Saori Miyagishi

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.

Repeated water avoidance stress induces visceral hypersensitivity: Role of interleukin-1, interleukin-6, and peripheral corticotropin-releasing factor: Stress and visceral hypersensitivity

Repeated water avoidance stress (WAS) induces visceral hypersensitivity. Additionally, it is also known to activate corticotropin‐releasing factor (CRF), mast cells, and pro‐inflammatory cytokines systems, but their precise roles on visceral sensation have not been determined definitely. The aim of the study was to explore this issue.

Involvement of the dopaminergic system in the central orexin-induced antinociceptive action against colonic distension in conscious rats

We have recently demonstrated that orexin acts centrally in the brain to induce antinociceptive action against colonic distension through orexin 1 receptors in conscious rats. Although the dopaminergic system can induce antinociceptive action for somatic pain, the association between changes in the dopaminergic system and visceral pain perception has not been investigated. In the present study, we hypothesized that the dopaminergic system may be involved in visceral nociception, and if so, the dopaminergic system may mediate the orexin-induced visceral antinociception. Visceral sensation was evaluated using the colonic distension-induced abdominal withdrawal reflex (AWR) in conscious rats. Intracisternal injection of D1 (SKF38398) or D2 (quinpirole) dopamine receptor agonist increased the threshold volume of colonic distension-induced AWR in a dose-dependent manner. Pretreatment with either the D1 or D2 dopamine receptor antagonist (SCH23390 or sulpiride, respectively) potently blocked the centrally injected orexin-A-induced antinociceptive action against colonic distension. These results suggest for the first time that dopaminergic signaling via D1 and D2 dopamine receptors in the brain may induce visceral antinociception and that the dopaminergic signaling may be involved in the central orexin-induced antinociceptive action against colonic distension.

Repeated water avoidance stress induces visceral hypersensitivity; role of IL‐1, IL‐6 and peripheral corticotropin‐releasing factor

Repeated water avoidance stress (WAS) induces visceral hypersensitivity. Additionally, it is also known to activate corticotropin‐releasing factor (CRF), mast cells, and pro‐inflammatory cytokines systems, but their precise roles on visceral sensation have not been determined definitely. The aim of the study was to explore this issue.

Water avoidance stress induces visceral hyposensitivity through peripheral corticotropin releasing factor receptor type 2 and central dopamine D2 receptor in rats.

Water avoidance stress (WAS) is reported to induce functional changes in visceral sensory function in rodents, but the results which have been demonstrated so far are not consistent, i.e., hypersensitivity or hyposensitivity. We determined the effect of WAS on visceral sensation and evaluated the mechanisms of the action.

A glucagon-like peptide-1 analog, liraglutide improves visceral sensation and gut permeability in rats

A glucagon‐like peptide‐1 analog, liraglutide, has been reported to block inflammatory somatic pain. We hypothesized that liraglutide attenuates lipopolysaccharide (LPS)‐induced and repeated water avoidance stress (WAS)‐induced visceral hypersensitivity and tested the hypothesis in rats.

Adenosine A1 receptors mediate the intracisternal injection of orexin-induced antinociceptive action against colonic distension in conscious rats

We have recently demonstrated that orexin acts centrally through the brain orexin 1 receptors to induce an antinociceptive action against colonic distension in conscious rats. Adenosine signaling is capable of inducing an antinociceptive action against somatic pain; however, the association between changes in the adenosinergic system and visceral pain perception has not been investigated. In the present study, we hypothesized that the adenosinergic system may be involved in visceral nociception, and thus, adenosine signaling may mediate orexin-induced visceral antinociception. Visceral sensation was evaluated based on the colonic distension-induced abdominal withdrawal reflex (AWR) in conscious rats. Subcutaneous (0.04-0.2mg/rat) or intracisternal (0.8-4μg/rat) injection of N(6)-cyclopentyladenosine (CPA), an adenosine A1 receptor (A1R) agonist, increased the threshold volume of colonic distension-induced AWR in a dose-dependent manner, thereby suggesting that CPA acts centrally in the brain to induce an antinociceptive action against colonic distension. Pretreatment with theophylline, an adenosine antagonist, or 1,3-dipropyl-8-cyclopentylxanthine, an A1R antagonist, subcutaneously injected potently blocked the centrally injected CPA- or orexin-A-induced antinociceptive action against colonic distension. These results suggest that adenosinergic signaling via A1Rs in the brain induces visceral antinociception and that adenosinergic signaling is involved in the central orexin-induced antinociceptive action against colonic distension.

Lovastatin inhibits visceral allodynia and increased colonic permeability induced by lipopolysaccharide or repeated water avoidance stress in rats

Abstract Statins have been reported to block inflammatory somatic pain and have an anti‐cytokine property. Lipopolysaccharide (LPS) or repeated water avoidance stress (WAS) induces visceral hypersensitivity and increases gut permeability in rats, which are mediated through proinflammatory cytokine‐dependent pathways. Since visceral hypersensitivity with increased gut permeability plays a crucial role in the pathophysiology of irritable bowel syndrome (IBS), these above animal models are considered to simulate IBS. We hypothesized that lovastatin improves symptoms in the patients with IBS by attenuating these visceral changes. The threshold of visceromotor response (VMR) induced by colonic balloon distention was measured for the assessment of visceral sensation in rats. Colonic permeability was determined in vivo by quantifying the absorbed Evans blue in colonic tissue for 15 min using a spectrophotometer. Subcutaneously (s.c.) injected LPS (1 mg/kg) reduced the threshold of VMR after 3 h. Pretreatment with lovastatin (20 mg/kg s.c. daily for 3 days) abolished this response by LPS. Repeated WAS (1 h daily for 3 days) induced visceral allodynia, which was also blocked by repeated injection of lovastatin before each stress session. The antinociceptive effect of lovastatin on the LPS‐induced allodynia was reversed by mevalonolactone, NG‐nitro‐L‐arginine methyl ester or naloxone. Lovastatin also blocked the LPS‐ or repeated WAS‐induced increased gut permeability. These results indicate the possibility that lovastatin can be useful for treating IBS.

Metformin inhibits visceral allodynia and increased gut permeability induced by stress in rats: Metformin improves visceral pain

Metformin has been shown to have anti‐cytokine property. Lipopolysaccharide (LPS)‐induced or repeated water avoidance stress (WAS)‐induced visceral allodynia and increased gut permeability were pro‐inflammatory cytokine‐dependent responses, which were considered to be animal models of irritable bowel syndrome (IBS). We hypothesized that metformin improves symptoms in the patients with IBS by attenuating these visceral changes and tested the hypothesis in rats.

Cold Exposure Related Fever with an Mediterranean Fever (MEFV) Gene Mutation

Familial Mediterranean fever (FMF) is a genetic autoinflammatory disease characterized by recurrent fever with serosal inflammation. We experienced a 53-year-old male who had been suffering from periodic attacks with slight fever and myalgia which were mainly triggered by cold exposure in winter. Although his clinical course did not satisfy the criteria for familial Mediterranean fever, heterozygous E148Q/M694I mutation in the Mediterranean fever (MEFV) gene was detected. Further attacks were prevented by treatment with colchicine. Attention should therefore be paid to the possibility of atypical FMF symptoms, which should be accurately diagnosed by genetic analyses to prevent the development of amyloidosis.