European journal of pharmacology
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TRPA1 is a member of the transient receptor potential (TRP) channel family expressed in sensory neurons. The present study focused on the effects of TRPA1 activation on contractile responses in isolated mouse intestine preparations. The jejunum, ileum, and proximal and distal colon were surgically isolated from male ddY mice. ⋯ Menthol-induced relaxation in the colon was not inhibited by tetrodotoxin and atropine. RT-PCR analysis revealed the expression of TRPA1 and TRPV1, but not TRPM8, throughout the mouse intestine. These results suggest that TRPA1, but not TRPM8, are functionally expressed in the enteric nervous system throughout the mouse intestine on neurons that may also co-express TRPV1, yet the contractile responses to TRPA1 activation differ depending on their location along the intestine.
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The effects of glycyrrhizin isolated from licorice root were investigated on acute hepatitis induced by lipopolysaccharide (LPS) and d-galactosamine in mice. Serum alanine aminotransferase (ALT) activity was markedly increased 6 h to 8 h after administration of LPS/d-galactosamine. Levels in serum of cytokines such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, IL-10 and IL-12 reached a maximum by 2 h, whereas levels of IL-18, as well as of ALT, were maximal at 8 h. ⋯ Glycyrrhizin reduced the responsiveness of cells to IL-18 in the liver injury. These results suggest that glycyrrhizin inhibits the LPS/d-galactosamine-induced liver injury through preventing inflammatory responses and IL-18 production. Furthermore, it seems that glycyrrhizin prevents IL-18-mediated inflammation in liver injury.
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Emerging epidemiological data indicates that diabetes is a potential predisposing factor for neuropsychiatric deficits as stroke, cerebrovascular diseases, diabetic encephalopathy, depression and anxiety. Diabetic encephalopathy, characterized by impaired cognitive functions and neurochemical and structural abnormalities, involves direct neuronal damage caused by intracellular glucose. Curcumin, a well-established phenolic antioxidant and anti-inflammatory molecule, is capable of playing an important role against amyloid and dendritic pathology and thus has neuroprotective properties. ⋯ Serum TNF-alpha, a marker for inflammation, was found to increase by 1100% in diabetic rats. Chronic treatment with curcumin (60 mg/kg; p.o.) significantly attenuated cognitive deficit, cholinergic dysfunction, oxidative stress and inflammation in diabetic rats. The results emphasize the involvement of cholinergic dysfunction, oxidative stress and inflammation in the development of cognitive impairment in diabetic animals and point towards the potential of curcumin as an adjuvant therapy to conventional anti-hyperglycemic regimens for the prevention and treatment of diabetic encephalopathy.
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In spite of prominent progress in basic pain research, neuropathic pain remains a significant medical problem, because it is often poorly relieved by conventional analgesics. Thus this situation encourages us to make more sophisticated efforts toward the discovery of new analgesics. We previously showed that i.t. administration of acromelic acid-A (ACRO-A), a Japanese mushroom poison, provoked prominent tactile pain (allodynia) at an extremely low dose of 1 fg/mouse. ⋯ In contrast, it did not affect thermal or mechanical nociception or inflammatory pain. PSPA-1 reduced the increase in neuronal nitric oxide synthase activity in the spinal cord of neuropathic pain mice assessed by NADPH-diaphorase histochemistry and blocked the allodynia induced by N-methyl-d-aspartate. These results demonstrate that PSPA-1 may represent a novel class of anti-allodynic agents for neuropathic pain acting by blocking the glutamate-nitric oxide pathway.
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Altered functioning of monoamine-containing pathways descending from supraspinal structures to the spinal dorsal horn contributes to injury-induced sensitization of nociceptive transmission. Antidepressant drugs as typified by the dual serotonin (5-HT) and noradrenaline reuptake inhibitor duloxetine attenuate various signs and symptoms of persistent pain in animals and humans. The current study assessed whether dopamine receptor agonists could further enhance the antinociceptive activity of duloxetine in an animal model of injury-induced central sensitization, the rat formalin test. ⋯ Remarkably, when completely inactive doses of duloxetine (3 mg/kg) and SKF-82958 (0.3 mg/kg) were combined, a marked attenuation of second phase nociceptive behaviours occurred (P<0.05 vs vehicle), indicative of analgesic synergy. Similarly, when an active antinociceptive dose of quinpirole (0.03 mg/kg, P<0.05 vs vehicle) was combined with an inactive dose of duloxetine (3 mg/kg), a potentiation of duloxetine-mediated antinociception was observed (P<0.001 vs vehicle). Taken together, these results suggest that antidepressant drugs that can enhance the activity of 5-HT, noradrenaline and dopamine neurotransmission within nociceptive pathways should provide a broader spectrum of antinociception than dual mechanism of action reuptake inhibitors in animal models of injury-induced persistent nociception.