sr-144528 has been researched along with palmidrol* in 19 studies
1 review(s) available for sr-144528 and palmidrol
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Cannabinoids and pain.
Recent advances have dramatically increased our understanding of cannabinoid pharmacology: the psychoactive constituents of Cannabis sativa have been isolated, synthetic cannabinoids described and an endocannabinoid system identified, together with its component receptors, ligands and their biochemistry. Strong laboratory evidence now underwrites anecdotal claims of cannabinoid analgesia in inflammatory and neuropathic pain. Sites of analgesic action have been identified in brain, spinal cord and the periphery, with the latter two presenting attractive targets for divorcing the analgesic and psychotrophic effects of cannabinoids. Clinical trials are now required, but are hindered by a paucity of cannabinoids of suitable bioavailability and therapeutic ratio. Topics: Amides; Amidohydrolases; Analgesics; Animals; Arachidonic Acids; Benzoxazines; Brain; Camphanes; Cannabinoid Receptor Modulators; Cannabinoids; Cell Membrane; Clinical Trials as Topic; Disease Models, Animal; Drug Design; Drug Interactions; Endocannabinoids; Enzyme Inhibitors; Ethanolamines; Glycerides; Humans; Injections, Spinal; Molecular Structure; Morpholines; Naphthalenes; Pain; Palmitates; Palmitic Acids; Piperidines; Plant Extracts; Polyunsaturated Alkamides; Pyrazoles; Receptors, Cannabinoid; Receptors, Drug; Rimonabant; Spinal Cord | 2001 |
18 other study(ies) available for sr-144528 and palmidrol
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Effects of palmitoylethanolamide on aqueous humor outflow.
To study the effects of palmitoylethanolamide (PEA), a fatty acid ethanolamide, on aqueous humor outflow facility.. The effects of PEA on outflow facility were measured using a porcine anterior segment-perfused organ culture model. The involvements of different receptors in PEA-induced changes were investigated using receptor antagonists and adenovirus delivered small hairpin RNAs (shRNAs). PEA-induced activation of p42/44 mitogen-activated protein kinase (MAPK) was determined by Western blot analysis using an antiphospho p42/44 MAPK antibody.. PEA caused a concentration-dependent enhancement of outflow facility, with the maximum effect (151.08 ± 11.12% of basal outflow facility) achieved at 30 nM of PEA. Pretreatment of anterior segments with 1 μM cannabinoid receptor 2 antagonist SR144528 and 1 μM PPARα antagonist GW6471, but not 1 μM cannabinoid receptor 1 antagonist SR141716A, produced a partial antagonism on the PEA-induced increase of outflow facility. Treatment of TM cells with PEA for 10 minutes activated phosphorylation of p42/44 MAPK, which was blocked by pretreatment with SR1444528 and GW6471, but not SR141716A. Knocking down the expression of either GPR55 or PPARα receptors with specific shRNAs for these receptors partially blocked PEA-induced increase in outflow facility and abolished PEA-induced phosphorylation of p42/44 MAPK. PD98059, an inhibitor of the p42/44 MAPK pathway, blocked both PEA-induced enhancement of aqueous humor outflow facility and PEA-induced phosphorylation of p42/44 MAPK.. Our results demonstrate that PEA increases aqueous humor outflow through the TM pathway and these effects are mediated by GPR55 and PPARα receptors through activation of p42/44 MAPK. Topics: Amides; Animals; Aqueous Humor; Blotting, Western; Camphanes; Dose-Response Relationship, Drug; Endocannabinoids; Enzyme Activation; Ethanolamines; Humans; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Organ Culture Techniques; Oxazoles; Palmitic Acids; Phosphorylation; Piperidines; PPAR alpha; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Receptors, Cannabinoid; Receptors, G-Protein-Coupled; Rimonabant; Swine; Trabecular Meshwork; Tyrosine | 2012 |
Regulation and possible role of endocannabinoids and related mediators in hypercholesterolemic mice with atherosclerosis.
In this study we analysed the possible modulation of endocannabinoids and related molecules during atherosclerosis development in mice. Wild-type and apolipoprotein E knockout (ApoE(-/-)) mice were fed either normal chow or high-cholesterol diet for 8-12 weeks, and tissue endocannabinoid levels were measured by liquid chromatography-mass spectrometry. We found increased levels of 2-AG in aortas and visceral adipose tissue (VAT) of ApoE(-/-) mice fed on high-cholesterol diet for 12 weeks as compared to ApoE(-/-) mice fed on normal chow or wild-type mice fed on cholesterol. No significant difference in 2-AG levels was observed after 8 weeks of diet, and no changes in anandamide levels were found in any group. The levels of the anandamide-related mediators with anti-inflammatory or anti-lipogenic properties, palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), decreased or increased only in VAT or in both tissues, respectively. Endocannabinoid- and OEA/PEA-degrading enzymes were expressed by macrophages within atherosclerotic lesions. In vitro, 2-AG and OEA-induced monocyte migration at 0.3-1microM, which corresponds to the levels observed in aortas. PEA 1microM also induced monocyte migration but counteracted the effect of 2-AG, whereas OEA enhanced it. Enhanced 2-AG levels in advanced atherosclerotic lesions may trigger the inflammatory process by recruiting more inflammatory cells and inducing extracellular matrix degradation via CB(2) receptors, and this possibility was supported in vitro but not in vivo by experiments with the CB(2) antagonist, SR144528. Topics: Amides; Animals; Aorta; Apolipoproteins E; Atherosclerosis; Camphanes; Cannabinoid Receptor Modulators; Cholesterol; Endocannabinoids; Ethanolamines; Hypercholesterolemia; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Oleic Acids; Palmitic Acids; Pyrazoles; Receptor, Cannabinoid, CB2 | 2009 |
A saturated N-acylethanolamine other than N-palmitoyl ethanolamine with anti-inflammatory properties: a neglected story...
N-acylethanolamines, which include the endocannabinoid anandamide and the cannabinoid receptor-inactive saturated compounds N-palmitoyl ethanolamine and N-stearoyl ethanolamine, are ethanolamines of long-chain fatty acids degraded by fatty acid amide hydrolase (FAAH) known to accumulate in degenerating tissues and cells. Whilst much evidence supports a protective anti-inflammatory role of both anandamide and N-palmitoyl ethanolamine, very little information is available with regard to the bioactivity of N-stearoyl ethanolamine. Employing a murine model of passive IgE-induced cutaneous anaphylaxis, we have found that N-stearoyl ethanolamine is endowed with marked anti-inflammatory properties in vivo, supporting the hypothesis that endogenous N-stearoyl ethanolamine is, in analogy to N-palmitoyl ethanolamine, a bioactive signalling lipid capable of downregulating allergic inflammation in the skin. This effect, although mimicked by synthetic, non-selective, CB(1)/CB(2) receptor agonists, such as WIN55, 212-2, was not sensitive to CB(1) or CB(2) receptor antagonists, but rather was fully reversed by capsazepine, a competitive antagonist of the TRPV1 receptor. Moreover, CB(1) receptor antagonists, although effective in antagonising the WIN55,212-2-induced hypothermia, did not reduce the anti-inflammatory effect of WIN55,212-2, whilst CB(2) receptor antagonists, per se inactive, potentiated the WIN55,212-2 effect, suggesting an involvement of non-CB(1)/CB(2) receptors in the anti-inflammatory action of WIN55,212-2. All this, together with demonstration of FAAH as a major regulator of the in vivo concentrations of saturated N-stearoyl ethanolamine, in addition to N-palmitoyl ethanolamine, raise the speculation that pharmacological treatments with saturated N-acylethanolamines such as N-stearoyl ethanolamine, or alternatively FAAH inhibitors able to increase their local concentration, rather than selective CB receptor agonists, might be of promising therapeutic benefit in reducing allergic inflammation in the skin. Topics: Amides; Animals; Anti-Inflammatory Agents; Benzoxazines; Body Temperature; Camphanes; Cannabinoid Receptor Agonists; Cannabinoid Receptor Antagonists; Cannabinoids; Ear Auricle; Edema; Endocannabinoids; Ethanolamines; Fatty Acids; Female; Inflammation; Mice; Mice, Inbred BALB C; Morpholines; Naphthalenes; Palmitic Acids; Passive Cutaneous Anaphylaxis; Piperidines; Pyrazoles; Rimonabant; Stearic Acids; Time Factors | 2008 |
The effect of the palmitoylethanolamide analogue, palmitoylallylamide (L-29) on pain behaviour in rodent models of neuropathy.
Cannabinoids are associated with analgesia in acute and chronic pain states. A spectrum of central cannabinoid (CB(1)) receptor-mediated motor and psychotropic side effects limit their therapeutic potential. Here, we investigate the analgesic effect of the palmitoylethanolamide (PEA) analogue, palmitoylallylamide (L-29), which via inhibition of fatty acid amide hydrolase (FAAH) may potentiate endocannabinoids thereby avoiding psychotropic side effects.. The in vivo analysis of the effect of L-29 on measures of pain behaviour in three rat models of neuropathic pain.. Systemically administered L-29 (10 mg kg(-1)) reduced hypersensitivity to mechanical and thermal stimuli in the partial sciatic nerve injury (PSNI) model of neuropathic pain; and mechanical hypersensitivity in a model of antiretroviral (ddC)-associated hypersensitivity and a model of varicella zoster virus (VZV)-associated hypersensitivity. The effects of L-29 were comparable to those of gabapentin (50 mg kg(-1)). The CB(1) receptor antagonist SR141716a (1 mg kg(-1)) and the CB(2) receptor antagonist SR144528 (1 mg kg(-1)) reduced the effect of L-29 on hypersensitivity in the PSNI and ddC models, but not in the VZV model. The peroxisome proliferator-activated receptor-alpha antagonist, MK-886 (1 mg kg(-1)), partially attenuated the effect of L-29 on hypersensitivity in the PSNI model. L-29 (10 mg kg(-1)) significantly attenuated thigmotactic behaviour in the open field arena without effect on locomotor activity.. L-29 produces analgesia in a range of neuropathic pain models. This presents L-29 as a novel analgesic compound that may target the endogenous cannabinoid system while avoiding undesirable side effects associated with direct cannabinoid receptor activation. Topics: Amides; Amines; Animals; Behavior, Animal; Camphanes; Cyclohexanecarboxylic Acids; Dose-Response Relationship, Drug; Endocannabinoids; Ethanolamines; Gabapentin; gamma-Aminobutyric Acid; Hindlimb; Indoles; Injections, Intraperitoneal; Male; Pain; Pain Measurement; Pain Threshold; Palmitic Acids; Physical Stimulation; Piperidines; PPAR alpha; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Rimonabant; Sciatic Neuropathy; Temperature; Zalcitabine | 2007 |
Cannabinoid receptor agonists inhibit Ca(2+) influx to synaptosomes from rat brain.
We examined the effects of cannabinoid receptor agonists on (45)Ca(2+) uptake in rat brain synaptosomes. A cannabinoid receptor agonist, (R)-(+)-[2,3-dihydro-5-methyl-3-[(4-merpholino)methyl]pyrrolo-[1,2,3-de]-1,4-benzoxazin-6-yl](1-naphthyl)methanone (WIN 55212-2) dose-dependently inhibited (45)Ca(2+) uptake in rat synaptosomes. Only an endogenous cannabinoid receptor agonist, anandamide, dose-dependently inhibited (45)Ca(2+) uptake in rat synaptosomes, but not an endogenous cannabinoid receptor agonist, palmitoylethanolamide. Only a cannabinoid CB1 antagonist, [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamidehydrochloride] (SR 141716A), reversed the inhibitory effect of these WIN 55212-2 and anandamide on (45)Ca(2+) uptake in rat synaptosomes, but not a cannabinoid CB2 receptor antagonist, [N-[(1S)-endo-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)pyrazole-3-carboxamide] (SR 144528). The inhibitory effects of WIN 55212-2 and anandamide on (45)Ca(2+) uptake in rat synaptosomes were reversed by the pretreatment of a voltage-sensitive A-type K(+) channel blocker, dendrotoxin, but no other type of K(+) channel blockers, i.e. iberiotoxin, charybdotoxin or glibenclamide. These findings suggest that cannabinoid receptors inhibit Ca(2+) influx into rat brain nerves via the activation of CB1 receptors and the opening of voltage-sensitive A-type K(+) channels. Topics: Amides; Animals; Benzoxazines; Biological Transport; Brain; Calcium; Camphanes; Cannabinoid Receptor Agonists; Cannabinoid Receptor Antagonists; Dose-Response Relationship, Drug; Elapid Venoms; Endocannabinoids; Ethanolamines; In Vitro Techniques; Male; Morpholines; Naphthalenes; Palmitic Acids; Piperidines; Potassium Channel Blockers; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Rimonabant; Synaptosomes | 2006 |
Non-cannabinoid CB1, non-cannabinoid CB2 antinociceptive effects of several novel compounds in the PPQ stretch test in mice.
The analgesic and anti-hyperalgesic effects of cannabinoid- and vanilloid-like compounds, plus the fatty acid amide hydrolase (FAAH) inhibitor Cyclohexylcarbamic acid 3'-carbamoyl-biphenyl-3-yl ester (URB597), and acetaminophen, were evaluated in the phenyl-p-quinone (PPQ) pain model, using different routes of administration in combination with opioid and cannabinoid receptor antagonists. All the compounds tested produced analgesic effects. Delta(9)-tetrahydrocannabinol (Delta(9)-THC) and (R)-(+)-arachidonyl-1'-hydroxy-2'-propylamide ((R)-methanandamide) were active by three routes of administration: i.p., s.c. and, p.o. Delta(9)-THC produced ED(50)s of 2.2 mg/kg (0.3-15.6) i.p., 9 mg/kg (4.3-18.9) s.c., and 6.4 mg/kg (5.5-7.6) p.o. Similarly, (R)-methanandamide yielded ED(50)s of 2.9 mg/kg (1-8) i.p., 11 mg/kg (7-17) s.c., and 11 mg/kg (0.9-134) p.o. N-vanillyl-arachidonyl-amide (arvanil) was active by two routes, producing ED(50)s of 4.7 mg/kg (3.0-7.4) s.c. and 0.06 mg/kg (0.02-0.2) i.p. Palmitoylethanolamide, URB597, and acetaminophen were active i.p., resulting in ED(50)s of 3.7 mg/kg (3.2-4.2), 22.9 mg/kg (11.1-47.2), and 160 mg/kg (63-405), respectively. None of the cannabinoid or opioid receptor antagonists tested blocked the compounds evaluated, with two exceptions: the antinociceptive effects of Delta(9)-THC and URB597 were completely blocked by SR141716A, a cannabinoid CB(1) receptor antagonist. Western immunoassays performed using three opioid receptor antibodies, a cannabinoid CB(1) receptor antibody and a transient receptor potential vanilloid type 1(TRPV(1)) receptor antibody, yielded no change in receptor protein levels after short-term arvanil, (R)-methanandamide or Delta(9)-THC administration. These data suggest that all the compounds tested, except Delta(9)-THC and URB597, produced analgesia via a non-cannabinoid CB(1), non-cannabinoid CB(2) pain pathway not yet identified. Topics: Acetaminophen; Amides; Analgesics; Animals; Arachidonic Acids; Benzamides; Benzoquinones; Camphanes; Capsaicin; Carbamates; Dose-Response Relationship, Drug; Dronabinol; Endocannabinoids; Ethanolamines; Hyperalgesia; Male; Mesencephalon; Mice; Mice, Inbred ICR; Narcotic Antagonists; Pain; Palmitic Acids; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Receptors, Opioid; Rimonabant; Spinal Cord; TRPV Cation Channels | 2006 |
Endogenous cannabinoid receptor agonists inhibit neurogenic inflammations in guinea pig airways.
Although neurogenic inflammation via the activation of C fibers in the airway must have an important role in the pathogenesis of asthma, their regulatory mechanism remains uncertain.. The pharmacological profiles of endogenous cannabinoid receptor agonists on the activation of C fibers in airway tissues were investigated and the mechanisms how cannabinoids regulate airway inflammatory reactions were clarified.. The effects of endogenous cannabinoid receptor agonists on electrical field stimulation-induced bronchial smooth muscle contraction, capsaicin-induced bronchoconstriction and capsaicin-induced substance P release in guinea pig airway tissues were investigated. The influences of cannabinoid receptor antagonists and K+ channel blockers to the effects of cannabinoid receptor agonists on these respiratory reactions were examined.. Both endogenous cannabinoid receptor agonists, anandamide and palmitoylethanolamide, inhibited electrical field stimulation-induced guinea pig bronchial smooth muscle contraction, but not neurokinin A-induced contraction. A cannabinoid CB2 antagonist, SR 144528, reduced the inhibitory effect of endogenous agonists, but not a cannabinoid CB1 antagonist, SR 141716A. Inhibitory effects of agonists were also reduced by the pretreatment of large conductance Ca2+ -activated K+ channel (maxi-K+ channel) blockers, iberiotoxin and charybdotoxin, but not by other K+ channel blockers, dendrotoxin or glibenclamide. Anandamide and palmitoylethanolamide blocked the capsaicin-induced release of substance P-like immunoreactivity from guinea pig airway tissues. Additionally, intravenous injection of palmitoylethanolamide dose-dependently inhibited capsaicin-induced guinea pig bronchoconstriction, but not neurokinin A-induced reaction. However, anandamide did not reduce capsaicin-induced guinea pig bronchoconstriction.. These findings suggest that endogenous cannabinoid receptor agonists inhibit the activation of C fibers via cannabinoid CB2 receptors and maxi-K+ channels in guinea pig airways. Topics: Amides; Animals; Arachidonic Acids; Bronchi; Bronchoconstriction; Calcium Channel Blockers; Camphanes; Cannabinoid Receptor Agonists; Capsaicin; Electric Stimulation; Endocannabinoids; Ethanolamines; Guinea Pigs; Male; Muscle Contraction; Muscle, Smooth; Nerve Fibers, Unmyelinated; Neurogenic Inflammation; Organ Culture Techniques; Palmitic Acids; Piperidines; Polyunsaturated Alkamides; Potassium Channel Blockers; Pyrazoles; Receptors, Cannabinoid; Rimonabant; Substance P | 2005 |
Contribution of endocannabinoids in the endothelial protection afforded by ischemic preconditioning in the isolated rat heart.
The aim of the present study was to assess the contribution of endogenous cannabinoids in the protective effect of ischemic preconditioning on the endothelial function in coronary arteries of the rat. Isolated rat hearts were exposed to a 30-min low flow ischemia (1 ml/min) followed by 20-min reperfusion, after which the response to the endothelium-dependent vasodilator, serotonine (5-HT), was compared with that of the endothelium-independent vasodilator, sodium nitroprusside (SNP). In untreated hearts, ischemia-reperfusion diminished selectively 5-HT-induced vasodilatation, compared with time-matched sham hearts, the vasodilatation to SNP being unaffected. A 5-min zero-flow preconditioning ischemia in untreated hearts preserved the vasodilatation produced by 5-HT. Blockade of either CB(1)-receptors with SR141716A or CB(2)-receptors with SR144528 abolished the protective effect of preconditioning on the 5-HT vasodilatation. Perfusion with either palmitoylethanolamide or 2-arachidonoylglycerol 15 min before and throughout the ischemia mimicked preconditioning inasmuch as it protected the endothelium in a similar fashion. This protection was blocked by SR144528 in both cases, whereas SR141716A only blocked the effect of PEA. The presence of CB(1) and CB(2)-receptors in isolated rat hearts was confirmed by Western blots. In conclusion, the data suggest that endogenous cannabinoids contribute to the endothelial protective effect of ischemic preconditioning in rat coronary arteries. Topics: Amides; Animals; Arachidonic Acids; Blotting, Western; Camphanes; Cannabinoid Receptor Modulators; Cannabinoids; Coronary Vessels; Endocannabinoids; Endothelium, Vascular; Ethanolamines; Fatty Acids, Unsaturated; Glycerides; Heart; Ischemic Preconditioning, Myocardial; Male; Myocardium; Nitroprusside; Palmitic Acids; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB2; Receptors, Cannabinoid; Receptors, Drug; Rimonabant; Serotonin; Vasodilation | 2003 |
Endocannabinoids protect the rat isolated heart against ischaemia.
1 The purpose of this study was to determine whether endocannabinoids can protect the heart against ischaemia and reperfusion. 2 Rat isolated hearts were exposed to low-flow ischaemia (0.5-0.6 ml min(-1)) and reperfusion. Functional recovery as well as CK and LDH overflow into the coronary effluent were monitored. Infarct size was determined at the end of the experiments. Phosphorylation levels of p38, ERK1/2, and JNK/SAPK kinases were measured by Western blots. 3 None of the untreated hearts recovered from ischaemia during the reperfusion period. Perfusion with either 300 nM palmitoylethanolamide (PEA) or 300 nM 2-arachidonoylglycerol (2-AG), but not anandamide (up to 1 micro M), 15 min before and throughout the ischaemic period, improved myocardial recovery and decreased the levels of coronary CK and LDH. PEA and 2-AG also reduced infarct size. 4 The CB(2)-receptor antagonist, SR144528, blocked completely the cardioprotective effect of both PEA and 2-AG, whereas the CB(1)-receptor antagonist, SR141716A, blocked partially the effect of 2-AG only. In contrast, both ACEA and JWH015, two selective agonists for CB(1)- and CB(2)- receptors, respectively, reduced infarct size at a concentration of 50 nM. 5 PEA enhanced the phosphorylation level of p38 MAP kinase during ischaemia. PEA perfusion doubled the baseline phosphorylation level of ERK1/2, and enhanced its increase upon reperfusion. The cardioprotective effect of PEA was completely blocked by the p38 MAP kinase inhibitor, SB203580, and significantly reduced by the ERK1/2 inhibitor, PD98059, and the PKC inhibitor, chelerythrine. 6 In conclusion, endocannabinoids exert a strong cardioprotective effect in a rat model of ischaemia-reperfusion that is mediated mainly through CB(2)-receptors, and involves p38, ERK1/2, as well as PKC activation. Topics: Amides; Animals; Arachidonic Acids; Biomarkers; Blotting, Western; Camphanes; Cannabinoid Receptor Modulators; Endocannabinoids; Ethanolamines; Glycerides; Heart; Imidazoles; L-Lactate Dehydrogenase; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; p38 Mitogen-Activated Protein Kinases; Palmitic Acids; Piperidines; Protein Kinase C; Pyrazoles; Pyridines; Rats; Rats, Sprague-Dawley; Rimonabant; Signal Transduction | 2003 |
Inhibitory effect of anandamide on resiniferatoxin-induced sensory neuropeptide release in vivo and neuropathic hyperalgesia in the rat.
Anandamide (AEA) is an endogenous cannabinoid ligand acting predominantly on the cannabinoid 1 (CB(1)) receptor, but it is also an agonist on the capsaicin VR(1)/TRPV(1) receptor. In the present study we examined the effects of AEA and the naturally occurring cannabinoid 2 (CB(2)) receptor agonist palmitylethanolamide (PEA) on basal and resiniferatoxin (RTX)-induced release of calcitonin gene-related peptide (CGRP) and somatostatin in vivo. Since these sensory neuropeptides play important role in the development of neuropathic hyperalgesia, the effect of AEA and PEA was also examined on mechanonociceptive threshold changes after partial ligation of the sciatic nerve. Neither AEA nor PEA affected basal plasma peptide concentrations, but both of them inhibited RTX-induced release. The inhibitory effect of AEA was prevented by the CB(1) receptor antagonist SR141716A. AEA abolished and PEA significantly decreased neuropathic mechanical hyperalgesia 7 days after unilateral sciatic nerve ligation, which was antagonized by SR141716A and the CB(2) receptor antagonist SR144528, respectively. Both SR141716A and SR144528 increased hyperalgesia, indicating that endogenous cannabinoids acting on CB(1) and peripheral CB(2)-like receptors play substantial role in neuropathic conditions to diminish hyperalgesia. AEA and PEA exert inhibitory effect on mechanonociceptive hyperalgesia and sensory neuropeptide release in vivo suggesting their potential therapeutical use to treat chronic neuropathic pain. Topics: Amides; Animals; Arachidonic Acids; Calcitonin Gene-Related Peptide; Camphanes; Cannabinoids; Diterpenes; Dose-Response Relationship, Drug; Endocannabinoids; Ethanolamines; Hyperalgesia; Injections, Intravenous; Male; Neuropeptides; Neurotoxins; Palmitic Acids; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats; Rats, Wistar; Rimonabant; Sciatic Nerve; Sciatic Neuropathy; Somatostatin | 2003 |
Antiinflammatory action of endocannabinoid palmitoylethanolamide and the synthetic cannabinoid nabilone in a model of acute inflammation in the rat.
1. The antiinflammatory activity of synthetic cannabinoid nabilone in the rat model of carrageenan-induced acute hindpaw inflammation was compared with that of the endocannabinoid palmitoylethanolamide and the nonsteroidal antiinflammatory drug indomethacin. 2. Preliminary experiments in rats used a tetrad of behavioural tests, specific for tetrahydrocannabinol-type activity in the CNS. These showed that the oral dose of nabilone 2.5 mg kg(-1) had no cannabinoid psychoactivity. 3. Intraplantar injection of carrageenan (1% w v(-1)) elicited a time-dependent increase in paw volume and thermal hyperalgesia. 4. Nabilone (0.75, 1.5, 2.5 mg kg(-1), p.o.), given 1 h before carrageenan, reduced the development of oedema and the associated hyperalgesia in a dose-related manner. Nabilone 2.5 mg kg(-1), palmitoylethanolamide 10 mg kg(-1) and indomethacin 5 mg kg(-1), given p.o. 1 h before carrageenan, also reduced the inflammatory parameters in a time-dependent manner. 5. The selective CB(2) cannabinoid receptor antagonist [N-[(1S)-endo-1,3,3-trimethyl bicyclo [2.2.1]heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)pyrazole-3 carboxamide] (SR 144528), 3 mg kg(-1) p.o. 1 h before nabilone and palmitoylethanolamide, prevented the anti-oedema and antihyperalgesic effects of the two cannabinoid agonists 3 h after carrageenan. 6. Our findings show the antiinflammatory effect of nabilone and confirm that of palmitoylethanolamide indicating that these actions are mediated by an uncharacterized CB(2)-like cannabinoid receptor. Topics: Acute Disease; Amides; Animals; Anti-Inflammatory Agents, Non-Steroidal; Camphanes; Cannabinoid Receptor Modulators; Cannabinoids; Carrageenan; Disease Models, Animal; Dronabinol; Edema; Endocannabinoids; Ethanolamines; Hindlimb; Hyperalgesia; Indomethacin; Inflammation; Male; Motor Activity; Palmitic Acids; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB2; Receptors, Cannabinoid; Receptors, Drug | 2002 |
Attenuation of nerve growth factor-induced visceral hyperalgesia via cannabinoid CB(1) and CB(2)-like receptors.
Cannabinoids have previously been shown to possess analgesic properties in a model of visceral hyperalgesia in which the neurotrophin, nerve growth factor (NGF), plays a pivotal role. The purpose of this study was to investigate the antihyperalgesic effects of two cannabinoids in NGF-evoked visceral hyperalgesia in order to test the hypothesis that endocannabinoids may modulate the NGF-driven elements of inflammatory hyperalgesia. Intra-vesical installation of NGF replicates many features of visceral hyperalgesia, including a bladder hyper-reflexia and increased expression of the immediate early gene c fos in the spinal cord. We investigated the action of anandamide and palmitoylethanolamide (PEA) on these parameters. Both anandamide (at a dose of 25 mg/kg) and PEA (at a dose of 2.5 mg/kg) attenuated the bladder hyper-reflexia induced by intra-vesical NGF. The use of cannabinoid CB1 receptor (SR141617A) and CB2 receptor (SR144528) antagonists suggested that the effect of anandamide was mediated by both CB1 and CB2 cannabinoid receptors whilst the action of PEA was via CB2 (or CB2-like) receptors only. Furthermore, anandamide (25 mg/kg) and PEA (2.5 mg/kg) reduced intra-vesical NGF-evoked spinal cord Fos expression at the appropriate level (L6) by 35 and 43%, respectively. However, neither CB1 nor CB2 receptor antagonists altered the action of anandamide. PEA-induced reduction in Fos expression was abrogated by SR144528. These data add to the growing evidence of a therapeutic potential for cannabinoids, and support the hypothesis that the endogenous cannabinoid system modulates the NGF-mediated components of inflammatory processes. Topics: Amides; Animals; Arachidonic Acids; Camphanes; Cannabinoid Receptor Modulators; Cannabinoids; Endocannabinoids; Ethanolamines; Female; Hyperalgesia; Nerve Growth Factor; Palmitic Acids; Piperidines; Polyunsaturated Alkamides; Proto-Oncogene Proteins c-fos; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB2; Receptors, Cannabinoid; Receptors, Drug; Reflex, Abnormal; Rimonabant; Spinal Cord; Urinary Bladder; Visceral Afferents | 2002 |
Antinociceptive activity of the endogenous fatty acid amide, palmitylethanolamide.
The endogenous fatty acid ethanolamide, palmitylethanolamide, alleviated, in a dose-dependent manner, pain behaviors elicited in mice by injections of formalin (5%, intraplantar), acetic acid (0.6%, 0.5 ml per animal, intraperitoneal, i.p.), kaolin (2.5 mg per animal, i.p.), and magnesium sulfate (120 mg per kg, i.p.). The antinociceptive effects of palmitylethanolamide were prevented by the cannabinoid CB2 receptor antagonist SR144528 [N-([1s]-endo-1.3.3-trimethylbicyclo[2.3.1]heptan-2-yl)-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide], not by the cannabinoid CB1 receptor antagonist SR141716A [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide x HCl]. By contrast, palmitylethanolamide had no effect on capsaicin-evoked pain behavior or thermal nociception. The endogenous cannabinoid, anandamide (arachidonylethanolamide), alleviated nociception in all tests (formalin, acetic acid, kaolin, magnesium sulfate, capsaicin and hot plate). These effects were prevented by the cannabinoid CB1 receptor antagonist SR141716A, not the cannabinoid CB2 receptor antagonist SR141716A. Additional fatty acid ethanolamides (oleylethanolamide, myristylethanolamide, palmitoleylethanolamide, palmitelaidylethanolamide) had little or no effect on formalin-evoked pain behavior, and were not investigated in other pain models. These results support the hypothesis that endogenous palmitylethanolamide participates in the intrinsic control of pain initiation. They also suggest that the putative receptor site activated by palmitylethanolamide may provide a novel target for peripherally acting analgesic drugs. Topics: Amides; Analgesics; Analysis of Variance; Animals; Arachidonic Acids; Calcium Channel Blockers; Camphanes; Dose-Response Relationship, Drug; Drug Synergism; Endocannabinoids; Ethanolamines; Formaldehyde; Male; Mice; Pain; Palmitic Acids; Polyunsaturated Alkamides; Pyrazoles | 2001 |
Palmitoylethanolamide inhibits the expression of fatty acid amide hydrolase and enhances the anti-proliferative effect of anandamide in human breast cancer cells.
Palmitoylethanolamide (PEA) has been shown to act in synergy with anandamide (arachidonoylethanolamide; AEA), an endogenous agonist of cannabinoid receptor type 1 (CB(1)). This synergistic effect was reduced by the CB(2) cannabinoid receptor antagonist SR144528, although PEA does not activate either CB(1) or CB(2) receptors. Here we show that PEA potently enhances the anti-proliferative effects of AEA on human breast cancer cells (HBCCs), in part by inhibiting the expression of fatty acid amide hydrolase (FAAH), the major enzyme catalysing AEA degradation. PEA (1-10 microM) enhanced in a dose-related manner the inhibitory effect of AEA on both basal and nerve growth factor (NGF)-induced HBCC proliferation, without inducing any cytostatic effect by itself. PEA (5 microM) decreased the IC(50) values for AEA inhibitory effects by 3-6-fold. This effect was not blocked by the CB(2) receptor antagonist SR144528, and was not mimicked by a selective agonist of CB(2) receptors. PEA enhanced AEA-evoked inhibition of the expression of NGF Trk receptors, which underlies the anti-proliferative effect of the endocannabinoid on NGF-stimulated MCF-7 cells. The effect of PEA was due in part to inhibition of AEA degradation, since treatment of MCF-7 cells with 5 microM PEA caused a approximately 30-40% down-regulation of FAAH expression and activity. However, PEA also enhanced the cytostatic effect of the cannabinoid receptor agonist HU-210, although less potently than with AEA. PEA did not modify the affinity of ligands for CB(1) or CB(2) receptors, and neither did it alter the CB(1)/CB(2)-mediated inhibitory effect of AEA on adenylate cyclase type V, nor the expression of CB(1) and CB(2) receptors in MCF-7 cells. We suggest that long-term PEA treatment of cells may positively affect the pharmacological activity of AEA, in part by inhibiting FAAH expression. Topics: Amides; Amidohydrolases; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Arachidonic Acids; Blotting, Western; Breast Neoplasms; Camphanes; Cannabinoid Receptor Modulators; Cannabinoids; Capsaicin; Cell Division; Colforsin; COS Cells; Cyclic AMP; Dose-Response Relationship, Drug; Endocannabinoids; Ethanolamines; Glycerides; Humans; Hydrolysis; Inhibitory Concentration 50; Palmitic Acids; Polyunsaturated Alkamides; Protein Binding; Pyrazoles; Receptors, Cannabinoid; Receptors, Drug; Reverse Transcriptase Polymerase Chain Reaction; Transfection; Tumor Cells, Cultured | 2001 |
Inhibitory effect of palmitoylethanolamide on gastrointestinal motility in mice.
1. We have studied the effect of palmitoylethanolamide (PEA, 2.5 - 30 mg kg(-1), i.p.) on upper gastrointestinal transit in control mice and in mice with chronic intestinal inflammation induced by croton oil. 2. PEA significantly and dose-dependently decreased intestinal transit. The inhibitory effect of PEA (10 mg kg(-1)) was not modified by the cannabinoid CB(1) receptor antagonist SR141716A (0.3 mg kg(-1), i.p.), the cannabinoid CB(2) receptor antagonist SR144528 (1 mg kg(-1), i.p.), N(G)-nitro-L-arginine methyl ester (L-NAME, 25 mg kg(-1), i.p.), yohimbine (1 mg kg(-1), i.p.), naloxone (2 mg kg(-1), i.p.) or hexamethonium (1 mg kg(-1), i.p.). 3. PEA levels were significantly decreased in the small intestine of croton oil-treated mice. In these animals, PEA also inhibited motility and this effect was not counteracted by SR141716A (0.3 mg kg(-1)), or SR144528 (1 mg kg(-1)). 4. Pre-treatment of mice with the amidase inhibitor phenylmethyl sulphonil fluoride (PMSF, 30 mg kg(-1), i.p.) did not modify the inhibitory effect of PEA, either in control or in mice with inflammation. 5. It is concluded that PEA inhibits intestinal motility with a peripheral mechanism independent from cannabinoid receptor activation. The decreased levels of PEA in croton oil-treated might contribute, at least in part, to the exaggerated transit observed during chronic intestinal inflammation. Topics: Adrenergic alpha-Antagonists; Amides; Animals; Anti-Inflammatory Agents, Non-Steroidal; Camphanes; Croton Oil; Dose-Response Relationship, Drug; Endocannabinoids; Enzyme Inhibitors; Ethanolamines; Gastrointestinal Motility; Gastrointestinal Transit; Hexamethonium; Inflammation; Intestine, Small; Male; Mice; Mice, Inbred ICR; Naloxone; NG-Nitroarginine Methyl Ester; Nicotinic Antagonists; Nitric Oxide Synthase; Palmitic Acids; Phenylmethylsulfonyl Fluoride; Piperidines; Pyrazoles; Receptors, Cannabinoid; Receptors, Drug; Rimonabant; Yohimbine | 2001 |
Evidence that 2-arachidonoylglycerol but not N-palmitoylethanolamine or anandamide is the physiological ligand for the cannabinoid CB2 receptor. Comparison of the agonistic activities of various cannabinoid receptor ligands in HL-60 cells.
We examined the effect of 2-arachidonoylglycerol, an endogenous cannabinoid receptor ligand, on the intracellular free Ca(2+) concentrations in HL-60 cells that express the cannabinoid CB2 receptor. We found that 2-arachidonoylglycerol induces a rapid transient increase in intracellular free Ca(2+) concentrations in HL-60 cells. The response was affected by neither cyclooxygenase inhibitors nor lipoxygenase inhibitors, suggesting that arachidonic acid metabolites are not involved. Consistent with this notion, free arachidonic acid was devoid of any agonistic activity. Importantly, the Ca(2+) transient induced by 2-arachidonoylglycerol was blocked by pretreatment of the cells with SR144528, a CB2 receptor-specific antagonist, but not with SR141716A, a CB1 receptor-specific antagonist, indicating the involvement of the CB2 receptor but not the CB1 receptor in this cellular response. G(i) or G(o) is also assumed to be involved, because pertussis toxin treatment of the cells abolished the response. We further examined the structure-activity relationship. We found that 2-arachidonoylglycerol is the most potent compound among a number of naturally occurring cannabimimetic molecules. Interestingly, anandamide and N-palmitoylethanolamine, other putative endogenous ligands, were found to be a weak partial agonist and an inactive ligand, respectively. These results strongly suggest that the CB2 receptor is originally a 2-arachidonoylglycerol receptor, and 2-arachidonoylglycerol is the intrinsic natural ligand for the CB2 receptor that is abundant in the immune system. Topics: Amides; Arachidonic Acids; Calcium Signaling; Camphanes; Cannabinoids; Cyclohexanols; Cyclooxygenase Inhibitors; Drug Interactions; Endocannabinoids; Ethanolamines; Glycerides; HL-60 Cells; Humans; Ligands; Lipoxygenase Inhibitors; Molecular Mimicry; Palmitic Acids; Pertussis Toxin; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Receptors, Cannabinoid; Receptors, Drug; Rimonabant; RNA, Messenger; Structure-Activity Relationship; Virulence Factors, Bordetella | 2000 |
Inhibition of nitric oxide production in RAW264.7 macrophages by cannabinoids and palmitoylethanolamide.
We have investigated the inhibition of lipopolysaccharide stimulated nitric oxide production in RAW264.7 macrophages by the cannabinoids and the putative cannabinoid CB(2)-like receptor ligand, palmitoylethanolamide. (R)-(+)-[2, 3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo-[1,2,3-de]-1, 4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate ((+)-WIN55212) and, to a lesser extent (-)-cis-3-[2-hydroxy-4-(1, 1-dimethylheptyl)phenyl]-trans-4-(3-hydroxy-propyl)cyclohexan++ +-1-ol (CP55940), significantly inhibited lipopolysaccharide stimulated nitric oxide production. The level of inhibition was found to be dependent on the concentration of lipopolysaccharide used to induce nitric oxide production. Palmitoylethanolamide significantly inhibited nitric oxide production induced by lipopolysaccharide. The inhibition of nitric oxide production by (+)-WIN55212 but not palmitoylethanolamide was significantly attenuated in the presence of the cannabinoid CB(2) receptor antagonist, N-[(1S)-endo-1,3, 3-trimethyl bicyclo [2.2.1] heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazo le- 3-carboxamide (SR144528). (+)-WIN55212 produced a pertussis toxin-sensitive parallel rightward shift in the log concentration-response curve for lipopolysaccharide, causing a fivefold increase in the EC(50) value for lipopolysaccharide with no change in the E(max) value. (-)-WIN55212 had no effect on the log concentration-response curve for lipopolysaccharide. Palmitoylethanolamide did not produce a rightward shift in the lipopolysaccharide concentration-response curve. However, it did produce a pertussis toxin-insensitive reduction in the E(max) value. The results suggest that the inhibition of lipopolysaccharide mediated nitric oxide release by (+)-WIN55212 in murine macrophages is mediated by cannabinoid CB(2) receptors. In contrast, the inhibition by palmitoylethanolamide does not appear to be mediated by cannabinoid receptors. Topics: Amides; Animals; Benzoxazines; Camphanes; Cannabinoids; Cell Line; CHO Cells; Colforsin; Cricetinae; Cyclic AMP; Dose-Response Relationship, Drug; Endocannabinoids; Ethanolamines; Humans; Lipopolysaccharides; Macrophages; Morpholines; Naphthalenes; Nitric Oxide; Palmitic Acids; Pertussis Toxin; Piperidines; Pyrazoles; Receptors, Cannabinoid; Receptors, Drug; Rimonabant; Stereoisomerism; Time Factors; Virulence Factors, Bordetella | 2000 |
Watching the pot boil.
Topics: Amides; Analgesics; Animals; Arachidonic Acids; Camphanes; Cannabinoids; Endocannabinoids; Ethanolamines; Mice; Palmitic Acids; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Receptors, Cannabinoid; Receptors, Drug; Rimonabant | 1998 |