Neuropharmacology
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Comparative Study
The CB2 cannabinoid receptor-selective agonist O-3223 reduces pain and inflammation without apparent cannabinoid behavioral effects.
Although Δ(9)-tetrahydrocannabinol (THC) and other mixed CB(1)/CB(2) receptor agonists are well established to elicit antinociceptive effects, their psychomimetic actions and potential for abuse have dampened enthusiasm for their therapeutic development. Conversely, CB(2) receptor-selective agonists have been shown to reduce pain and inflammation, without eliciting apparent cannabinoid behavioral effects. In the present study, we developed a novel ethyl sulfonamide THC analog, O-3223, and compared its pharmacological effects to those of the potent, mixed CB(1)/CB(2) receptor agonist, CP55,940, in a battery of preclinical pain models. ⋯ Unlike CP55,940, O-3223 did not elicit acute antinociceptive effects in the hot-plate test, hypothermia, or motor disturbances, as assessed in the rotarod test. These data indicate that the CB(2) receptor-selective agonist, O-3223, reduces inflammatory and neuropathic nociception, without affecting basal nociception or eliciting overt behavioral effects. Moreover, this compound can serve as a template to develop new CB(2) receptor agonists with increased receptor selectivity and increased potency in treating inflammatory and neuropathic pain.
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Comparative Study
Stimulation of α2-adrenergic receptors in the central nucleus of the amygdala attenuates stress-induced reinstatement of nicotine seeking in rats.
Tobacco addiction is a chronic disorder that is characterized by craving for tobacco products, withdrawal upon smoking cessation, and relapse after periods of abstinence. Previous studies demonstrated that systemic administration of α2-adrenergic receptor agonists attenuates stress-induced reinstatement of drug seeking in rats. The aim of the present experiments was to investigate the role of noradrenergic transmission in the central nucleus of amygdala (CeA) in stress-induced reinstatement of nicotine seeking. ⋯ This suggests that the effects of clonidine and dexmedetomidine on stress-induced reinstatement of nicotine seeking were not mediated by motor impairments or sedation. Taken together, these findings indicate that stimulation of α2-adrenergic receptors, but not blockade of α1 or β-adrenergic receptors, in the CeA attenuates stress-induced reinstatement of nicotine seeking. These findings suggest that α2-adrenergic receptor agonists may at least partly attenuate stress-induced reinstatement of nicotine seeking by stimulating α2-adrenergic receptors in the CeA.
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Ligands acting at the same receptor can differentially activate distinct signal transduction pathways, which in turn, can have diverse functional consequences. Further, receptors expressed in different tissues may utilize intracellular signaling proteins in response to a ligand differently as well. The mu opioid receptor (MOR), which mediates many of the pharmacological actions of opiate therapeutics, is also subject to differential signaling in response to diverse agonists. ⋯ While there are no differences in withdrawal responses between genotypes at the highest dose of morphine tested (48 mg/kg/day), the βarr2-KO mice display several less severe withdrawal responses when the infusion dose is lowered (12 or 24 mg/kg/day). Chronic infusion of methadone, fentanyl, and oxycodone all lead to equivalent naloxone-precipitated withdrawal responses in both genotypes at all doses tested. These results lend further evidence that distinct agonists can differentially impact on opioid-mediated responses in vivo in a βarrestin2-dependent manner.
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Our laboratory has recently demonstrated that an increase in the spinal neurosteroid, dehydroepiandrosterone sulfate (DHEAS) facilitates nociception via the activation of sigma-1 receptors and/or the allosteric inhibition GABA(A) receptors. Several lines of evidence have suggested that DHEAS positively modulates N-methyl-d-aspartate (NMDA) receptor activity within the central nervous system. Moreover, we have demonstrated that the activation of sigma-1 receptors increases NMDA receptor activity. ⋯ Conversely the GABA(A) receptor antagonist, bicuculline did not affect NMDA-induced pain behavior or pNR1 expression. The results of this study suggest that the DHEAS-induced enhancement of NMDA-mediated nociception is dependent on an increase in PKC- and PKA-dependent pNR1. Moreover, this effect of DHEAS on NMDA receptor activity is mediated by the activation of spinal sigma-1 receptors and not through the inhibition of GABA(A) receptors.
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Celecoxib is a non-steroidal anti-inflammatory drug (NSAID) that selectively inhibits cyclooxygenase-2 (COX-2). Like most NSAIDs, celecoxib exhibits analgesic effects in models of inflammatory pain but these appear to be dependent on endogenous opioid release. Therefore, this study has assessed the ability of celecoxib to induce tolerance in rats, comparable to that induced by morphine. ⋯ Naltrexone prevented induction of tolerance to morphine or celecoxib. The present results strengthen the possibility that celecoxib has also mechanisms of analgesia unrelated to COX inhibition but dependent on endogenous opioid release. Our results also imply the existence of a new class of analgesics without the deleterious effects of COX inhibitors.