20 research outputs found
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Cold exposure stimulates synthesis of the bioactive lipid oleoylethanolamide in rat adipose tissue
No full textOleoylethanolamide (OEA) is an endogenous lipid mediator that inhibits feeding and stimulates lipolysis by activating the nuclear receptor peroxisome proliferator-activating receptor-alpha. Little is known about the physiological regulation of this compound outside of the gastrointestinal tract, where its production is regulated by feeding. Here we show that cold exposure increases OEA levels in rat white adipose tissue but not in liver or intestine. This change is accompanied by parallel elevations in the activity of N-acyltransferase, a key enzyme responsible for OEA synthesis, without concomitant changes in fatty acid amide hydrolase, an enzyme responsible for OEA degradation. Moreover, cold stimulates the production of two species of N-oleoylphosphatidylethanolamine OEA precursors. The changes in OEA biosynthesis are reversed by pretreatment with the beta-receptor antagonist propranolol, suggesting a role for beta-adrenoreceptors in this response. In agreement with these findings, the beta-agonists noradrenaline and isoproterenol stimulate OEA production in isolated adipocytes, an effect that is mimicked by the adenylyl cyclase activator forskolin. Collectively, these results identify cold exposure as a natural stimulus for OEA formation in white fat and suggest a role for the sympathetic nervous system in regulating OEA biosynthesis
The search for the palmitoylethanolamide receptor.
No full textPalmitoylethanolamide (PEA), the naturally occurring amide of ethanolamine and palmitic acid, is an endogenous lipid that modulates pain and inflammation. Although the anti-inflammatory effects of PEA were first characterized nearly 50 years ago, the identity of the receptor mediating these actions has long remained elusive. We recently identified the ligand-activated transcription factor, peroxisome proliferator-activated receptor-alpha (PPAR-alpha), as the receptor mediating the anti-inflammatory actions of this lipid amide. Here we outline the history of PEA, starting with its initial discovery in the 1950s, and discuss the pharmacological properties of this compound, particularly in regards to its ability to activate PPAR-alpha
Synthesis and pharmacological characterization of URB447, a new cannabinoid receptor neutral antagonist
No full textTipo ministeriale Proceeding
XIX National Meeting on Medicinal Chemistry, Book of Abstracts, P-163, 254 (Poster
Rapid broad-spectrum analgesia through activation of peroxisome proliferator-activated receptor-alpha.
No full textWe report that agonists of the nuclear receptor PPAR-α (peroxisome proliferator-activated receptor- α ) suppress pain behaviors induced in mice by chemical tissue injury, nerve damage, or inflammation. The PPAR- α agonists GW7647 [2-(4-(2-(1-cyclohexanebutyl)-3-cyclohexylureido)ethyl)phenylthio)-2-methylpropionic acid], Wy-14643 [4-chloro-6-(2,3-xylidino)-2- pyrimidinylthioacetic acid], and palmitoylethanolamide (PEA) reduced nocifensive behaviors elicited in mice by intraplantar (i.pl.) injection of formalin or i.p. injection of magnesium sulfate. These effects were absent in PPAR- α -null mice yet occurred within minutes of agonist administration in wild-type mice, suggesting that they were mediated through a transcriptionindependent mechanism. Consistent with this hypothesis, blockade of calcium-operated IKca (KCa3.1) and BKca (KCa1.1) potassium channels prevented the effects of GW7647 and PEA in the formalin test. Three observations suggest that PPAR- α agonists may inhibit nocifensive responses by acting on peripheral PPAR- α. (i) PEA reduced formalin-induced pain at i.pl. doses that produced no increase in systemic PEA levels; (ii) PPAR-_ was expressed in dorsal root ganglia neurons of wildtype but not PPAR- α -null mice; and (ii) GW7647 and PEA prevented formalin-induced firing of spinal cord nociceptive neurons in rats. In addition to modulating nociception, GW7647 and PEA reduced hyperalgesic responses in the chronic constriction injury model of neuropathic pain; these effects were also contingent on PPAR- α expression and were observed following either acute or subchronic PPAR- α agonist administration. Finally, acute administration of GW7647 and PEA reduced hyperalgesic responses in the complete Freund’s adjuvant and carrageenan models of inflammatory pain. Our results suggest that PPAR- α agonists may represent a novel class of analgesics
Regulation of food intake by oleoylethanolamide
No full textOleoylethanolamide (OEA), the naturally occurring amide of ethanolamine and oleic acid, is an endogenous lipid that modulates feeding, body weight and lipid metabolism by binding with high affinity to the ligand-activated transcription factor, peroxisome proliferator-activated receptor-alpha (PPAR-α). In the present article, we describe the biochemical pathways responsible for the initiation and termination of OEA signaling, and outline the pharmacological properties of this compound in relation to its ability to activate PPAR-α. Finally, we discuss the possible role of OEA as a peripheral satiety hormone. © Birkhäuser Verlag, Basel, 2005
Synthesis and characterization of a peripherally restricted CB1 cannabinoid antagonist, URB447, that reduces feeding and body weight gain in mice.
No full textSynthesis and characterization of a peripherally restricted CB1 cannabinoid antagonist, URB447, that reduces feeding and body-weight gain in mice
No full textSynergistic antinociception by the cannabinoid receptor agonist anandamide and the PPAR-alpha receptor agonist GW7647.
No full textThe analgesic properties of cannabinoid receptor agonists are well characterized. However, numerous side effects limit the therapeutic potential of these agents. Here we report a synergistic antinociceptive interaction between the endogenous cannabinoid receptor agonist anandamide and the synthetic peroxisome proliferator-activated receptor-alpha (PPAR-alpha) agonist 2-(4-(2-(1-Cyclohexanebutyl)-3-cyclohexylureido)ethyl)phenylthio)-2-methylpropionic acid (GW7647) in a model of acute chemical-induced pain. Moreover, we show that anandamide synergistically interacts with the large-conductance potassium channel (KCa1.1, BK) activator isopimaric acid. These findings reveal a synergistic interaction between the endocannabinoid and PPAR-alpha systems that might be exploited clinically and identify a new pharmacological effect of the BK channel activator isopimaric acid
The Fatty Acid Amide Hydrolase Inhibitor URB597 (Cyclohexylcarbamic Acid 3’-Carbamoylbiphenyl-3-yl Ester) Reduces Neuropathic Pain after Oral Administration in Mice
No full textFatty acid amide hydrolase (FAAH) is an intracellular serine hydrolase that catalyzes the cleavage of bioactive fatty acid ethanolamides, such as the endogenous cannabinoid agonist anandamide. Genetic deletion of the faah gene in mice elevates brain anandamide levels and amplifies the antinociceptive effects of this compound. Likewise, pharmacological blockade of FAAH activity reduces nocifensive behavior in animal models of acute and inflammatory pain. In the present study, we investigated the effects of the selective FAAH inhibitor URB597 (KDS-4103, cyclohexylcarbamic acid 3'-carbamoylbiphenyl-3-yl ester) in the mouse chronic constriction injury (CCI) model of neuropathic pain. Oral administration of URB597 (1-50 mg/kg, once daily) for 4 days produced a dose-dependent reduction in nocifensive responses to thermal and mechanical stimuli, which was prevented by a single i.p. administration of the cannabinoid CB(1) receptor antagonist rimonabant (1 mg/kg). The antihyperalgesic effects of URB597 were accompanied by a reduction in plasma extravasation induced by CCI, which was prevented by rimonabant (1 mg/kg i.p.) and attenuated by the CB(2) antagonist SR144528 (1 mg/kg i.p.). Oral dosing with URB597 achieved significant, albeit transient, drug levels in plasma, inhibited brain FAAH activity, and elevated spinal cord anandamide content. The results provide new evidence for a role of the endocannabinoid system in pain modulation and reinforce the proposed role of FAAH as a target for analgesic drug development
