The Journal of pharmacology and experimental therapeutics
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J. Pharmacol. Exp. Ther. · Mar 2016
An Important Role for N-Acylethanolamine Acid Amidase in the Complete Freund's Adjuvant Rat Model of Arthritis.
The endogenous lipid amides, palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), exert marked antinociceptive and anti-inflammatory effects in animal models by engaging nuclear peroxisome proliferator-activated receptor-α. PEA and OEA are produced by macrophages and other host-defense cells and are deactivated by the cysteine amidase, N-acylethanolamine acid amidase (NAAA), which is highly expressed in macrophages and B-lymphocytes. In the present study, we examined whether a) NAAA might be involved in the inflammatory reaction triggered by injection of complete Freund's adjuvant (CFA) into the rat paw and b) administration of 4-cyclohexylbutyl-N-[(S)-2-oxoazetidin-3-yl]-carbamate (ARN726), a novel systemically active NAAA inhibitor, attenuates such reaction. ⋯ Administration of undec-10-ynyl-N-[(3S)-2-oxoazetidin-3-yl] carbamate (ARN14686), a NAAA-preferring activity-based probe, revealed that NAAA was catalytically active in CFA-treated paws. Administration of ARN726 reduced NAAA activity and restored PEA and OEA levels in inflamed tissues, and significantly decreased CFA-induced inflammatory symptoms, including pus production and myeloperoxidase activity. The results confirm the usefulness of ARN726 as a probe to investigate the functions of NAAA in health and disease and suggest that this enzyme may provide a new molecular target for the treatment of arthritis.
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J. Pharmacol. Exp. Ther. · Mar 2016
Modeling respiratory depression induced by remifentanil and propofol during sedation and analgesia using a continuous noninvasive measurement of pCO2.
Respiratory depression is a common adverse effect of propofol and remifentanil. We aimed to develop a model for respiratory depressant effects of propofol with remifentanil in patients undergoing endoscopy with sedation. Data were available for 136 patients undergoing endoscopy with sedation. ⋯ Noxious stimuli and genotype were not significant covariates. An indirect-effect model with a rebound mechanism can describe remifentanil- and propofol-induced changes in pCO2 in patients undergoing noxious procedures. The model may be useful for identifying optimal dosing schedules for these drugs in a combination that provides adequate sedation but avoids respiratory depression.
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J. Pharmacol. Exp. Ther. · Mar 2016
Spinal Functions of B-Type Natriuretic Peptide, Gastrin-Releasing Peptide, and Their Cognate Receptors for Regulating Itch in Mice.
B-type natriuretic peptide (BNP)-natriuretic peptide receptor A (NPRA) and gastrin-releasing peptide (GRP)-GRP receptor (GRPR) systems contribute to spinal processing of itch. However, pharmacological and anatomic evidence of these two spinal ligand-receptor systems are still not clear. The aim of this study was to determine the spinal functions of BNP-NPRA and GRP-GRPR systems for regulating scratching activities in mice by using pharmacological and immunohistochemical approaches. ⋯ Pretreatment with intrathecal A71915 did not affect scratching responses elicited by all four pruritogens, whereas pretreatment with RC-3095 only inhibited SLIGRL-induced scratching. Interestingly, immunostaining showed that RC-3095, but not A71915, inhibited SLIGRL-elicited c-Fos activation in the spinal dorsal horn, which was in line with behavioral outcomes. These findings demonstrate that: 1) BNP-NPRA system may function upstream of the GRP-GRPR system to regulate itch in the mouse spinal cord, and 2) both NPRA and GRPR antagonists may have antipruritic efficacy against centrally, but not peripherally, elicited itch.