European journal of pharmacology
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Comparative Study
Opioid receptor desensitization contributes to thermal hyperalgesia in infant rats.
Central nociceptive processing includes spinal and supraspinal neurons, but the supraspinal mechanisms mediating changes in pain threshold remain unclear. We investigated the role of forebrain neurons in capsaicin-induced hyperalgesia. Long-Evans rat pups at 21 days were randomized to undisturbed control group, or to receive tactile stimulation, saline injection (0.9% w/v) or capsaicin injection (0.01% w/v) applied to each paw at hourly intervals. ⋯ Dose responses to systemic morphine were also reduced in the capsaicin group compared to the tactile group (P < 0.05). Capsaicin-induced hyperalgesia in 21-day-old rats was associated with an uncoupling of micro-opioid receptors in the forebrain. Opioid receptor desensitization in the forebrain may reduce opioidergic inputs to the descending inhibitory controls, associated with behavioral hyperalgesia and reduced responsiveness to morphine analgesia in capsaicin-injected young rats.
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Comparative Study
Pharmacological profile of parecoxib: a novel, potent injectable selective cyclooxygenase-2 inhibitor.
The antinociceptive, anti-inflammatory, antipyretic effects along with gastric safety profile of parecoxib, a novel, potent selective cyclooxygenase-2 inhibiting prodrug, and those of ketorolac, a nonselective cyclooxygenase inhibitor, were evaluated in various animal models. Parecoxib (up to 20 mg/kg, i.v.) had no effect in two acute pain models, namely, the acetic acid-induced writhing (visceral pain) and the formalin test (tonic pain). However, ketorolac (up to 10 mg/kg, i.v.) showed marked antinociceptive effects in these models. ⋯ Further, ketorolac (10 mg/kg, i.v.) produced visible gastric lesions with prominent petechiae and hemorrhagic streaks. However, parecoxib was without any effect on gastric mucosa. The present results showed that the cyclooxygenase-2 inhibitor, parecoxib, when administered parenterally, has potent antihyperalgesic, anti-inflammatory, antipyretic effects and has a better safety profile than with ketorolac, with sparing of cyclooxygenase-1 in the stomach in these animal models.
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Review
Hippocampal synaptic plasticity and glutamate receptor regulation: influences of diabetes mellitus.
Diabetes mellitus is an endocrine disorder of carbohydrate metabolism resulting primarily from inadequate insulin release (Type 1 insulin-dependent diabetes mellitus) or insulin insensitivity coupled with inadequate compensatory insulin release (Type 2 non-insulin-dependent diabetes mellitus). Previous studies involving behavioural and electrophysiological analysis indicate that diabetes mellitus induces cognitive impairment and defects of long-term potentiation in the hippocampus. Considered to be an important mechanism of learning and memory in mammals, long-term potentiation is known to require regulation of the glutamate receptor properties. ⋯ We review here the changes in glutamate receptors that may account for modifications of long-term potentiation in various models of diabetes mellitus. As glutamate receptors are also involved in the appearance of neurodegenerative states, we discuss the possibility that deficits in long-term potentiation during chronic diabetes might arise from dysfunction of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors in early stages of the disease. This review addresses the possible role of hyperglycaemia and insulin in regulating these receptors.
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Insulin and specific insulin receptors are found widely distributed in the central nervous system (CNS) networks related in particular to energy homeostasis. This review highlights the complex regulatory loop between dietary nutrients, brain insulin and feeding. It is well documented that brain insulin has a negative, anorexigenic effect on food intake. ⋯ In the hypothalamus, insulin and leptin share a common signaling pathway involved in food intake, namely the insulin receptor substrate, phosphatidylinositol 3-kinase pathway. Over or under-feeding, unbalanced single meals or diets, in particular diets enriched in fat, modify the amount of insulin actively transported into the brain, the release of brain insulin, the expression of insulin messenger RNA and potentially disrupt insulin signaling in the CNS. This impairment may result in disorders related to feeding behavior and energy homeostasis leading to profound dysregulations, obesity or diabetes.
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Using the rat paw pressure test, in which increased sensitivity is induced by intraplantar injection of prostaglandin E2, we assessed the antinociceptive effect of the ATP-sensitive K+ channel opener diazoxide and the large-conductance Ca(2+)-activated K+ channel opener NS-1619 (1,3-dihydro-1-[2-hydroxy-5-(trifluoromethyl) phenyl]-5-(trifluoromethyl)-2H-benzimidazol-2-one) on the peripheral hyperalgesia induced by prostaglandin E2. Diazoxide, administered locally into the right hindpaw (20, 38, 75, 150, 300 and 600 microg), elicited a dose-dependent antinociceptive effect on prostaglandin E2-induced hyperalgesia (2 microg/paw). The effect of diazoxide at the dose of 300 microg/paw was shown to be local since it did not produce any effect when administered in the contralateral paw. ⋯ A low dose of diazoxide (20 microg/paw) administered together with a low dose of sodium nitroprusside (125 microg/paw) or dibutyryl cGMP (db-cGMP, 50 microg/paw) induced a marked antinociceptive effect similar to that observed when each drug was administered alone. NS1619 (75, 150 and 300 microg/paw), a specific opener of large-conductance Ca(2+)-activated K+ channels, had no antinociceptive action on prostaglandin E2-induced hyperalgesia. This series of experiments provides evidence for a peripheral antinociceptive action of diazoxide and supports the suggestion that the activation of ATP-sensitive K+ channels could be the mechanism by which sodium nitroprusside and db-cGMP induce peripheral antinociception, excluding the involvement of large-contuctance Ca(2+)-activated K+ channels in the process.