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Inhibition of human neutrophil chemotaxis by endogenous cannabinoids and phytocannabinoids: evidence for a site distinct from CB1 and CB2.
Mol Pharmacol. 2008 Feb; 73(2):441-50.MP

Abstract

Here, we show a novel pharmacology for inhibition of human neutrophil migration by endocannabinoids, phytocannabinoids, and related compounds. The endocannabinoids virodhamine and N-arachidonoyl dopamine are potent inhibitors of N-formyl-l-methionyl-l-leucyl-l-phenylalanine-induced migration of human neutrophils, with IC(50) values of 0.2 and 8.80 nM, respectively. The endocannabinoid anandamide inhibits human neutrophil migration at nanomolar concentrations in a biphasic manner. The phytocannabinoid (-)-cannabidiol is a partial agonist, being approximately 40 fold more potent than (+)-cannabidiol; abnormal-cannabidiol is a full agonist. Furthermore, the abnormal-cannabidiol (CBD) analog trans-4-[3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-5-methyl-1,3-benzenediol (O-1602) inhibits migration, with an IC(50) value of 33 nM. This reported profile of agonist efficacy and potency parallels with the pharmacology of the novel "abnormal-cannabidiol" receptor or a related orphan G protein-coupled receptor, which are already known to modulate cell migration. Although having no effect alone, N-arachidonoyl l-serine attenuated inhibition of human neutrophil migration induced by anandamide, virodhamine, and abnormal-CBD. Our data also suggest that there is cross-talk/negative co-operativity between the cannabinoid CB(2) receptor and this novel target: CB(2) receptor antagonists significantly enhance the inhibition observed with anandamide and virodhamine. This study reveals that certain endogenous lipids, phytocannabinoids, and related ligands are potent inhibitors of human neutrophil migration, and it implicates a novel pharmacological target distinct from cannabinoid CB(1) and CB(2) receptors; this target is antagonized by the endogenous compound N-arachidonoyl l-serine. Furthermore, our findings have implications for the potential pharmacological manipulation of elements of the endocannabinoid system for the treatment of various inflammatory conditions.

Authors+Show Affiliations

Institute of Medical Sciences, University of Aberdeen, Aberdeen, AB25 2ZD, Scotland, UK.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17965195

Citation

McHugh, Douglas, et al. "Inhibition of Human Neutrophil Chemotaxis By Endogenous Cannabinoids and Phytocannabinoids: Evidence for a Site Distinct From CB1 and CB2." Molecular Pharmacology, vol. 73, no. 2, 2008, pp. 441-50.
McHugh D, Tanner C, Mechoulam R, et al. Inhibition of human neutrophil chemotaxis by endogenous cannabinoids and phytocannabinoids: evidence for a site distinct from CB1 and CB2. Mol Pharmacol. 2008;73(2):441-50.
McHugh, D., Tanner, C., Mechoulam, R., Pertwee, R. G., & Ross, R. A. (2008). Inhibition of human neutrophil chemotaxis by endogenous cannabinoids and phytocannabinoids: evidence for a site distinct from CB1 and CB2. Molecular Pharmacology, 73(2), 441-50.
McHugh D, et al. Inhibition of Human Neutrophil Chemotaxis By Endogenous Cannabinoids and Phytocannabinoids: Evidence for a Site Distinct From CB1 and CB2. Mol Pharmacol. 2008;73(2):441-50. PubMed PMID: 17965195.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of human neutrophil chemotaxis by endogenous cannabinoids and phytocannabinoids: evidence for a site distinct from CB1 and CB2. AU - McHugh,Douglas, AU - Tanner,Carolyn, AU - Mechoulam,Raphael, AU - Pertwee,Roger G, AU - Ross,Ruth A, Y1 - 2007/10/26/ PY - 2007/10/30/pubmed PY - 2008/2/20/medline PY - 2007/10/30/entrez SP - 441 EP - 50 JF - Molecular pharmacology JO - Mol. Pharmacol. VL - 73 IS - 2 N2 - Here, we show a novel pharmacology for inhibition of human neutrophil migration by endocannabinoids, phytocannabinoids, and related compounds. The endocannabinoids virodhamine and N-arachidonoyl dopamine are potent inhibitors of N-formyl-l-methionyl-l-leucyl-l-phenylalanine-induced migration of human neutrophils, with IC(50) values of 0.2 and 8.80 nM, respectively. The endocannabinoid anandamide inhibits human neutrophil migration at nanomolar concentrations in a biphasic manner. The phytocannabinoid (-)-cannabidiol is a partial agonist, being approximately 40 fold more potent than (+)-cannabidiol; abnormal-cannabidiol is a full agonist. Furthermore, the abnormal-cannabidiol (CBD) analog trans-4-[3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-5-methyl-1,3-benzenediol (O-1602) inhibits migration, with an IC(50) value of 33 nM. This reported profile of agonist efficacy and potency parallels with the pharmacology of the novel "abnormal-cannabidiol" receptor or a related orphan G protein-coupled receptor, which are already known to modulate cell migration. Although having no effect alone, N-arachidonoyl l-serine attenuated inhibition of human neutrophil migration induced by anandamide, virodhamine, and abnormal-CBD. Our data also suggest that there is cross-talk/negative co-operativity between the cannabinoid CB(2) receptor and this novel target: CB(2) receptor antagonists significantly enhance the inhibition observed with anandamide and virodhamine. This study reveals that certain endogenous lipids, phytocannabinoids, and related ligands are potent inhibitors of human neutrophil migration, and it implicates a novel pharmacological target distinct from cannabinoid CB(1) and CB(2) receptors; this target is antagonized by the endogenous compound N-arachidonoyl l-serine. Furthermore, our findings have implications for the potential pharmacological manipulation of elements of the endocannabinoid system for the treatment of various inflammatory conditions. SN - 1521-0111 UR - https://www.unboundmedicine.com/medline/citation/17965195/Inhibition_of_human_neutrophil_chemotaxis_by_endogenous_cannabinoids_and_phytocannabinoids:_evidence_for_a_site_distinct_from_CB1_and_CB2_ DB - PRIME DP - Unbound Medicine ER -