Symposium

Symposium 19 New mechanisms of the somatosensory system in host defense and homeostasis シンポジウム19 痛覚伝達システムの新しい生体ディフェンスと恒常性維持機構

SY19-1 Introducing Osteo-nociceptive-immune system as a novel anti-fungal immunity 骨-痛覚-免疫トライアングル恒常性を介した真菌性self defense機構の提唱と応用 Maruyama Kenta（丸山健太） Immunology Frontier Research Center, Osaka University Candida albicans can enter skeletal tissue through a skin wound in an immunocompromised host or by contamination during orthopedic surgery. Such Candida osteomyelitis is accompanied by severe pain and bone destruction. It is established that nociceptor innervation occurs in skin and bone, but the mechanisms of nociceptive modulation in fungal inflammation remain unclear. In this study, we show that C. albicans stimulates Nav1.8-positive nociceptors via the β-glucan receptor Dectin-1 to induce CGRP. This induction of CGRP is independent of Bcl-10 or Malt-1 but dependent on TRPV1/TRPA1 ion channels. Hind paw β-glucan injection after Nav1.8-positive nociceptor ablation or in TRPV1/TRPA1 deficiency showed dramatically increased osteo-inflammation accompanied by impaired CGRP production. Strikingly, CGRP suppressed β-glucan-induced inflammation and osteoclast multinucleation via direct suppression of NF-κB p65 by the transcriptional repressor Jdp2 and inhibition of actin polymerization, respectively. These findings clearly suggest the role of Dectin-1-mediated sensocrine pathways in the resolution of fungal osteo-inflammation.		SY19-2 Regulation of sleep/wakefulness and pain by orexin neurons オレキシン神経による睡眠覚醒調節と痛みの制御 Yamanaka Akihiro（山中章弘）^1,2,3 ¹Dep. Neurosci. II, RIEM, Nagoya Univ. ²Department of Neural regulation, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan ³CREST, JST Orexin is neuropeptide which generated in small number of neurons in the lateral hypothalamus. Sleep disorder "Narcolepsy" is caused by specific degeneration of orexin neurons. From these facts, orexin neurons are implicated in the maintenance of wakefulness. Recently we applied optogenetics or chemicogenetics to orexin neurons and controlled its activity. Activation of orexin neurons increased time in wakefulness. In addition to this, activation of orexin neurons increased pain threshold. To record the activity of orexin neurons, fiber photometory was applied. Orexin-cre mice were injected adeno-assocoated virus (AAV) vector expressing calsium indicator protein in the presence of Cre recombinase. And found that activity of orexin neurons were increased when animals were applied pain. In this symposium, I will discuss the role of orexin neurons in the regulation of sleep/wakefulness and pain perception.

SY19-3 Global understanding of “ Sensory neuron-tumor cell ” interaction and “ Stress/pain-tumor growth ” immune-interaction 「知覚神経-がん細胞」連関及び「ストレス/痛み-腫瘍増殖」免疫連関の統合的理解 Narita Minoru（成田年）^1,2，近藤貴茂¹，濱田祐輔²，葛巻直子^1,2 ¹Department of Pharmacology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Tokyo, Japan ²Life Science Tokyo Advanced Research Center (L-StaR), Hoshi University School of Pharmacy and Pharmaceutical Sciences, Tokyo, Japan The integration of palliative care early in the disease trajectory can lead to significant improvements in quality of life, symptom control and even survival, indicating that bilateral interactions between tumor cells and nerve cells should be at the focus of cancer therapy. The molecular mediators of nerve-tumor cell crosstalk within the tumor microenvironment may be neurotrophic factors released by nerves. Along with severe pain sensation, stress and depression have also been suggested to contribute to the pathogenesis of cancer. Chronic depression has been linked to poor survival and higher mortality in a large variety of tumor types. It is generally accepted that stress affects the functions in several brain areas. Corticotropin-releasing hormone (CRH) neurons are most strongly implicated in the stress response because the hypothalamic pituitary adrenal (HPA) axis is activated by invoking the release of CRH. On the other hand, Β-endorphin, a cleavage product of POMC, is an endogenous Μ-opioid polypeptide that is primarily produced by the hypothalamus. Β-Endorphin released by the activation of hypothalamic POMC neurons and the dopamine-related reward network closely interact to control positive emotion. Positive emotion is believed to change innate immune function. Based on this background, we hypothesize that the control of pain itself by encouraging motivation in patients via central anti-CRH/opioid/dopamine systems could result in significant improvements in quality of life, symptom control and even survival. In this symposium, we will discuss "sensory neuron-tumor cell cross-talk"and "central-peripheral immune-interaction".		SY19-4 PET technology for pathophysiological studies on pain-related psychiatric disorders PETイメージング技術を用いた疼痛ー精神病態機構解明研究 Ouchi Yasuomi（尾内康臣） Department of Biofunctional Imaging, Hamamatsu University School of Medicine Positron emission tomography (PET) is one of the molecular imaging technologies that allow visualization of living biological functions. Depiction of tissue function as a system in the living human brain on a molecular level makes PET valuable. Pain is processed in different brain regions in parallel. Reportedly, the lateral thalamus, primary/secondary sensory cortices and insula subserve pain discrimination, and insula and anterior cingulate cortex are involved in pain-related emotional valence, and anterior cingulate and prefrontal cortices relate to pain recognition. Each of domains is not specific to pain processing, but rather the combination of these regions shows functional linkage peculiar to pain processes. Studies of functional network in pain processes are what not PET but fMRI can contribute to.PET is superior in molecular imaging as mentioned above. An opioid receptor ligand [11C]diprenorphine binding decreases in the brain of patients with psychogenic pain, suggesting low pain control. The findings of low binding of a μ-opioid receptor ligand [11C]carfentanil in the limbic region and its high binding in the thalamus in patients with chronic back pain suggest a heterogeneity of μ-opioid receptor density in the disease. Regarding the monoaminergic system, there is low [18F]FDOPA uptake in the midbrain and limbic region with reduction of pain-induced dopamine release in patients with fibromyalgia. A study with a serotonin transporter ligand [11C]DASB suggested that serotonergic function is altered in people suffering from strong pain. PET also allows to visualize neuroinflammation that may develop easily in the disorganized brain. In this talk, PET technology is introduced as a good tool for elucidation of the pathophyisology of pain disorders.

SY19-5 The role of inflammasome in pain and depression うつ病・疼痛におけるインフラマソーム・ミクログリアを介した病態機構 Iwata Masaaki（岩田正明） Division of Neuropsychiatry, Department of Brain and Neurosciences, Faculty of Medicine, Tottori University Inflammation, which is usually caused by the injury such as tissue damages, is now considered to be involved in the pathology not only of physical illnesses but also of mental disorders. Except for organic, including symptomatic, mental disorders, there is no physical “injury” in psychiatric disorders. But the “stress” is assumed to be the injury. We had previously demonstrated that stress releases ATP in the brain, which in turn causes a series of inflammation. ATP is sensed by microglia and releases pro-inflammatory cytokines such as interleukin 1 β (IL-1β). ATP activates P2X7 receptor, an ATP receptor on microglia, which in turn releases K ions from the cell. This change is captured by the NLRP3, which is a pattern recognition receptor presents in microglia, and releases IL-1β. Our results showed that depression-like behavior caused by the chronic stress to rats were improved by the P2X7 inhibitor, NLRP3 gene knocked-down, and the neutralization of IL-1β by antibody. Therefore, stress is thought to cause a series of inflammation, and eventually causes cell damages. Because NLRP3 can detect not only the release of K ions but also various danger substances, NLRP3 is considered to be involved in the pathology of many chronic inflammatory diseases. Thus, NLRP3 might be a hub of these diseases, and can be a novel therapeutic target of these diseases. Pain is known to be implicated in the P2X7 receptor, and the various P2X7 receptor inhibitors have been developed as a drug. Now we have focused on the downstream of P2X7 receptor, NLRP3, and are developing the strategy of its control. Inhibition of NLRP3 is expected to extend the therapeutic applicability for various physical disorders including pain and also psychiatric disorders.