The Journal of pharmacology and experimental therapeutics
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J. Pharmacol. Exp. Ther. · Jun 2007
Roles of 5-hydroxytryptamine (5-HT) receptor subtypes in the inhibitory effects of 5-HT on C-fiber responses of spinal wide dynamic range neurons in rats.
5-Hydroxytryptamine (5-HT; serotonin) plays an important role in the descending control of nociception. 5-HT and its receptors have been extensively studied in the modulation of nociceptive transmission at the spinal level using behavioral tests that may be affected by the effects of 5-HT on motor performance and skin temperature. Using electrophysiological methods, the present study aimed to systematically investigate the roles of 5-HT receptor subtypes on the inhibitory effects of 5-HT on responses of the spinal wide dynamic range (WDR) neurons to C-fiber inputs in rats. ⋯ Topical administration of agonists of 5-HT(1A) [(2R)-(+)-8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide], 5-HT(1B) [CGS 12066 [7-trifluoromethyl-4-(4-methyl-1-piperazinyl)pyrrolo-[1,2-a]quinoxaline maleate salt]], 5-HT(2A) (alpha-methyl-5-hydroxytryptamine maleate), 5-HT(2C) [MK 212 [6-chloro-2-(1-piperazinyl)pyrazine hydrochloride]], 5-HT(3) [1-(3-chlorophenyl)biguanide hydrochloride], and 5-HT(4) [2-[1-(4-piperonyl)piperazinyl]benzothiazole] also inhibited the C-responses. These results suggest that, under basal conditions, there is no tonic serotonergic inhibition on the C-responses of dorsal horn neurons, and multiple 5-HT receptor subtypes including 1B, 2A, 2C, 3, and 4 may be involved in mediating the inhibitory effects of 5-HT.
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J. Pharmacol. Exp. Ther. · Jun 2007
Pharmacological characterization of the nociceptin/orphanin FQ receptor antagonist SB-612111 [(-)-cis-1-methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol]: in vivo studies.
The excellent pharmacological profile displayed by the selective nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptor antagonist SB-612111 [(-)-cis-1-methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol] in vitro prompted us to investigate the actions of this compound in vivo. In the mouse tail withdrawal assay, SB-612111 given i.p. up to 3 mg/kg did not modify per se tail withdrawal latencies but was able to prevent the pronociceptive and the antinociceptive action of 1 nmol of N/OFQ given i.c.v. and i.t., respectively. In food intake studies performed in sated mice, SB-612111 (1 mg/kg i.p.) had no effect on food consumption but fully prevented the orexigenic effect of 1 nmol of N/OFQ i.c.v. ⋯ The antidepressant-like effect elicited by SB-612111 in the forced swimming test was reversed by the i.c.v. injection of 1 nmol of N/OFQ and no longer evident in mice knockout for the NOP receptor gene. In conclusion, the present findings demonstrate that SB-612111 behaves in vivo as a potent and selective NOP antagonist and suggest that the N/OFQ-NOP receptor endogenous system plays an important role in regulating mood-related behaviors. The use of SB-612111 in future pathophysiological studies will certainly contribute to define the therapeutic potential of selective NOP receptor antagonists in different disease areas.
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J. Pharmacol. Exp. Ther. · Jun 2007
Characterization of the antinociceptive actions of bicifadine in models of acute, persistent, and chronic pain.
Bicifadine (1-p-tolyl-3-azabicyclo[3.1.0]hexane) inhibits monoamine neurotransmitter uptake by recombinant human transporters in vitro with a relative potency of norepinephrine > serotonin > dopamine (approximately 1:2:17). This in vitro profile is supported by microdialysis studies in freely moving rats, where bicifadine (20 mg/kg i.p.) increased extrasynaptic norepinephrine and serotonin levels in the prefrontal cortex, norepinephrine levels in the locus coeruleus, and dopamine levels in the striatum. Orally administered bicifadine is an effective antinociceptive in several models of acute, persistent, and chronic pain. ⋯ Mechanical hyperalgesia was also reduced by bicifadine in the streptozotocin model of neuropathic pain. Administration of the D(2) receptor antagonist (-)-sulpiride reduced the effects of bicifadine in the mechanical hyperalgesia assessment in rats with spinal nerve ligations. These results indicate that bicifadine is a functional triple reuptake inhibitor with antinociceptive and antiallodynic activity in acute, persistent, and chronic pain models, with activation of dopaminergic pathways contributing to its antihyperalgesic actions.
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J. Pharmacol. Exp. Ther. · May 2007
Pharmacokinetic-pharmacodynamic modeling of the respiratory depressant effect of norbuprenorphine in rats.
The objective of this investigation was to characterize the pharmacokinetic-pharmacodynamic (PK-PD) correlation of buprenorphine's active metabolite norbuprenorphine for the effect on respiration in rats. Following i.v. administration in rats (dose range 0.32-1.848 mg), the time course of the concentration in plasma was determined in conjunction with the effect in ventilation as determined with a novel whole-body plethysmography technique. The PK of norbuprenorphine was best described by a three-compartment PK model with nonlinear elimination. ⋯ In a separate analysis, the time course of the plasma concentrations of buprenorphine and norbuprenorphine following administration of both the parent drug and the metabolite were simultaneously analyzed based on a six-compartment PK model with nonlinear elimination of norbuprenorphine. This analysis showed that following i.v. administration, 10% of the administered dose of buprenorphine is converted into norbuprenorphine. By simulation it is shown that following i.v. administration of buprenorphine, the concentrations of norbuprenorphine reach values that are well below the values causing an effect on respiration.
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J. Pharmacol. Exp. Ther. · May 2007
The novel alpha7 nicotinic acetylcholine receptor agonist N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-[2-(methoxy)phenyl]-1-benzofuran-2-carboxamide improves working and recognition memory in rodents.
The relative contribution of alpha4beta2, alpha7 and other nicotinic acetylcholine receptor (nAChR) subtypes to the memory enhancing versus the addictive effects of nicotine is the subject of ongoing debate. In the present study, we characterized the pharmacological and behavioral properties of the alpha7 nAChR agonist N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-[2-(methoxy)phenyl]-1-benzofuran-2-carboxamide (ABBF). ABBF bound to alpha7 nAChR in rat brain membranes (Ki=62 nM) and to recombinant human 5-hydroxytryptamine (5-HT)3 receptors (Ki=60 nM). ⋯ In addition, ABBF improved working memory of aged rats in a water maze repeated acquisition paradigm (1 mg/kg p.o.) and object recognition memory in mice (0.3-1 mg/kg p.o.). Rats trained to discriminate nicotine (0.4 mg/kg s.c.) from vehicle did not generalize to ABBF (0.3-30 mg/kg p.o.), suggesting that the nicotine cue is not mediated by the alpha7 nAChR and that selective alpha7 nAChR agonists may not share the abuse liability of nicotine. Our results support the hypothesis that alpha7 nAChR agonists may provide a novel therapeutic strategy for the treatment of cognitive deficits with low abuse potential.