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A Calignano

Publications and source records attributed to A Calignano.

At least 19 recordsLinked to original sources
PubMed2006

Modulation of neuropathic and inflammatory pain by the endocannabinoid transport inhibitor AM404 [N-(4-hydroxyphenyl)-eicosa-5,8,11,14-tetraenamide].

The endocannabinoid system may serve important functions in the central and peripheral regulation of pain. In the present study, we investigated the effects of the endocannabinoid transport inhibitor AM404 [N-(4-hydroxyphenyl)-eicosa-5,8,11,14-tetraenamide] on rodent models of acute and persistent nociception (intraplantar formalin injection in the mouse), neuropathic pain (sciatic nerve ligation in the rat), and inflammatory pain (complete Freund's adjuvant injection in the rat). In the formalin model, administration of AM404 (1-10 mg/kg i.p.) elicited dose-dependent antinociceptive effects, which were prevented by the CB(1) cannabinoid receptor antagonist rimonabant (SR141716A; 1 mg/kg i.p.) but not by the CB2 antagonist SR144528 (1 mg/kg i.p.) or the vanilloid antagonist capsazepine (30 mg/kg i.p.). Comparable effects were observed with UCM707 [N-(3-furylmethyl)-eicosa-5,8,11,14-tetraenamide], another anandamide transport inhibitor. In both the chronic constriction injury and complete Freund's adjuvant model, daily treatment with AM404 (1-10 mg/kg s.c.) for 14 days produced a dose-dependent reduction in nocifensive responses to thermal and mechanical stimuli, which was prevented by a single administration of rimonabant (1 mg/kg i.p.) and was accompanied by decreased expression of cyclooxygenase-2 and inducible nitric-oxide synthase in the sciatic nerve. The results provide new evidence for a role of the endocannabinoid system in pain modulation and point to anandamide transport as a potential target for analgesic drug development.

Animals↗
PubMed2001

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.

Amides↗
PubMed2001

Substance P and its transglutaminase-synthesized spermine derivative elicit yawning behavior via nitric oxide in rats.

Previously, we showed that intranigrostriatal injection of substance P (SP) cause behavioral changes in rats. Those effects, such as locomotion and food intake, resulted related to catecholamines release modulated by nitric oxide [18]. Here we report that intranigrostriatal injection of SP elicited yawning in rats. Moreover, since in previous studies we demonstrated that transglutaminase-synthesized gamma-(glutamyl5)spermine derivative of SP (Spm-SP) could be a useful tool in differentiating NK1 receptors [5,19,26], we reports the effects of injecting the selective septide-sensitive NK1 receptor agonist Spm-SP into the nigrostriatal region of the rat brain on yawning. The administration of L-N(omega)-nitroarginine methyl ester, a NO-synthase inhibitor, stereospecifically reduced in a dose related manner both SP and Spm-SP-induced yawning. In contrast, L-arginine pretreatment prevented the effect of NO-synthase inhibitor. Moreover, the NK1 antagonist RP,67580 blocked yawning behavior induced by both SP and Spm-SP, whereas the pretreatment with systemic reserpine determined its increase. The administration of NO-synthase inhibitor resulted ineffective in reducing SP and Spm-SP-induced yawns in reserpinized rats. Finally, yawns elicited by SP or Spm-SP were blocked when rats were treated with scopolamine but not with methylscopolamine. These results indicate that yawning induced in rats by SP injection is dependent upon endogenous dopamine levels in brain nigrostriatal area. Moreover, we demonstrate, by using Spm-SP, that septide-sensitive NK1 receptor are specifically involved in yawning behavior.

Animals↗
PubMed2000

Bidirectional control of airway responsiveness by endogenous cannabinoids.

Smoking marijuana or administration of its main active constituent, delta9-tetrahydrocannabinol (delta9-THC), may exert potent dilating effects on human airways. But the physiological significance of this observation and its potential therapeutic value are obscured by the fact that some asthmatic patients respond to these compounds with a paradoxical bronchospasm. The mechanisms underlying these contrasting responses remain unresolved. Here we show that the endogenous cannabinoid anandamide exerts dual effects on bronchial responsiveness in rodents: it strongly inhibits bronchospasm and cough evoked by the chemical irritant, capsaicin, but causes bronchospasm when the constricting tone exerted by the vagus nerve is removed. Both effects are mediated through peripheral CB1 cannabinoid receptors found on axon terminals of airway nerves. Biochemical analyses indicate that anandamide is synthesized in lung tissue on calcium-ion stimulation, suggesting that locally generated anandamide participates in the intrinsic control of airway responsiveness. In support of this conclusion, the CB1 antagonist SR141716A enhances capsaicin-evoked bronchospasm and cough. Our results may account for the contrasting bronchial actions of cannabis-like drugs in humans, and provide a framework for the development of more selective cannabinoid-based agents for the treatment of respiratory pathologies.

Animals↗
PubMed2000

Reversal of dopamine D(2) receptor responses by an anandamide transport inhibitor.

We characterized the pharmacological properties of the anandamide transport inhibitor N-(4-hydroxyphenyl)-arachidonamide (AM404) in rats and investigated the effects of this drug on behavioral responses associated with activation of dopamine D(2) family receptors. Rat brain slices accumulated [(3)H]anandamide via a high-affinity transport mechanism that was blocked by AM404. When administered alone in vivo, AM404 caused a mild and slow-developing hypokinesia that was significant 60 min after intracerebroventricular injection of the drug and was reversed by the CB1 cannabinoid receptor antagonist SR141716A. AM404 produced no significant catalepsy or analgesia, two typical effects of direct-acting cannabinoid agonists. However, AM404 prevented the stereotypic yawning produced by systemic administration of a low dose of apomorphine, an effect that was dose-dependent and blocked by SR141716A. Furthermore, AM404 reduced the stimulation of motor behaviors elicited by the selective D(2) family receptor agonist quinpirole. Finally, AM404 reduced hyperactivity in juvenile spontaneously hypertensive rats, a putative model of attention deficit hyperactivity disorder. The results support a primary role of the endocannabinoid system in the regulation of psychomotor activity and point to anandamide transport as a potential target for neuropsychiatric medicines.

Animals↗
PubMed2000

The endocannabinoid system as a target for therapeutic drugs.

Cannabinoid receptors, the molecular targets of the cannabis constituent Delta9-tetrahydrocannabinol, are present throughout the body and are normally bound by a family of endogenous lipids - the endocannabinoids. Release of endocannabinoids is stimulated in a receptor-dependent manner by neurotransmitters and requires the enzymatic cleavage of phospholipid precursors present in the membranes of neurons and other cells. Once released, the endocannabinoids activate cannabinoid receptors on nearby cells and are rapidly inactivated by transport and subsequent enzymatic hydrolysis. These compounds might act near their site of synthesis to serve a variety of regulatory functions, some of which are now beginning to be understood. Recent advances in the biochemistry and pharmacology of the endocannabinoid system in relation to the opportunities that this system offers for the development of novel therapeutic agents will be discussed.

Animals↗
PubMed2000

Anti-very late antigen-1 monoclonal antibody modulates the development of secondary lesion and T-cell response in experimental arthritis.

Rats injected in the hind paw with a mixture of Mycobacterium butirricum emulsified in mineral oil (FA) developed a severe polyarthritis that shared some immunological features with human rheumatoid arthritis. After this local administration, rats developed a secondary lesion (edema) in the contralateral paw, which is a hallmark of immune system activation. In vivo intravenous treatment with a monoclonal anti-very late antigen (VLA)-1 antibody (HA31/8) significantly reduced the edema formation in the contralateral paw. T cells isolated from contralateral paw draining lymph nodes of FA rats treated with HA31/8 showed a reduced cell proliferation in vitro, after stimulation with concanavalin A. Furthermore FACS analysis showed that the reduction in proliferation was concomitant to a reduction in the number of T cells positive to surface IL-2 receptor expression. Our data indicate that after in vivo treatment with a monoclonal anti-very late antigen-1 antibody, there is a beneficial effect on the development of the secondary lesion, which correlates to the reduced ability of T cells to proliferate in vitro as well as to a reduced surface expression of IL-2 receptor. The association of this antibody to other drugs interfering at other levels in rheumatoid arthritis may open a new therapeutic window.

Animals↗
PubMed2000

NO-naproxen modulates inflammation, nociception and downregulates T cell response in rat Freund's adjuvant arthritis.

1. Anti-inflammatory non steroidal drugs releasing NO (NO-NSAIDs) are a new class of anti-inflammatory drugs to which has been added an NO-releasing moiety. These compounds have been shown to retain the anti-inflammatory, analgesic and antipyretic activity of the parent compound but to be devoid of gastrointestinal (GI) toxicity. 2. Freund's adjuvant (FA) arthritis was induced in rats by a single intraplantar injection into the right hindpaw of 100 microl of mycobacterium butirricum (6 mg ml(-1)). The effect of equimolar doses of naproxen (1, 3 and 10 mg kg(-1)) and NO-naproxen (1.5, 4.5 and 16 mg kg(-1)) was evaluated using two dosage regimen protocols: (i) preventive, starting oral administration of the drugs at the time of induction of arthritis and for the following 21 days (day 1 - 21); (ii) therapeutic, starting oral administration of the drugs 7 days after adjuvant injection and for the following 14 days (day 7 - 21). 3. Hindpaw swelling (days 3, 7, 11, 14, 17, 21) and nociception (days 15 and 21) were measured. On day 22 rats were sacrificed, draining lymph nodes were removed and T cells isolated. In vitro proliferation of T cells following stimulation with concanavalin A (0.5 - 5 microg ml(-1)) was measured using a tritiated thymidine incorporation assay. IL-2 receptor expression on T cells was measured by FACS analysis. 4. Naproxen and NO-naproxen showed similar activity in reducing oedema formation in the non-injected (controlateral) hindpaw. Both drugs showed anti-nociceptive effect. NO-naproxen was anti-nociceptive at a dose of 4.5 mg kg(-1) while naproxen showed the same extent of inhibition only at a dose of 10 mg kg(-1). 5. T cells were isolated and characterized by FACS analysis. Stimulation of isolated T cells with concanavallin A in vitro caused a significant increase in thymidine uptake. NO-naproxen at a dose of 4.5 mg kg(-1) inhibited T cell proliferation to the same extent as 10 mg kg(-1) of naproxen. 6. Inhibition of T cell proliferation was well correlated with reduced IL-2 receptor expression on T cells. In addition, NO-naproxen reduced both IL-1beta and TNFalpha plasma levels whilst naproxen reduced IL-1beta levels only. 7. In conclusion, both naproxen and NO-naproxen reduce inflammation and nociception associated with arthritis. In addition NO-naproxen interferes to a larger extent with cellular mechanism involved in T cell activation in rat adjuvant arthritis indicating that introduction of the NO moiety in the naproxen structure increases the effect at the level of the immune system.

Animals↗
PubMed2000

Effect of spironolactone and its metabolites on contractile property of isolated rat aorta rings.

Spironolactone and its active metabolites canrenone and potassium canrenoate are normally used as antihypertensive drugs. Although they are classified as antagonists of aldosterone, their mechanism of action cannot be ascribed solely to the regulation of ion transport in the distal tubule of nephrons. Here we have evaluated the effects of spironolactone, canrenone, and potassium canrenoate on contractile properties of isolated rat aorta rings. Spironolactone (1-300 microM), canrenone (1-300 microM), and potassium canrenoate (0.01-10 mM), in a concentration-dependent manner, relaxed rat aorta rings precontracted with phenylephrine (1 microM) or KCl (40 mM). These relaxant effects were not affected by prior treatment with either aldosterone (100 microM), glibenclamide (10 microM), or tetraethylammonium (10 mM), excluding the possibility that these drugs can be involved in either the nongenomic effect of aldosterone or on activation of potassium channels. Spironolactone and canrenone at concentrations of 30 and 100 microM, but not at 10 microM, and potassium canrenoate at concentrations of 0.3 and 1 mM, but not at 0.1 mM, significantly inhibited the phenylephrine (0.001-3 microM) concentration-response curve. Conversely, all tested concentrations of spironolactone (10, 30, and 100 microM), canrenone (10, 30, and 100 microM), and potassium canrenoate (0.1, 0.3, and 1 mM) significantly inhibited the concentration-response curve induced by cumulative concentrations of KCI (10-80 mM). Because both phenylephrine- and KCl-induced contractions imply an intracellular Ca2+ influx, we suggest that these drugs could act through an inhibition of voltage-dependent Ca2+ channels.

Animals↗
PubMed1999

Synthesis and structure-activity relationships of 2-(substituted phenyl)-3-[3-(N,N-dimethylamino)propyl]-1,3-thiazolidin-4-ones acting as H1-histamine antagonists.

2-(Substituted-phenyl)-3-[3-(N,N-dimethylamino)propyl]-1,3-thiazolidi n-4- ones (1-15) showed dependence of the potency of the H1-histamine antagonism on the m- and p-substituents suggesting that the aromatic moiety binds the receptor by a strong pi-interaction. Electron-withdrawing substituents decrease the potency while the electron-donating alkyl substituents, enhancing the aryl HOMO energy, increase the antihistamine activity. The m-substituents with the capability to form hydrogen bonds, seems to share an extra-interaction with hydrogen accepting or donating groups of the histamine receptor and exhibits very high potency.

Histamine H1 Antagonists↗
PubMed1998

Control of pain initiation by endogenous cannabinoids.

The potent analgesic effects of cannabis-like drugs and the presence of CB1-type cannabinoid receptors in pain-processing areas of the brain and spinal cord indicate that endogenous cannabinoids such as anandamide may contribute to the control of pain transmission within the central nervous system (CNS). Here we show that anandamide attenuates the pain behaviour produced by chemical damage to cutaneous tissue by interacting with CB1-like cannabinoid receptors located outside the CNS. Palmitylethanolamide (PEA), which is released together with anandamide from a common phospholipid precursor, exerts a similar effect by activating peripheral CB2-like receptors. When administered together, the two compounds act synergistically, reducing pain responses 100-fold more potently than does each compound alone. Gas-chromatography/mass-spectrometry measurements indicate that the levels of anandamide and PEA in the skin are enough to cause a tonic activation of local cannabinoid receptors. In agreement with this possibility, the CB1 antagonist SR141716A and the CB2 antagonist SR144528 prolong and enhance the pain behaviour produced by tissue damage. These results indicate that peripheral CB1-like and CB2-like receptors participate in the intrinsic control of pain initiation and that locally generated anandamide and PEA may mediate this effect.

Amides↗
PubMed1998

Cyclooxygenase-independent chemoprevention with an aspirin derivative in a rat model of colonic adenocarcinoma.

Aspirin decreases the risk of colorectal cancer, reportedly through suppression of cyclooxygenase (COX) activity. Using a rat model of colonic adenocarcinoma, we compared the chemopreventative effects of aspirin versus a nitric oxide-releasing derivative (NCX-4016) which does not inhibit COX. Beginning six weeks after intracolonic administration of trinitrobenzene sulfonic acid, the rats were given azoxymethane weekly (15 mg/kg i.p.) for 4 weeks. Over the same 4-week period, the rats were treated daily with vehicle, aspirin (10 mg/kg) or NCX-4016 (equimolar dose). Six weeks later, the number of aberrant crypt foci (an early preneoplastic lesion) were blindly counted by light microscopy. Effects of aspirin vs. NCX-4016 on COX-1 and COX-2 activity were compared, as was their analgesic activity. Rats receiving vehicle developed a mean of 856 +/- 260 aberrant crypt foci in the colon. Aspirin reduced the number of aberrant crypt foci by 64%, while NCX-4016 produced an 85% reduction. Aspirin, but not NCX-4016, markedly suppressed systemic COX-1 and COX-2 activity, and colonic prostaglandin synthesis. Despite not inhibiting COX, NCX-4016 exhibited comparable analgesic activity to aspirin. These results demonstrate that NCX-4016, a nitric oxide-releasing aspirin derivative, exhibited superior chemopreventative effects to aspirin in this model of colon cancer. This effect occurred independent of inhibition of COX-1 or COX-2.

Adenocarcinoma↗
PubMed1998

Transglutaminase-synthesized gamma-(glutamyl5) spermidine derivative of substance P is a selective tool for neurokinin-2 receptors characterization.

The ability of transglutaminase-synthesized 1,3-diaminopropane, spermidine (Spd), spermine (Spm), and monodansylcadaverine gamma-(glutamyl5)derivatives of substance P (SP) to produce bronchoconstriction was investigated. In urethane-anaesthetized guinea pigs, intravenous injections of SP derivatives contracted differently bronchial smooth muscle and caused hypotension. The most effective bronchoconstrictor among SP analogs was the gamma-(glutamyl5)Spd derivative of SP (Spd-SP; EC50 = 5.3 nmol/kg), which was more potent than the native peptide (EC50 = 26.5 nmol/kg). In contrast, the gamma-(glutamyl5)Spm derivative of SP (Spm-SP) was found completely unable to cause bronchoconstriction and was significantly less effective than SP in determining hypotension. The contractile effect of Spd-SP and Spm-SP was investigated in vitro on rat isolated colon, a well-characterized preparation rich in NK2 receptors. In addition, Spd-SP was tested on the endothelium-denuded rabbit pulmonary artery (RPA) and the hamster isolated trachea (HT), both tissue preparations containing only a single functional receptor subtype (NK2A and NK2B, respectively). The results obtained showed that Spd-SP recognizes NK2 receptors occurring on rat isolated colon more effectively (EC50 = 11 nM) than the native peptide (EC50 = 45 nM). Conversely, Spm-SP evokes a contractile response less effective than that elicited by SP (EC50 = 312 nM). Furthermore, Spd-SP (0.1-10 microg kg(-1)) produced a concentration-dependent contraction of both HT and RPA, exhibiting a potency respectively 12 and 30 times higher than SP in contracting HT and RPA. Our results indicate that the introduction of a Spd moiety at the level of glutamine-5 of SP gives rise to an analog that possesses a different capability to recognize NK2 receptors than the parent peptide. Moreover, since Spd-SP seems to contract more effectively RPA than HT, we conclude that it preferentially recognizes the NK2A receptor subtype.

Animals↗
PubMed1997

Inhibition of intestinal motility by anandamide, an endogenous cannabinoid.

The endogenous cannabinoid ligand anandamide (arachidonylethanolamide) inhibited the intestinal passage of a charcoal meal when administered s.c. in mice at doses ranging from 0.1 to 50 mg/kg. This effect was prevented by the cannabinoid CB1 receptor antagonist SR141716A [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-me thyl-1H-pyrazole-3-carboxamide x HCl] (1 mg/kg s.c.), but it was not affected by the anandamide transport inhibitor, N-(4-hydroxyphenyl) arachidonylethanolamide (AM404) (50 mg/kg, s.c.). The results indicate that anandamide modulates intestinal motility in mice by activating cannabinoid CB1 receptors. They also suggest that anandamide transport, which was previously shown to participate in terminating neural and vascular responses to anandamide, does not contribute to anandamide inactivation in intestinal tissue.

Animals↗
PubMed1997

Potentiation of anandamide hypotension by the transport inhibitor, AM404.

The putative endogenous cannabinoid, anandamide (0.2-2 mg/kg i.v.), decreased systemic blood pressure dose-dependently in anesthesized guinea pigs. These effects were prevented by the CB1 cannabinoid receptor antagonist SR141716A [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-me thyl-1H-pyrazole-3-carboxamide x HCl] at the dose of 0.2 mg/kg i.v. The vasodepressor responses to anandamide were significantly potentiated and prolonged by a novel inhibitor of carrier-mediated anandamide transport, N-(4-hydroxyphenyl) arachidonylethanolamide (AM404) (10 mg/kg, i.v.). These results suggest that anandamide transport participates in terminating the vascular actions of anandamide.

Animals↗
PubMed1997

Functional role of high-affinity anandamide transport, as revealed by selective inhibition.

Anandamide, an endogenous ligand for central cannabinoid receptors, is released from neurons on depolarization and rapidly inactivated. Anandamide inactivation is not completely understood, but it may occur by transport into cells or by enzymatic hydrolysis. The compound N-(4-hydroxyphenyl)arachidonylamide (AM404) was shown to inhibit high-affinity anandamide accumulation in rat neurons and astrocytes in vitro, an indication that this accumulation resulted from carrier-mediated transport. Although AM404 did not activate cannabinoid receptors or inhibit anandamide hydrolysis, it enhanced receptor-mediated anandamide responses in vitro and in vivo. The data indicate that carrier-mediated transport may be essential for termination of the biological effects of anandamide, and may represent a potential drug target.

Analgesics↗
PubMed1997

Fluoroaluminate induces rapid release of endothelin-1 in the isolated perfused arterial and venous vessels of the rat mesentery.

1. Endothelin-1 (ET-1) production from endothelial cells is generally believed to be a process that happens over the course of hours. 2. When fluoroaluminate (AIF-4) was infused in the isolated perfused arterial and venous vessels of the rat mesentery there was an increase in perfusion pressure on both sides. 3. Treatment of mesentery with the endothelin receptor antagonists FR 139317 (ETA receptor selective) or PD 145065 (ETA-ETB receptor nonselective) caused inhibition on both the arterial and venous sides, suggesting that response is mediated predominantly by endothelin-1 through ETA receptors. 4. Endothelial denudation attenuated changes in perfusion pressure of mesenteric circulation generated by fluoroaluminate, but not those caused by exogenously added PGF2 alpha. 5. Our data demonstrate that there is an immediate release of endothelin-1 following fluoroaluminate infusion which could be partially mediated by activation of phospholipase C.

Aluminum↗