Validation of the Modified Fatigue Impact Scale and the relationships among fatigue, pain and serum interleukin-6 levels in patients with neuromyelitis optica spectrum disorder.

Fatigue and pain are disabling symptoms in patients with neuromyelitis optica spectrum disorder (NMOSD). The Modified Fatigue Impact Scale (MFIS) has not yet been validated in patients with NMOSD, and anti-interleukin-6 (IL-6) receptor antibody was reported to decrease pain and fatigue in patients with NMOSD. The aim of this study was to validate MFIS and to investigate the relationships among fatigue, pain and serum IL-6 levels in patients with NMOSD.

Efficacy and safety of the emedastine patch, a novel transdermal drug delivery system for allergic rhinitis: Phase III, multicenter, randomized, double-blinded, placebo-controlled, parallel-group comparative study in patients with seasonal allergic rhinitis.

Background: The emedastine patch was developed in Japan as the first transdermal drug delivery system of emedastine difumarate for allergic rhinitis.

Methods: A multicenter, randomized, double-blind, placebo-controlled, parallel-group comparison was conducted in patients with seasonal allergic rhinitis. Patients were administered Emedastine patches (4 or 8 mg), placebo, or levocetirizine hydrochloride (5 mg tablet) once daily for 2 weeks (double-dummy technique).

Optimum Dose of Once-Daily Oxybutynin Patch in Japanese Patients with Overactive Bladder: A Randomized Double-Blind Trial Versus Placebo.

Objective: To evaluate the efficacy, safety, and optimum dose of once-daily oxybutynin patch for overactive bladder.

Methods: A randomized double-blind trial was conducted in patients with overactive bladder symptoms for ≥24 weeks, who received an oxybutynin patch (73.5 or 105 mg) or placebo once daily for 8 weeks.

Prostaglandin transporter in the rat brain: its localization and induction by lipopolysaccharide.

Prostaglandin E2 (PGE2) is produced in the brain during infectious/inflammatory diseases, and it mediates acute-phase responses including fever. In the recovery phase of such diseases, PGE2 disappears from the brain through yet unidentified mechanisms. Rat prostaglandin transporter (PGT), which facilitates transmembrane transport of PGE2, might be involved in the clearance of PGE2 from the brain.

Temperature receptors in cutaneous nerve endings are thermostat molecules that induce thermoregulatory behaviors against thermal load.

When skin temperature falls below a set-point, mammals experience "cold in the skin" and exhibit heat-seeking behaviors for error correction. Physiological thermostats should perform the behavioral thermoregulation, and it is important to identify the thermostats. A classical model of the sensory system states that thermoreceptors (e.

Efficacy and safety of once-daily oxybutynin patch versus placebo and propiverine in Japanese patients with overactive bladder: A randomized double-blind trial.

Objectives: To evaluate the efficacy and safety of once-daily oxybutynin patch therapy for overactive bladder.

Methods: A randomized double-blind trial was carried out in patients with overactive bladder syndrome, who received an oxybutynin patch, propiverine (20 mg) or placebo once daily for 12 weeks. The primary efficacy end-point was the change of the mean daily number of micturitions in week 12.

Sensory stimuli induce nuclear translocation and phosphorylation of nuclear factor κ B in primary sensory neurons of mice.

Nuclear factor kappa B (NF-κB) is a transcription factor, which is translocated to the nucleus when activated. Herein, we demonstrate immunohistochemically that electrical, chemical, and thermal stimuli, applied to the skin of mice, all induced nuclear translocation and phosphorylation of NF-κB in dorsal root ganglia (DRG) neurons. The latency of this response was short, with effects observable in as little as 3min following stimulation.

Intragastric administration of allyl isothiocyanate increases carbohydrate oxidation via TRPV1 but not TRPA1 in mice.

The transient receptor potential (TRP) channel family is composed of a wide variety of cation-permeable channels activated polymodally by various stimuli and is implicated in a variety of cellular functions. Recent investigations have revealed that activation of TRP channels is involved not only in nociception and thermosensation but also in thermoregulation and energy metabolism. We investigated the effect of intragastric administration of TRP channel agonists on changes in energy substrate utilization of mice.

Cooling-sensitive TRPM8 is thermostat of skin temperature against cooling.

We have shown that cutaneous cooling-sensitive receptors can work as thermostats of skin temperature against cooling. However, molecule of the thermostat is not known. Here, we studied whether cooling-sensitive TRPM8 channels act as thermostats.

Activation of transient receptor potential ankyrin 1 by hydrogen peroxide.

Hydrogen peroxide (H(2)O(2)), which is contained in industrial products, is also generated within cells. H(2)O(2) causes pain but it has not been elucidated how it activates sensory neurons in the pain pathway. Here we show that transient receptor potential ankyrin 1 (TRPA1), expressed by sensory neurons in the pain pathway, is a receptor for H(2)O(2).

Application of menthol to the skin of whole trunk in mice induces autonomic and behavioral heat-gain responses.

When ambient temperature is decreased in mammals, autonomic and behavioral heat-gain responses occur to maintain their core temperatures. However, what molecules in cutaneous sensory nerve endings mediate cooling-induced responses is unclear. Recently, transient receptor potential melastatin-8 (TRPM8) has been identified in cell bodies of sensory neurons as low-temperature and menthol-activated cation channel.

Cold sensitivity of recombinant TRPA1 channels.

TRPM8 and TRPA1, members of the transient receptor potential (TRP) channel family, are candidates for cooling-activated receptors. It is accepted that TRPM8 responds to moderate cooling, although it is controversial whether TRPA1 responds to deep cooling. Here, using Ca(2+) imaging and/or patch-clamp recordings, we examined the thermal sensitivity of primary cultured dorsal root ganglion (DRG) neurons and mouse TRPA1-expressing human embryonic kidney (HEK) 293 cells.

Transient receptor potential channel TRPM8 agonists stimulate calcium influx and neurotensin secretion in neuroendocrine tumor cells.

TRPM8 is a member of the melastatin-type transient receptor potential ion channel family. Activation by cold or by agonists (menthol, icilin) induces a transient rise in intracellular free calcium concentration ([Ca(2+)](i)). Our previous study demonstrated that Ca(2+)-permeable cation channels play a role in IGF-1-induced secretion of chromogranin A in human neuroendocrine tumor (NET) cell line BON [Mergler et al.

Cellular and molecular bases of the initiation of fever.

All phases of lipopolysaccharide (LPS)-induced fever are mediated by prostaglandin (PG) E2. It is known that the second febrile phase (which starts at approximately 1.5 h post-LPS) and subsequent phases are mediated by PGE2 that originated in endotheliocytes and perivascular cells of the brain.

Ca2+-dependent PKC activation mediates menthol-induced desensitization of transient receptor potential M8.

In 1950, Hensel and Zotterman reported cooling-induced desensitization of cold receptors by extracellular discharge recordings of cold fibers. Since then, however, its intracellular mechanism has remained unresolved. We studied menthol-induced desensitization of cold/menthol receptors (TRPM8, transient receptor potential M8) expressed in HEK cells.

Direct pyrogenic input from prostaglandin EP3 receptor-expressing preoptic neurons to the dorsomedial hypothalamus.

Fever is induced by a neuronal mechanism in the brain. Prostaglandin (PG) E2 acts as a pyrogenic mediator in the preoptic area (POA) probably through the EP3 subtype of PGE receptor expressed on GABAergic neurons, and this PGE2 action triggers neuronal pathways for sympathetic thermogenesis in peripheral effector organs including brown adipose tissue (BAT). To explore pyrogenic efferent pathways from the POA, we determined projection targets of EP3 receptor-expressing POA neurons with a special focus on rat hypothalamic regions including the dorsomedial hypothalamic nucleus (DMH), which is known as a center for autonomic responses to stress.

TRPM8 protein localization in trigeminal ganglion and taste papillae.

TRPM8 is a TRP family cation channel which can be activated by cold stimuli or l-menthol. However, TRPM8 protein localization of nerve terminals in sensory organs remains unknown. Here we generated an antibody against TRPM8 and analyzed TRPM8 protein localization in trigeminal ganglia (TG) and in sensory nerve fibers in the tongue.

Visualization of synaptic Ca2+ /calmodulin-dependent protein kinase II activity in living neurons.

Ca2+/calmodulin-dependent protein kinase II (CaMKII) is highly enriched in excitatory synapses in the CNS and critically involved in synaptic plasticity, learning, and memory. However, the precise temporal and spatial regulation of CaMKII activity in living cells has not been well described, because of a lack of specific methods. We tried to address this by optically detecting the conformational change in CaMKII during activation using fluorescence resonance energy transfer (FRET).

Sympathetic premotor neurons mediating thermoregulatory functions.

The sympathetic nervous system controls various homeostatic conditions, such as blood circulation, body temperature, and energy expenditure, through the regulation of diverse peripheral effector organs. In this system, sympathetic premotor neurons play a crucial role by mediating efferent signals from higher autonomic centers directly to sympathetic preganglionic neurons in the intermediolateral cell column of the spinal cord. The medulla oblongata is thought to subsume many sympathetic premotor neurons, and the rostral ventrolateral medulla (RVLM) has been established to contain the sympathetic premotor neurons responsible for cardiovascular control.

Signaling the brain in inflammation: the role of endothelial cells.

Peripheral inflammation signals the brain primarily via blood-borne proinflammatory cytokines, released from activated immune cells. In addition to these cytokines, immune-brain signaling is known to involve another key mediator, prostaglandin E2 (PGE2), the level of which is elevated in the brain during various inflammatory states and which acts to influence the central neuronal activity to evoke some, but not all, of the sickness behavior including fever and the activation of hypothalamo-pituitary-adrenal axis. Studies over the last decade have indicated that brain endothelial cells are the major source of PGE2 under various inflammatory states.

Identification of sympathetic premotor neurons in medullary raphe regions mediating fever and other thermoregulatory functions.

Sympathetic premotor neurons directly control sympathetic preganglionic neurons (SPNs) in the intermediolateral cell column (IML) of the thoracic spinal cord, and many of these premotor neurons are localized in the medulla oblongata. The rostral ventrolateral medulla contains premotor neurons controlling the cardiovascular conditions, whereas rostral medullary raphe regions are a candidate source of sympathetic premotor neurons for thermoregulatory functions. Here, we show that these medullary raphe regions contain putative glutamatergic neurons and that these neurons directly control thermoregulatory SPNs.

Burn injury enhances brain prostaglandin E2 production through induction of cyclooxygenase-2 and microsomal prostaglandin E synthase in cerebral vascular endothelial cells in rats.

Objectives: To examine whether peripheral burn injury in rats elevates prostaglandin E2 in the central nervous system and to determine where in the central nervous system enzymes responsible for prostaglandin E2 synthesis are expressed.

Design: Prospective controlled animal study.

Setting: University research laboratory.

Noxious heat receptors present in cold-sensory cells in rats.

Noxious heat above approximately 45 degrees C applied on cold spots evokes a paradoxical cold sensation by activating cold fibers. It remains unresolved whether cold receptors respond to heat as well, or whether noxious-heat receptors and cold receptors coexist in the same fiber. Recently, noxious heat receptors (TRPV1) and cold receptors (TRPM8) have been cloned.