European journal of pharmacology
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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.
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The actions of intravenous anaesthetics on 5-HT(3AB) receptors have not been studied. Using oocyte electrophysiology, the effects of etomidate, propofol, and pentobarbital on human 5-HT(3A) and 5-HT(3AB) receptors were studied and compared. Inhibition of peak currents by all three compounds in both receptor subtypes was anaesthetic concentration-dependant and non-competitive. Because the half-maximal inhibitory concentrations for etomidate, propofol and pentobarbital in 5-HT(3A) and 5-HT(3AB) receptors were all above their respective anaesthetic concentrations, the results of our study suggest that neither 5-HT(3) receptor subtype contributes to the anaesthetic actions of etomidate, propofol or pentobarbital.
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Kinin receptors are involved in the genesis of inflammatory pain. However, there is controversy concerning the mechanism by which B(1) and B(2) kinin receptors mediate inflammatory hypernociception. In the present study, the role of these receptors on inflammatory hypernociception in mice was addressed. ⋯ Moreover, B(1) but not B(2) kinin receptor antagonist inhibited carrageenin-induced hypernociception, and TNF-alpha and IL-1beta release as well, in LPS-primed mice. These results suggest that in naïve mice the B(2) kinin receptor mediates inflammatory hypernociception dependent on prostanoids and sympathetic amines, through a cytokine-independent mechanism. On the other hand, in LPS-primed mice, the B(1) kinin receptor mediates hypernociception by a mechanism dependent on TNF-alpha and IL-1beta, which could stimulate prostanoid and sympathetic amine production.