Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0344307 (analgesia)
 28,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Medetomidine, (+/-)-4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole, is a very potent, selective and specific full agonist at both pre- and postsynaptic alpha 2-adrenoceptors as demonstrated in several models both in vitro and in vivo. In receptor binding experiments the alpha 2/alpha 1 selectivity ratio of medetomidine is 1620 compared to 260, 220 and 160 for detomidine, clonidine and xylazine, respectively. The alpha 2-adrenoceptor activity of medetomidine resides predominantly in its d-enantiomer (dexmedetomidine). Medetomidine induces a dose-dependent decrease in the release and turnover of noradrenaline, dopamine and serotonin in the CNS as measured by changes in metabolite concentrations or using pharmacological intervention techniques. Inhibition of sympathetic tone in the CNS by medetomidine leads for a characteristic pattern of pharmacodynamic responses including e.g. hypotension, bradycardia, sedation, relief of anxiety, analgesia and hypothermia. The potent, dose-dependent sedative effects of medetomidine have been demonstrated in several classical animal models (e.g. decrease in spontaneous motility in rats and mice, potentiation of barbiturate-induced anaesthesia in rats and mice, induction of sleep in young chicks). At high doses medetomidine has hypnotic of anaesthetic effects, a property which distinguishes it clearly from detomidine, clonidine and other alpha 2-agonists. The pharmacological, neurochemical and behavioral effects of medetomidine can be inhibited by prior, simultaneous of subsequent administration of a selective and specific alpha 2-antagonist, atipamezole. Besides verifying that the main pharmacodynamic effects of medetomidine are alpha 2-mediated, this finding forms a strong basis for the use of atipamezole as a reversing agent against medetomidine-induced effects in veterinary practice.
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PMID:Pharmacological profiles of medetomidine and its antagonist, atipamezole. 257 Dec 75

The neurotransmitters adrenaline and noradrenaline are non-selective adrenergic agonists which interact with both subtypes of alpha- and beta-receptors. Clonidine, an alpha 2-adrenergic drug with a selectivity ratio of 200/1 for alpha 2/alpha 1 has been used in clinical practice for more than 20 years. Although alpha 2-agonists have vasoconstrictor properties, sympatholytic effects on the central nervous system predominate. As a result, the sympathetic outflow from the medullary pressor centres is decreased mediating the hypotensive effects of the alpha 2-agonists. These compounds also exhibit sedative, anxiolytic, analgesic, and haemodynamic stabilising properties. The identification of alpha 2-adrenoceptors has yielded information on their biochemical properties, signal transduction, modulation of the sympathetic nervous system and neurotransmission. The classification of alpha 2-receptors based on anatomical locations and identified as presynaptic alpha 2-receptors and postsynaptic alpha 1-receptors proved to be untenable after postsynaptic and extrasynaptic alpha 2-receptor locations had been identified. At least 3 isoreceptors which are heterologously distributed in the brain have been identified. Guanine nucleotide proteins (G proteins) couple the receptor to an effector mechanism (i.e. intracellular messenger cascade, ion channel). More selective for the alpha 2-adrenoceptor than clonidine is dexmedetomidine (1600/1 of alpha 2/alpha 1), a very potent agonist at the alpha 2-adrenoceptor. Imidazole derivatives (like clonidine and dexmedetomidine) also bind to other nonadrenergic receptors ("imidazoline receptors") which may produce some effects (i.e. vagotonia) previously ascribed to alpha 2-adrenoceptors. alpha 2-receptors exist in brain tissue and several peripheral organs and tissues including the liver, eye, kidney, pancreas and platelets. Anaesthetic interest has focussed on reductions in anaesthetic requirements since experimental and clinical studies have shown that alpha 2-agonists expert powerful analgesic and anaesthetic effects. The hypnotic response is probably mediated by activation of alpha 2-adrenoceptors in the locus coeruleus. Analgesia is induced by modulation of the nociceptive pathway at the level of the dorsal root neuron and other sites not yet unambiguously characterised. Dexmedetomidine reduces the anaesthetic requirements for halothane by more than 90%. Cerebral blood flow and intraocular pressure are reduced by alpha 2-agonists. Epidural, intrathecal, intravenous and transdermal application of clonidine resulted in pain reduction, during and following surgery and in patients with neurogenic or otherwise intractable cancer pain. Administration of alpha 2-agonists induces only minor respiratory effects. Salivary flow is reduced by alpha 2-agonists and gastric and small-bowel motility is decreased.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[Alpha 2-agonists in anesthesia and intensive medicine]. 809 70

Compelling evidence has suggested that spinal glial cells were activated by chronic morphine treatment and involved in the development of morphine tolerance. However, the mechanisms of glial activation were still largely unknown in morphine tolerance. In present study, we investigated the role of p38 mitogen-activated protein kinase (p38 MAPK) in the spinal cord in the development of chronic morphine antinociceptive tolerance. We found that intrathecal administration of morphine (15 microg) daily for 7 consecutive days significantly induced an increase in number of phospho-p38 (p-p38) immunoreactive cells in the spinal cord compared with chronic saline or acute morphine treated rats. Double immunofluorescence staining revealed that p-p38 immunoreactivity was exclusively restricted in the activated spinal microglia, not in astrocytes or neurons. Repeated intrathecal administration of 4-(4-fluorophenyl)-2-(4-methylsulfonylphenyl)-5-(4-pyridyl)-1H-imidazole (SB203580) (10 microg or 2 microg), a specific p38 inhibitor, 30 min before each morphine injection for 7 consecutive days significantly attenuated tolerance to morphine analgesia assessed by tail flick test. However, a single intrathecal administration of SB203580 (10 microg) did not antagonize the established tolerance to morphine analgesia. Taken together, these findings suggested that p38 MAPK activation in the spinal microglia was involved in the development of morphine antinociceptive tolerance. Inhibition of p38 MAPK by SB203580 in the spinal cord attenuated but not reversed the tolerance to morphine analgesia. The present study provides the first evidence that p38 activation in spinal microglia played an important role in the development of tolerance to morphine analgesia.
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PMID:Activation of p38 mitogen-activated protein kinase in spinal microglia mediates morphine antinociceptive tolerance. 1640 66

Improgan, a chemical congener of cimetidine, is a highly effective non-opioid analgesic when injected into the CNS. Despite extensive characterization, neither the improgan receptor, nor a pharmacological antagonist of improgan has been previously described. Presently, the specific binding of [(3)H]cimetidine (3HCIM) in brain fractions was used to discover 4(5)-((4-iodobenzyl)thiomethyl)-1H-imidazole, which behaved in vivo as the first improgan antagonist. The synthesis and pharmacological properties of this drug (named CC12) are described herein. In rats, CC12 (50-500nmol, i.c.v.) produced dose-dependent inhibition of improgan (200-400nmol) antinociception on the tail flick and hot plate tests. When given alone to rats, CC12 had no effects on nociceptive latencies, or on other observable behavioral or motor functions. Maximal inhibitory effects of CC12 (500nmol) were fully surmounted with a large i.c.v. dose of improgan (800nmol), demonstrating competitive antagonism. In mice, CC12 (200-400nmol, i.c.v.) behaved as a partial agonist, producing incomplete improgan antagonism, but also limited antinociception when given alone. Radioligand binding, receptor autoradiography, and electrophysiology experiments showed that CC12's antagonist properties are not explained by activity at 25 sites relevant to analgesia, including known receptors for cannabinoids, opioids or histamine. The use of CC12 as an improgan antagonist will facilitate the characterization of improgan analgesia. Furthermore, because CC12 was also found presently to inhibit opioid and cannabinoid antinociception, it is suggested that this drug modifies a biochemical mechanism shared by several classes of analgesics. Elucidation of this mechanism will enhance understanding of the biochemistry of pain relief.
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PMID:CC12, a high-affinity ligand for [3H]cimetidine binding, is an improgan antagonist. 1733 43

The molecular mechanisms mediating stress-induced dysphoria in humans and conditioned place aversion in rodents are unknown. Here, we show that repeated swim stress caused activation of both kappa-opioid receptor (KOR) and p38 mitogen-activated protein kinase (MAPK) coexpressed in GABAergic neurons in the nucleus accumbens, cortex, and hippocampus. Sites of activation were visualized using phosphoselective antibodies against activated kappa receptors (KOR-P) and against phospho-p38 MAPK. Surprisingly, the increase in P-p38-IR caused by swim-stress exposure was completely KOR dependent; P-p38-IR did not increase in KOR(-/-) knock-out mice subjected to the same swim-paradigm or in wild-type mice pretreated with the KOR antagonist norbinaltorphimine. To understand the relationship between p38 activation and the behavioral effects after KOR activation, we administered the p38 inhibitor SB203580 [4-(4-fluorophenyl)-2-(4-methylsulfonylphenyl)-5-(4-pyridyl)-1H-imidazole (i.c.v.)] and found that it selectively blocked the conditioned place aversion caused by the kappa agonist trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-benzeneacetamide (U50488) and the KOR-dependent swim stress-induced immobility while not affecting kappa-opioid analgesia or nonselectively affecting associative learning. We found that the mechanism linking KOR and p38 activation in vivo was consistent with our previous in vitro data suggesting that beta-arrestin recruitment is required; mice lacking G-protein-coupled receptor kinase 3 also failed to increase p-p38-IR after KOR activation in vivo, failed to show swim stress-induced immobility, or develop conditioned place aversion to U50488. Our results indicate that activation of p38 MAPK signaling by the endogenous dynorphin-kappa-opioid system likely constitutes a key component of the molecular mechanisms mediating the aversive properties of stress.
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PMID:Stress-induced p38 mitogen-activated protein kinase activation mediates kappa-opioid-dependent dysphoria. 1832 76