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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Given the modulatory effect of exogenously administered corticotropin-releasing hormone (CRH) and gastrin-releasing peptide (GRP) on conditioned fear, the present study sought to measure the fear-induced endogenous release of CRH and GRP at the medial prefrontal cortex (mPFC) and basolateral amygdala (BLA) using in vivo microdialysis. Rats were divided into 2 training conditions; tone only (cue), or tone paired with shock. The day after conditioning, animals were tested for fear by scoring freezing behavior in response to the tone alone in cages different from the cages they were previously conditioned in. ⋯ Further, the release of CRH and GRP was significantly correlated with freezing levels (an indication of fear in the rat) such that animals that had higher levels of freezing also had higher interstitial peptide levels. These effects appeared site-specific, as they were not apparent at the mPFC. It appears that at the BLA, the release of CRH and GRP is related to fear.
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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.