Pharmacology, biochemistry, and behavior
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Pharmacol. Biochem. Behav. · Jul 2012
κ opioid regulation of anxiety-like behavior during acute ethanol withdrawal.
Withdrawal is one of the defining characteristics of alcohol dependence, and is often characterized by impaired physiological function and enhanced negative affect. Recent evidence suggests that the dynorphin (DYN)/kappa opioid receptor (KOR) system may be a key mediator in the negative affect often associated with drugs of abuse. The objective of the present experiments was to determine the role of the DYN/KOR system in the regulation of anxiety-related behavior during acute withdrawal from ethanol. ⋯ Similar decreases in open arm exploration were observed following injections with the KOR agonist, U50,488, an effect also reversed by pretreatment with nor-BNI. These results suggest that similar mechanisms are involved in the regulation of ethanol withdrawal- and KOR agonist-induced changes in behavior. Given the potential role of enhanced negative affect in persistent ethanol drinking, understanding the role of the DYN/KOR system in regulating anxiety associated with withdrawal may be critical in understanding the factors associated with the nature of alcohol dependence.
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Pharmacol. Biochem. Behav. · Jul 2012
Role of ATP-sensitive K+ channels in the antinociception induced by non-steroidal anti-inflammatory drugs in streptozotocin-diabetic and non-diabetic rats.
There is evidence that systemic sulfonylureas block diclofenac-induced antinociception in normal rat, suggesting that diclofenac activates ATP-sensitive K(+) channels. However, there is no evidence for the systemic interaction between different non-steroidal anti-inflammatory drugs (NSAIDs) and sulfonylureas in streptozotocin (STZ)-diabetic rats. Therefore, this work was undertaken to determine whether two sulfonylureas, glibenclamide and glipizide, have any effect on the systemic antinociception that is induced by diclofenac (30 mg/kg), lumiracoxib (56 mg/kg), meloxicam (30 mg/kg), metamizol (56 mg/kg) and indomethacin (30 mg/kg) using the non-diabetic and STZ-diabetic rat formalin test. ⋯ In contrast, pretreatment with glibenclamide or glipizide did not block lumiracoxib-, meloxicam-, metamizol-, and indomethacin-induced systemic antinociception (P>0.05) in both groups. Results showed that systemic NSAIDs are able to produce antinociception in STZ-diabetic rats. Likewise, data suggest that diclofenac, but not other NSAIDs, activated K(+) channels to induce its systemic antinociceptive effect in the non-diabetic and STZ-diabetic rat formalin test.
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Pharmacol. Biochem. Behav. · Jul 2012
Rolapitant (SCH 619734): a potent, selective and orally active neurokinin NK1 receptor antagonist with centrally-mediated antiemetic effects in ferrets.
NK1 receptor antagonists have been shown to have a variety of physiological and potential therapeutic effects in animal models and in humans. The present studies demonstrate that Rolapitant (SCH 619734, (5S)-8(S)-[[1(R)-[3,5 bis(trifluoromethyl)phenyl]ethoxy]methyl]-8-phenyl-1,7-diazaspiro[4,5]decan-2-one) is a selective, bioavailable, CNS penetrant neurokinin NK1 receptor antagonist that shows behavioral effects in animals models of emesis. In vitro studies indicate that rolapitant has a high affinity for the human NK1 receptor of 0.66 nM and high selectivity over the human NK2 and NK3 subtypes of >1000-fold, as well as preferential affinity for human, guinea pig, gerbil and monkey NK1 receptors over rat, mouse and rabbit. ⋯ Rolapitant reversed NK1 agonist-induced foot tapping in gerbils following both intravenous and oral administration up to 24 hours at a minimal effective dose (MED) of 0.1 mg/kg. Rolapitant was active at 0.1 and 1 mg/kg in both acute and delayed emesis models in ferrets, respectively, consistent with clinical data for other NK1 antagonists. Clinical efficacy of anti-emetics is highly correlated with efficacy in the ferret emesis model, suggesting rolapitant is a viable clinical candidate for this indication.
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Pharmacol. Biochem. Behav. · Jun 2012
Analgesic effects of lidocaine, morphine and diclofenac on movement-induced nociception, as assessed by the Knee-Bend and CatWalk tests in a rat model of osteoarthritis.
Pain is the major symptom of osteoarthritis (OA) and the main reason for patients seeking medical care, but its treatment is not optimal. Animal studies are necessary to elucidate mechanisms underlying OA-induced pain and assess analgesics' efficacy. Previously, we showed that the Knee-Bend test and dynamic weight bearing by the CatWalk test are clinically relevant methods for assessing movement-induced nociception in the mono-iodoacetate (MIA) OA model. ⋯ Diclofenac was highly effective in both tests on day 3, while on day 20 it induced a less pronounced decrease in the Knee-Bend score and was ineffective in the CatWalk test. The results showed that the Knee-Bend and CatWalk tests are reliable alternative methods for evaluating movement-induced nociception in OA animals, and measure nociception in a clinically relevant way, since an analgesic profile similar to the one described in humans was observed. Therefore, these tests might be important as good predictors of drug efficacy.
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Pharmacol. Biochem. Behav. · May 2012
Effects of koumine, an alkaloid of Gelsemium elegans Benth., on inflammatory and neuropathic pain models and possible mechanism with allopregnanolone.
Crude alkaloidal extraction from Gelsemium elegans Benth. produces analgesic property. However, its clinical utility has been obstructed by its narrow therapeutic index. Here, we investigated the potential of koumine, a monomer of Gelsemium alkaloids, to reduce both inflammatory and neuropathic pain. ⋯ Repeated administrations of koumine also dose-dependently reversed the CFA-, CCI- and L5 SNL-induced thermal hyperalgesia, as well as, CCI- and L5 SNL-induced mechanical allodynia in rats. The level of allopregnanolone, but not pregnenolone, in the L5-6 spinal cord was elevated by repeated treatment of koumine in CCI-induced neuropathic rats. These results demonstrate that koumine has a significant analgesic effect in rodent behavioral models of inflammatory and neuropathic pain, and that the reduction in neuropathic pain may be associated with the upregulation of allopregnanolone in the spinal cord.