The Journal of pharmacology and experimental therapeutics
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J. Pharmacol. Exp. Ther. · Apr 2004
Role of alpha-adrenergic receptors in the effect of the beta-adrenergic receptor ligands, CGP 12177, bupranolol, and SR 59230A, on the contraction of rat intrapulmonary artery.
This study investigates the effect of the aryloxypropanolamines 4-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-1,3-dihydro-2H-benzimidazol-2-one (CGP 12177), bupranolol, and 3-(2-ethylphenoxy)-1[(1S)-1,2,3,4-tetrahydronaphth-1-ylamino]-(2S)-2-propanol oxalate (SR 59230A) [commonly used as beta(3)- and/or atypical beta-adrenergic receptors (beta-AR) ligands] on the contractile function of rat intralobar pulmonary artery. Affinities of beta-AR ligands for alpha(1)-adrenergic receptors (alpha(1)-AR) were also evaluated using [(3)H]prazosin binding competition experiments performed in rat cortical membranes. In intralobar pulmonary artery, CGP 12177 did not modify the basal tone, but antagonized the contraction induced by the alpha(1)-AR agonist phenylephrine (PHE). ⋯ These data suggest that CGP 12177 exhibits partial agonist properties for alpha(1)-AR in rat pulmonary artery. They also show that bupranolol and SR 59230A exert an alpha(1)-AR antagonist effect. As a consequence, these aryloxypropanolamine compounds should be used with caution when investigating the role of beta(3)- and atypical beta-AR in the regulation of vascular tone.
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J. Pharmacol. Exp. Ther. · Apr 2004
Differential effects of delta9-tetrahydrocannabinol and methanandamide in CB1 knockout and wild-type mice.
Mice devoid of CB1 cannabinoid receptors (CB1-/- mice) provide a unique opportunity to further investigate the role of CB1 receptors in exocannabinoid and endocannabinoid effects. CB1-/- mice (N = 18) and their wild-type littermates (CB1+/+ mice; N = 12) were placed in standard mouse operant chambers and trained to lever press under a fixed ratio 10 schedule of reinforcement. When stable lever press responding under the fixed ratio 10 schedule had been established, cannabinoids and noncannabinoids were administered to both groups. ⋯ Because methanandamide binds poorly to CB2 receptors, these results suggest possible non-CB1, non-CB2 mechanisms of action for methanandamide-induced behavioral disruption of lever press responding. Ethanol and morphine elicited greater response decreases in CB1-/- mice than in CB1+/+ mice, suggesting a possible role of CB1 receptors in the rate disruptive effects of these drugs. In contrast, diazepam did not produce between group differences, suggesting that CB1 receptors are not involved in diazepam-induced disruption of lever press responding.
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J. Pharmacol. Exp. Ther. · Mar 2004
Salvinorin A, an active component of the hallucinogenic sage salvia divinorum is a highly efficacious kappa-opioid receptor agonist: structural and functional considerations.
The diterpene salvinorin A from Salvia divinorum has recently been reported to be a high-affinity and selective kappa-opioid receptor agonist (Roth et al., 2002). Salvinorin A and selected derivatives were found to be potent and efficacious agonists in several measures of agonist activity using cloned human kappa-opioid receptors expressed in human embryonic kidney-293 cells. Thus, salvinorin A, salvinorinyl-2-propionate, and salvinorinyl-2-heptanoate were found to be either full (salvinorin A) or partial (2-propionate, 2-heptanoate) agonists for inhibition of forskolin-stimulated cAMP production. ⋯ Because issues of receptor reserve complicate estimates of agonist efficacy and potency, we also examined the agonist actions of salvinorin A by measuring potassium conductance through G protein-gated K(+) channels coexpressed in Xenopus oocytes, a system in which receptor reserve is minimal. Salvinorin A was found to be a full agonist, being significantly more efficacious than (trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl] benzeneacetamide methane-sulfonate hydrate (U50488) or (trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl] benzeneacetamide methane-sulfonate hydrate (U69593) (two standard kappa-opioid agonists) and similar in efficacy to dynorphin A (the naturally occurring peptide ligand for kappa-opioid receptors). Salvinorin A thus represents the first known naturally occurring non-nitrogenous full agonist at kappa-opioid receptors.
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J. Pharmacol. Exp. Ther. · Mar 2004
The distribution of the HIV protease inhibitor, ritonavir, to the brain, cerebrospinal fluid, and choroid plexuses of the guinea pig.
Anti-human immunodeficiency virus (HIV) drug penetration into the brain and cerebrospinal fluid (CSF) is necessary to tackle HIV within the CNS. This study examines movement of [(3)H]ritonavir across the guinea pig blood-brain and blood-CSF barriers and accumulation within the brain, CSF, and choroid plexus. Ritonavir is a protease inhibitor, used in combination therapy (often as a pharmacoenhancer) to treat HIV. ⋯ Additionally, the involvement of transporters on [(3)H]ritonavir passage across the brain barriers was assessed. Results from in situ brain perfusions and capillary depletion analysis demonstrated that [(3)H]ritonavir uptake into the guinea pig brain was considerable (6.6 +/- 0.7 ml/100 g at 30 min, vascular space corrected), although a proportion of drug remained trapped in the cerebral capillaries and did not reach the brain parenchyma. CSF uptake was more limited (2.2 +/- 0.4 ml/100 g at 30 min), but choroid plexus uptake was abundant (176.7 +/- 46.3 ml/100 g at 30 min). [(3)H]Ritonavir brain and CSF uptake was unaffected by neither inhibitors of organic anion transport (probenecid and digoxin) or P-glycoprotein (progesterone), nor by any additional anti-HIV drugs, indicating that brain barrier efflux systems do not significantly limit brain or CSF [(3)H]ritonavir accumulation in this model. [(3)H]Ritonavir uptake into the perfused choroid plexus was significantly reduced by nevirapine and abacavir, additional perfusion studies, and isolated incubated choroid plexus experiments were carried out in an attempt to further characterize the transporter involved.
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J. Pharmacol. Exp. Ther. · Feb 2004
Selective activation of cannabinoid CB2 receptors suppresses hyperalgesia evoked by intradermal capsaicin.
The present studies were conducted to test the hypothesis that activation of peripheral cannabinoid CB(2) receptors would suppress hyperalgesia evoked by intradermal administration of capsaicin, the pungent ingredient in hot chili peppers. The CB(2)-selective cannabinoid agonist (2-iodo-5-nitro-phenyl)-[1-(1-methyl-piperidin-2-ylmethyl)-1H-indol-3-yl]-methanone (AM1241) (33, 330 microg/kg i.p.) suppressed the development of capsaicin-evoked thermal and mechanical hyperalgesia and allodynia. AM1241 also produced a dose-dependent suppression of capsaicin-evoked nocifensive behavior. ⋯ AM1241 (33 microg/kg i.pl.) suppressed capsaicin-evoked thermal and mechanical hyperalgesia and allodynia after local administration to the capsaicin-treated (ipsilateral) paw but was inactive after administration to the capsaicin-untreated (contralateral) paw. Our data indicate that AM1241 suppresses capsaicin-evoked hyperalgesia and allodynia through a local site of action. These data provide evidence that actions at cannabinoid CB(2) receptors are sufficient to normalize nociceptive thresholds and produce antinociception in persistent pain states.