survey was performed of 87 patients with esophagitis, aged 23 to 90 years, diagnosed by endoscopy. We assessed 12 clinical variables at the time of the endoscopy: symptoms, age, sex, severity of esophagitis (Los Angeles classification), grade of gastric mucosal atrophy, presence or absence of Barrett’s epithelium and sliding hernia, alcohol, smoking, body-mass index (BMI), comorbid diseases such as hypertension, diabetes and asthma, and medications such as calcium blocker and theophylline. Results. Most patients had grade A or B esophagitis; 64 patients were symptomatic, and the remaining 23 were asymptomatic. In a univariate analysis, the assessed variables sex, BMI, drinking, and smoking (habit and amount of consumption) were associated with asymptomatic esophagitis (P < 0.05). Then, multivariate logistic analysis performed using these four variables demonstrated that sex, BMI, and smoking (habit and number of cigarettes smoked daily) were significantly and in dependently associated with this disease (P < 0.05). Conclusions. Smoking, male sex, and lower BMI are independent factors associated with asymptomatic esophagitis. Since no information is available on the natural history of this disease, we should pay attention to patients with these characteristics.

Role of brain orexin in the pathophysiology of functional gastrointestinal disorders

Background and Aim:  Orexins are neuropeptides that are localized in neurons within the lateral hypothalamic area and regulate feeding behavior. The lateral hypothalamic area plays an important role in not only feeding but the central regulation of other functions including gut physiology. Accumulating evidence have shown that orexins acts in the brain to regulate a wide variety of body functions including gastrointestinal functions.

Modulatory effects of the GABAergic basal ganglia neurons on the PPN and the muscle tone inhibitory system in cats.

Pedunculopontine tegmental nucleus (PPN) contributes to the control muscle tone by modulating the activities of pontomedullary reticulospinal systems during wakefulness and rapid eye movement (REM) sleep. The PPN receives GABAergic projection from the substantia nigra pars reticulata (SNr), an output nucleus of the basal ganglia. Here we examined how GABAergic SNr-PPN projection controls the activity of the pontomedullary reticulospinal tract that constitutes muscle tone inhibitory system. Intracellular recording was made from 121 motoneurons in the lumbosacral segments in decerebrate cats (n=14). Short train pulses of stimuli (3 pulses with 5 ms intervals, 10-40 mA) applied to the PPN, where cholinergic neurons were densely distributed, evoked eye movements toward to the contralateral direction and bilaterally suppressed extensor muscle activities. The identical PPN stimulation induced IPSPs, which had a peak latency of 40-50 ms with a duration of 40-50 ms, in extensor and flexor motoneurons. The late-latency IPSPs were mediated by chloride ions. Microinjection of atropine sulfate (20 mM, 0.25 ml) into the pontine reticular formation (PRF) reduced the amplitude of the IPSPs. Although conditioning stimuli applied to the SNr (40-60 mA and 100 Hz) alone did not induce any postsynaptic effects on motoneurons, it reduced the amplitude of the PPN-induced IPSPs. Subsequent injection of bicuculline (5 mM, 0.25 ml) into the PPN blocked the SNr effects. Microinjections of NMDA (5 mM, 0.25 ml) and muscimol (5 mM, 0.25 ml) into the SNr reduced and increased the amplitude of the PPN-induced IPSPs, respectively. These results suggest that GABAergic basal ganglia output controls postural muscle tone by modulating the activity of cholinergic PPN neurons which activate the muscle tone inhibitory system. The SNr-PPN projection may contribute to not only control of muscle tone during movements in wakefulness but also modulation of muscular atonia of REM sleep. Dysfunction of the SNr-PPN projection may therefore be involved in sleep disturbances in basal ganglia disorders.

Central orexin-A increases colonic motility in conscious rats

Increasing evidence has indicated that brain orexin plays a vital role in the regulation of gastrointestinal physiology such as gastric secretion, gastric motility and pancreatic secretion. However, little is known whether orexin in the brain is involved in the physiology of the lower gastrointestinal tract. The aim of this study was therefore to elucidate whether orexin-A in the brain is involved in the regulation of colonic motility. In this study, we measured fecal pellet output and recorded intraluminal colonic pressure waves in freely moving conscious rats to evaluate the effects of central orexin-A on colonic motor functions. Intracisternal but not intraperitoneal injection of orexin-A dose-dependently (1-10 μg) increased fecal pellet output. Findings obtained from manometric recordings revealed that intracisternal administration of orexin-A at a dose of 10 μg significantly enhanced colonic motor contractions. These results suggest for the first time that orexin-A acts centrally in the brain to enhance fecal pellet output and stimulate colonic motility in conscious rats. The present study would furthermore support our hypothesis that orexin-A in the brain may be an important candidate as a mediator of the cephalic phase gut stimulation including stimulated colonic motility in addition to well known physiological response such as stimulation of gastric acid and pancreatic acid secretion, and gastric motility.

Corticotropin-releasing factor receptor type 1 and type 2 interaction in irritable bowel syndrome

Irritable bowel syndrome (IBS) displays chronic abdominal pain or discomfort with altered defecation, and stress-induced altered gut motility and visceral sensation play an important role in the pathophysiology. Corticotropin-releasing factor (CRF) is a main mediator of stress responses and mediates these gastrointestinal functional changes. CRF in brain and periphery acts through two subtype receptors such as CRF receptor type 1 (CRF1) and type 2 (CRF2), and activating CRF1 exclusively stimulates colonic motor function and induces visceral hypersensitivity. Meanwhile, several recent studies have demonstrated that CRF2 has a counter regulatory action against CRF1, which may imply that CRF2 inhibits stress response induced by CRF1 in order to prevent it from going into an overdrive state. Colonic contractility and sensation may be explained by the state of the intensity of CRF1 signaling. CRF2 signaling may play a role in CRF1-triggered enhanced colonic functions through modulation of CRF1 activity. Blocking CRF2 further enhances CRF-induced stimulation of colonic contractility and activating CRF2 inhibits stress-induced visceral sensitization. Therefore, we proposed the hypothesis, i.e., balance theory of CRF1 and CRF2 signaling as follows. Both CRF receptors may be activated simultaneously and the signaling balance of CRF1 and CRF2 may determine the functional changes of gastrointestinal tract induced by stress. CRF signaling balance might be abnormally shifted toward CRF1, leading to enhanced colonic motility and visceral sensitization in IBS. This theory may lead to understanding the pathophysiology and provide the novel therapeutic options targeting altered signaling balance of CRF1 and CRF2 in IBS.

Antinociceptive action against colonic distension by brain orexin in conscious rats.

Increasing evidence has suggested that brain orexins are implicated in a wide variety of physiological functions. With regard to gastrointestinal functions, orexin-A acts centrally to regulate gastrointestinal functions such as gastric and pancreatic secretion, and gastrointestinal motility. Visceral sensation is also known as one of key gastrointestinal functions which are controlled by the central nervous system. Little is, however, known about a role of central orexin in visceral sensation. This study was therefore performed to clarify whether brain orexin may be involved in the process of visceral sensation. Visceral sensation was evaluated by colonic distension-induced abdominal withdrawal reflex (AWR) in conscious rats. Intracisternally administered orexin-A dose-dependently increased the threshold volume of colonic distension-induced AWR. In contrast, neither intraperitoneal injection of orexin-A nor intracisternal orexin-B altered the threshold volume. While intracisternal SB334867, an orexin 1 receptor antagonist, by itself failed to change the threshold volume, SB334867 injected centrally completely blocked the morphine-induced antinociceptive action against colonic distension. These results suggest for the first time that orexin-A specifically acts centrally in the brain to enhance antinociceptive response to colonic distension. We would furthermore suggest that endogenous orexin-A indeed mediates the antinociceptive effect of morphine on visceral sensation through the orexin 1 receptors. All these evidence might indicate that brain orexin plays a role in the pathophysiology of functional gastrointestinal disorders such as irritable bowel syndrome because visceral hypersensitivity of the gut is considered to play a vital role in the diseases.

A Balance Theory of Peripheral Corticotropin-Releasing Factor Receptor Type 1 and Type 2 Signaling to Induce Colonic Contractions and Visceral Hyperalgesia in Rats

Several recent studies suggest that peripheral corticotropin-releasing factor (CRF) receptor type 1 (CRF1) and CRF2 have a counter regulatory action on gastrointestinal functions. We hypothesized that the activity balance of each CRF subtype signaling may determine the changes in colonic motility and visceral sensation. Colonic contractions were assessed by the perfused manometry, and contractions of colonic muscle strips were measured in vitro in rats. Visceromotor response was determined by measuring contractions of abdominal muscle in response to colorectal distensions (CRDs) (60 mm Hg for 10 min twice with a 30-min rest). All drugs were administered through ip route in in vivo studies. CRF increased colonic contractions. Pretreatment with astressin, a nonselective CRF antagonist, blocked the CRF-induced response, but astressin2-B, a selective CRF2 antagonist, enhanced the response by CRF. Cortagine, a selective CRF1 agonist, increased colonic contractions. In in vitro study, CRF increased contractions of muscle strips. Urocortin 2, a selective CRF2 agonist, itself did not alter the contractions but blocked this increased response by CRF. Visceromotor response to the second CRD was significantly higher than that of the first. Astressin blocked this CRD-induced sensitization, but astressin2-B or CRF did not affect it. Meanwhile, astressin2-B together with CRF significantly enhanced the sensitization. Urocortin 2 blocked, but cortagine significantly enhanced, the sensitization. These results indicated that peripheral CRF1 signaling enhanced colonic contractility and induced visceral sensitization, and these responses were modulated by peripheral CRF2 signaling. The activity balance of each subtype signaling may determine the colonic functions in response to stress.

Peripheral corticotropin-releasing factor (CRF) induces stimulation of gastric contractions in freely moving conscious rats: role of CRF receptor types 1 and 2

Background  Peripheral corticotrophin‐releasing factor (CRF) plays an important role in stress‐induced alterations of gastrointestinal motility. CRF injected peripherally inhibits gastric emptying, but its effect on gastric contractions has not been clarified in freely moving conscious rats.

Characteristics in patients with headache in an outpatient clinic in Japan

BackgroundLittle is known about the prevalence of primary and secondary headache in clinics in Japan. The aim of this study is to characterize patients with headache in an outpatient unit where primary care physicians are working in Japan.MethodsConsecutive outpatients who newly visited the Department of General Medicine, Asahikawa Medical College Hospital, Asahikawa, Japan between April 2005 and March 2009 were analyzed. Each parameter such as age, sex or diagnosis was investigated.ResultsOut of 4693 patients, 418 patients visited to our department because of headache. Primary headache was found in 167 patients (39.9%). The rate of tension-type headache (TTH) (30.8%) was highest, followed by migraine (9.1%). Approximately 3 times higher rate of migraine was observed in female patients when compared with male patients. In female patients, migraine was observed more frequently in younger patients. On the other hands, TTH was observed in almost all aged patients in males and females, and the rate of TTH peaks between the ages of 40 and 49 years in both sex. The present study also demonstrated that 8.4% of patients who chiefly complained of headache had been diagnosed as depression while 1.7% of remained patients had been diagnosed as depression, indicating 5-times higher rate of depression in patients with headache.ConclusionAll these results suggest that primary headache, especially TTH, is highly observed and depression should be considered in patients with headache in an outpatient clinic where primary care physicians are working in Japan.