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The cannabinoid CB2 receptor selective agonist JWH133 reduces mast cell oedema in response to compound 48/80 in vivo but not the release of beta-hexosaminidase from skin slices in vitro.
Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Pharmacology.
Umeå University, Faculty of Medicine, Odontology, Oral Cell Biology.
Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Pharmacology.
2006 (English)In: Life Sciences, ISSN 0024-3205, Vol. 78, no 6, 598-606 p.Article in journal (Refereed) Published
Abstract [en]

In a recent study so far published in abstract form, it was reported that the CB(2) receptor selective agonist AM1241 diminishes oedema produced as a result of mast cell degranulation in vivo. It is, however, not known whether other structurally different CB(2) agonists share this effect, and whether this is due to a direct effect on mast cell function. In the present study, we have investigated the effects of JWH133, a CB(2) receptor selective agonist, together with the anti-inflammatory agent palmitoylethanolamide and its analogue palmitoylisopropylamide, on compound 48/80-induced oedema and degranulation in vivo and in vitro. JWH133 (20 and 200 microg/mouse i.p.) significantly reduced the ability of compound 48/80 to induce oedema in vivo in the anaesthetised mouse following its injection into the ear pinna. Palmitoylethanolamide (200 microg/mouse i.p) also reduced the response to compound 48/80, whereas no firm conclusions could be drawn for palmitoylisopropylamide (20 and 200 microg/mouse i.p.). The CB(2) selective antagonist/inverse agonist SR144528 (60 microg/mouse i.p.) appeared to produce anti-inflammatory effects per se in this model, making it hard to interpret the effects of JWH133 in terms of CB(2) receptor mediated activation. In contrast to the situation in vivo, neither JWH133 (0.3 and 3 microM) nor palmitoylethanolamide (10 microM) affected mast cell degranulation, measured by following the release of the granular protein beta-hexosaminidase, produced by compound 48/80 in vitro in mouse skin slices. The two compounds were also ineffective in inhibiting the binding of [(3)H]pyrilamine to histamine H(1) receptors in vitro. It is concluded that the ability of JWH133 to affect mast cell dependent inflammation in vivo may be mediated by an indirect action upon the mast cells.

Place, publisher, year, edition, pages
2006. Vol. 78, no 6, 598-606 p.
Keyword [en]
Animals, Cannabinoids/*pharmacology, Capillary Permeability/drug effects, Edema/*prevention & control, Female, Mast Cells/*drug effects/physiology, Mice, Mice; Inbred BALB C, Palmitic Acids/pharmacology, Polymerase Chain Reaction, Receptor; Cannabinoid; CB2/*agonists, Receptors; Histamine H1/drug effects, Skin/*drug effects/secretion, beta-N-Acetylhexosaminidase/*secretion, p-Methoxy-N-methylphenethylamine/*pharmacology
URN: urn:nbn:se:umu:diva-5883DOI: 10.1016/j.lfs.2005.05.059PubMedID: 16111718OAI: diva2:145551
Available from: 2008-04-02 Created: 2008-04-02 Last updated: 2009-11-17Bibliographically approved
In thesis
1. Pharmacology of Palmitoylethanolamide and Related Compounds
Open this publication in new window or tab >>Pharmacology of Palmitoylethanolamide and Related Compounds
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Anandamide (AEA) is an endogenous fatty acid which activates the same cannabinoid receptors as ∆9-tetrahydrocannabinol, the psychoactive substance in marijuana. In vivo, anandamide exerts a number of actions including effects upon pain and inflammation. However, AEA has a short duration of action since it is rapidly metabolised, primarily by the intracellular enzyme fatty acid amide hydrolase (FAAH).

The general aim of this thesis has been to identify and characterize compounds capable of preventing the metabolism of anandamide. The chemical approach was based on the endogenous anti-inflammatory compound palmitoylethanolamide (PEA), a compound related to anandamide with the ability to inhibit anandamide degradation by substrate competition, but without the ability to directly activate cannabinoid receptors.

A number of compounds were identified as inhibitors of rat brain FAAH in the initial in vitro studies, without having major affinity for the cannabinoid receptors. In particular, palmitoylisopropylamide (PIA) was found to reduce the metabolism of AEA in intact C6 glioma cells with potency similar to the prototypical AEA reuptake inhibitor AM404. This compound was in addition found to exert less effect upon C6 glioma cell proliferation than either AM404 or the closely related uptake inhibitor VDM11. To evaluate if PIA was effective in vivo, a model of mast cell dependent inflammation, oedema of the ear following local injection of compound 48/80, was set up using anaesthetised mice. Initially, a CB2 cannabinoid receptor selective agonist was used to probe the model and demonstrated to produce an anti-oedema effect. In contrast, the compound was inactive in vitro in skin slice preparations. PIA showed a similar pattern, although there was a large variation in responses which affected the significance of the result obtained, as did the vehicle used to dissolve the compound.

Taken together, the present data would suggest that PIA can inhibit the degradation of AEA without having deleterious effects upon cell proliferation or affinity for the cannabinoid receptors. Further experimentation is necessary to elucidate the usefulness of this compound in vivo.

Place, publisher, year, edition, pages
Umeå: Farmakologi och klinisk neurovetenskap, 2005. 82 p.
Umeå University medical dissertations, ISSN 0346-6612 ; 942
Pharmacology, anandamide, cannabinoid, FAAH, palmitoylethanolamide, palmitoylisopropylamide, inflammation, mast cells, Farmakologi
National Category
Pharmacology and Toxicology
Research subject
Medical Pharmacology
urn:nbn:se:umu:diva-445 (URN)91-7305-821-1 (ISBN)
Public defence
2005-03-04, E04, 6E, Norrlands universitetssjukhus, Umeå, 09:00 (English)
Available from: 2005-02-09 Created: 2005-02-09 Last updated: 2009-11-17Bibliographically approved

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