European journal of pharmacology
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Cannabinoids are known to possess both anti-inflammatory and neuroprotective effects. In the present study, we have investigated the ability of cannabinoids to inhibit the transmigration of neutrophils in response to chemotaxic stimuli. The cannabinoid receptor agonist WIN 55,212-2 ((R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)-pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate) significantly decreased the number of migrating neutrophils across a monolayer of tumour necrosis factor alpha (TNF-alpha) activated ECV304 cells at concentrations >or=1 microM. ⋯ TNF-alpha treatment of ECV304 cells caused release of interleukin-8 (IL-8), but WIN 55,212-2 did not affect either the ability of neutrophils to migrate across chemotaxis plates in response to an IL-8 stimulus, or to change the percentage of CXC 1 and CXC 2 receptors expressed by the neutrophils. WIN 55,212-2 at a concentration of 1 microM, but not at lower concentrations, produced a significant inhibition of IL-8 release from ECV304 cells in response to TNF-alpha-stimulation. Thus WIN 55,212-2 reduces the transmigration of neutrophils across a monolayer of TNF-alpha-activated ECV304 cells by an indirect action upon the release of IL-8 and/or other chemokine release from the ECV304 cells, and that this effect is brought about mainly by a cannabinoid CB receptor-independent mechanism.
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We examined the effect of inhaled histamine on citric acid-induced coughs and clarified the role of ionotropic purinergic receptors in the resulting changes. Although the inhalation of 0.1 M citric acid by itself produced only a few coughs in guinea pigs, exposure to histamine, at concentrations of 0.3 to 1 mM, for 2 min concentration dependently increased the number of citric acid-induced coughs. This histamine-induced increase in the number of citric acid-induced coughs was dose dependently and significantly reduced when animals were pretreated with fexofenadine, a histamine H1 receptor antagonist. ⋯ Furthermore, the ATP-induced increase in the number of citric acid-induced coughs was dose dependently and significantly decreased when animals were pretreated with fexofenadine, at doses of 0.3, 1 and 3 mg/kg, p.o. These results suggest that histamine enhances the excitability of rapidly adapting receptors to tussive stimuli via modulation of ATP release in the airways. Furthermore, ATP might act not only on P2X receptors to directly activate rapidly adapting receptors, but also on P2Y receptors to increase histamine release, indirectly increasing the cough reflex sensitivity.
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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. ⋯ 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.
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The combined administration of low doses of opiates with non-steroidal anti-inflammatory drugs can produce additive or supra-additive analgesic effects while reducing unwanted side effects. We have recently reported that co-administration of morphine with dipyrone (metamizol) produces analgesic potentiation both in naïve and in morphine-tolerant rats. The purpose of this work was to determine the role of opioids on the acute potentiation observed between morphine and dipyrone i.v. in the rat tail flick test. ⋯ When naloxone was given after analgesics, it dose-dependently blocked the effects of morphine alone and in combination with dipyrone but with different potency in each case. As to dipyrone, naloxone delayed the time to antinociceptive peak effect. Taken together, these results support the notion that endogenous opioids are involved in the analgesic potentiation observed with the combination of morphine plus dipyrone.
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Previous studies have shown that the extracts obtained from Phyllanthus amarus, and some of the lignans isolated from it, exhibit pronounced antiinflammatory properties. In the present study, we have assessed whether the antiinflammatory actions of these lignans can be mediated by interaction with platelet activating factor (PAF) receptor or interference with the action of this lipid. The local administration of nirtetralin, phyltetralin or niranthin (30 nmol/paw), similar to WEB2170 (a PAF receptor antagonist, 30 nmol/paw), significantly inhibited PAF-induced paw oedema formation in mice. ⋯ Moreover, in the rat model of PAF-induced allodynia, both niranthin (30 nmol/paw) and WEB2170 (30 nmol/paw) treatment significantly inhibited PAF-induced allodynia. In addition, niranthin had a rapid onset and long-lasting antiallodynic action when compared with WEB2170. Collectively, the present findings suggest that niranthin exhibits antiinflammatory and antiallodynic actions which are probably mediated through its direct antagonistic action on the PAF receptor binding sites.