Yoshihide Nakai

Fyn kinase-mediated phosphorylation of NMDA receptor NR2B subunit at Tyr1472 is essential for maintenance of neuropathic pain

Despite abundant evidence implicating the importance of N‐methyl‐d‐aspartate (NMDA) receptors in the spinal cord for pain transmission, the signal transduction coupled to NMDA receptor activation is largely unknown for the neuropathic pain state that lasts over periods of weeks. To address this, we prepared mice with neuropathic pain by transection of spinal nerve L5. Wild‐type, NR2A‐deficient, and NR2D‐deficient mice developed neuropathic pain; in addition, phosphorylation of NR2B subunits of NMDA receptors at Tyr1472 was observed in the superficial dorsal horn of the spinal cord 1 week after nerve injury. Neuropathic pain and NR2B phosphorylation at Tyr1472 were attenuated by the NR2B‐selective antagonist CP‐101,606 and disappeared in mice lacking Fyn kinase, a Src‐family tyrosine kinase. Concomitant with the NR2B phosphorylation, an increase in neuronal nitric oxide synthase activity was visualized in the superficial dorsal horn of neuropathic pain mice by NADPH diaphorase histochemistry. Electron microscopy showed that the phosphorylated NR2B was localized at the postsynaptic density in the spinal cord of mice with neuropathic pain. Indomethacin, an inhibitor of prostaglandin (PG) synthesis, and PGE receptor subtype EP1‐selective antagonist reduced the NR2B phosphorylation in these mice. Conversely, EP1‐selective agonist stimulated Fyn kinase‐dependent nitric oxide formation in the spinal cord. The present study demonstrates that Tyr1472 phosphorylation of NR2B subunits by Fyn kinase may have dual roles in the retention of NMDA receptors in the postsynaptic density and in activation of nitric oxide synthase, and suggests that PGE2 is involved in the maintenance of neuropathic pain via the EP1 subtype.

Repeated administration of ghrelin to patients with functional dyspepsia: its effects on food intake and appetite.

BACKGROUND Ghrelin plays a major role in the regulation of food intake (FI), which makes it a strong candidate for the treatment of anorexia. OBJECTIVE We attempted to evaluate the clinical response to repeated ghrelin administration in patients with anorexia caused by functional disorders, such as functional dyspepsia (FD). SUBJECTS AND METHODS Subjects included in this study were those who 1) were diagnosed with functional anorexia, including FD and other eating disorders with the exception of anorexia nervosa; 2) were lean (body mass index (BMI)<22 kg/m(2)); and 3) exhibited decreased FI. Subjects received an i.v. infusion of ghrelin (3 microg/kg) for 30 min twice a day (before breakfast and dinner) for 2 weeks. We investigated the effects of ghrelin administration on FI, appetite, hormones, and metabolic parameters. RESULTS Six patients with FD were enrolled in this study. Ghrelin administration tended to increase daily FI in comparison with levels before and after completion of treatment, but this difference that was the primary endpoint of this study did not reach statistical significance (P=0.084). Hunger sensation was significantly elevated at the end of drip infusion (P<0.0001). No severe adverse effects were observed. CONCLUSIONS These results suggest that ghrelin administration is safe and that this treatment has stimulatory effects on appetite in patients with FD. Further studies are necessary to confirm the efficacy of ghrelin treatment for anorexia-related disorders.

Plasma acylated ghrelin levels correlate with subjective symptoms of functional dyspepsia in female patients

Objective Ghrelin is a brain-gut peptide that is mainly secreted from gastric endocrine cells (X/A like cells). In addition to promoting growth-hormone release and appetite, ghrelin also affects gastric motility and secretion. Circulating ghrelin levels are related to appetite and energy balance. Functional dyspepsia (FD) is a disorder characterized by the presence of chronic or recurrent symptoms of upper abdominal pain or discomfort. Although no known specific organic abnormalities are present in FD, abnormalities in gastrointestinal motility and sensitivity are thought to play a role in a substantial subgroup of patients. In addition, some patients also suffer from anorexia and body-weight loss. To investigate the role of ghrelin in the pathophysiology of FD, circulating ghrelin levels in affected patients were measured. Material and methods Eighteen Japanese female patients with functional dyspepsia and 18 healthy volunteers were recruited for the study. Acylated and desacyl forms of ghrelin were measured using commercially available enzyme-linked immunosorbent assay kits. Results Although plasma levels of acylated or desacyl ghrelin were not significantly different between healthy subjects and FD patients, plasma acylated, but not desacyl ghrelin, levels were correlated with a subjective symptom score in FD patients. In addition, the ratio of acylated to desacyl ghrelin (A/D ratio) was correlated strongly with acylated, but not desacyl, ghrelin levels. Conclusions The correlation of circulating acylated ghrelin levels with the subjective symptom score and the A/D ratio in FD patients suggest that acylated ghrelin may play a role in the pathophysiology of FD.

Depression and Anxiety Correlate Differently with Salivary Free Cortisol in the Morning in Patients with Functional Somatic Syndrome

Patients presenting with functional somatic syndrome (FSS) are common, and the symptoms are persistent and difficult to treat for doctors and costly for society. The aim of this study was to clarify the common pathophysiology of FSS, especially the relationship between hypothalamic-pituitary-adrenal (HPA) axis function and psychological characteristics of patients with FSS. The subjects were 45 patients with FSS and 29 healthy controls. Salivary free cortisol was measured in the morning, and psychological tests examining depression, anxiety and quality of life (QOL) were performed on the same day. In patients with FSS, depressive scores showed a significant negative correlation with salivary free cortisol in the morning, although in healthy controls, cortisol showed a significant positive correlation with depressive scores. In addition, the correlation between other psychological test scores and cortisol secretion in patients with FSS contrasted with that of controls. The relationship between cortisol and depression, anxiety or QOL, suggests that the HPA axis of patients with FSS is dysfunctional and does not function properly when patients with FSS are under stress. This dysfunction may explain the pathology of medically unexplained persistent symptoms of patients with FSS.

Psychological characteristics of Japanese patients with chronic pain assessed by the Rorschach test

BackgroundThe increasing number of patients with chronic pain in Japan has become a major issue in terms of the patients quality of life, medical costs, and related social problems. Pain is a multi-dimensional experience with physiological, affective, cognitive, behavioral and social components, and recommended to be managed via a combination of bio-psycho-social aspects. However, a biomedical approach is still the dominant method of pain treatment in Japan. The current study aimed to evaluate comprehensive psychological functions and processes in Japanese chronic pain patients.MethodsThe Rorschach Comprehensive System was administered to 49 in-patients with non-malignant chronic pain. Major variables and frequencies from the test were then compared to normative data from non-patient Japanese adults by way of the t-test and chi-square test.ResultsPatients exhibited high levels of emotional distress with a sense of helplessness with regard to situational stress, confusion, and ambivalent feelings. These emotions were managed by the patients in an inappropriate manner. Cognitive functions resulted in moderate dysfunction in all stages. Information processing tended to focus upon minute features in an inflexible manner. Mediational dysfunction was likely to occur with unstable affective conditions. Ideation was marked by pessimistic and less effective thinking. Since patients exhibited negative self-perception, their interpersonal relationship skills tended to be ineffective. Originally, our patients displayed average psychological resources for control, stress tolerance, and social skills for interpersonal relationships. However, patient coping styles were either situation- or emotion-dependent, and patients were more likely to exhibit emotional instability influenced by external stimuli, resulting in increased vulnerability to pain.ConclusionsData gathered from the Rorschach test suggested psychological approaches to support chronic pain patients that are likely to be highly beneficial, and we thus recommend their incorporation into the course of current pain treatments.

An exploratory study of subgrouping of patients with functional somatic syndrome based on the psychophysiological stress response: its relationship with moods and subjective variables.

Objective: To study the characteristics and subjective estimations of subgroups of patients with functional somatic syndrome (FSS). A characteristic in patients with FSS was reportedly hyporeactivity in the psychophysiological stress response (PSR). Methods: The PSR was measured in 59 FSS patients and 41 healthy controls. Autonomic lability scores (ALSs) of six psychophysiological measurements on PSR were calculated. Cluster analysis using the ALSs was performed in the FSS group. A discriminant analysis was also performed to identify the criterion of the subgrouping. Factor analysis scores of the six ALSs, and moods and subjective variables were compared between the subgroups. Results: Cluster analysis divided the FSS patients into two clusters. Three groups (low-lability, high-lability, and control groups) were compared. All factor scores of autonomic lability significantly differed between the low- and high-lability groups, and between the low-lability and control groups. The mood scores were higher in the high-lability group than in the low-lability group. The duration of suffering was significantly longer in the high-lability group than in the low-lability group. The distributions of symptoms and diagnosis did not significantly differ between the subgroups. Conclusions: We have tentatively verified that there are two subgroups based on the autonomic lability among FSS patients, which were independent of the type of symptoms and diagnostic category. Autonomic lability is an important axis in the multiaxial diagnosis of FSS. FSS = functional somatic syndrome; IBS = irritable bowel syndrome; FMS = fibromyalgia syndrome; FGID = functional gastrointestinal disorder; ALS = autonomic lability score; PSR = psychophysiological stress response; ANS = autonomic nervous system; VAS = visual analogue scale; SEMG = surface-electromyography; TEMP = skin temperature; SCL = skin conductance level; NSSCR = nonspecific skin conductance response; BVPAmp = blood volume pulse amplitude; STS = subjective tension score.

Current state and future prospects for psychosomatic medicine in Japan.

In this article, we describe the history and current state of psychosomatic medicine (PSM) in Japan and propose measures that could be considered based on our view of the future prospects of PSM in Japan. The Japanese Society of PSM (JSPM) was established in 1959, and the first Department of Psychosomatic Internal Medicine in Japan was established at Kyushu University In 1963. PSM in Japan has shown a prominent, unique development, with 3,300 members (as of March 2016), comprised of 71.6% of medical doctors including psychosomatic internal medicine (PIM) specialists, general internists, psychiatrists, pediatricians, obstetricians and gynecologists, dentists, dermatologists, and others. Most of the non-physician members include psychology and nursing staff specialists.The Japanese Society of Psychosomatic Internal Medicine (JSPIM), founded in 1996, is another major society with more than 1,200 physicians that is mainly composed of internists. The first joint congress of the five major PSM societies from each field was held in 2009. They included the Japanese Society of Psychosomatic Medicine, Psychosomatic Obstetrics and Gynecology, Psychosomatic Pediatric Medicine, Psychosomatic Dental Medicine, and Psychosomatic Internal Medicine. Several subdivided societies in related medical fields have also been established for cardiovascular, digestive, dermatological, and oriental medicine and for eating disorders, pain, fibromyalgia, stress science, behavioral medicine, and psycho-oncology. JSPM and JSPIM participate in international activities including publishing BioPsychoSocial Medicine (BPSM) and the establishment of a sister society relationship with the Germany College of PSM. PSM in Japan has adopted a variety of professional psychotherapies, including transactional analysis, autogenic therapy, and cognitive behavioral therapy. Mutual interrelationship has been promoted by the Japanese Union of Associations for Psycho-medical Therapy (UPM).Although PSM in Japan is functioning at a high level, there remain areas that could be improved. Among the 81 medical schools in Japan, just eight university hospitals have an independent department of PSM and of 29 dental schools only three dental university hospitals have a department of psychosomatic dentistry.Further accumulation of evidence regarding the mind-body relationship in clinical and basic science that is based on the latest advanced technology is necessary. The psychosomatic medicine community needs to make an even greater contribution to meeting the needs of modern society. The possibilities for the future development of PSM in Japan must be widely discussed.

Body Image Changes in Adolescents II Comparison among Patients with Eating Disorders and Controls with Thin, Normal and Obese Body Shapes

Abstract: The Self‐Rating Body Image (SRBI) test was used to determine whether the patients with eating disorders such as anorexia nervosa or bulimia showed their body image disturbance or not. The SRBI was completed by 120 subjects who consisted of 30 low weight (LW) controls, 30 normal weight (NW) controls, 30 high weight (HW) controls, 18 anorexic patients (AN) and 12 bulimic patients (BN). The AN group had a significantly greater dissatisfaction with the scales of the body shape, visceral organ and face image of the SRBI than the weight‐matched LW group. The BN group had a significantly greater dissatisfaction with the visceral organ image than the weight‐matched NW group. However, no significant difference in the body shape and face images between the BN and NW groups was found. Our results suggest that the anorexic patients may disturb more parts of the body image than the bulimic patients though both the anorexic and bulimic patients showed the disturbance of body image.