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Neutrophils are the earliest inflammatory cell to infiltrate tissue, playing an important role in early phagocytosis. Under pathological conditions, pro-inflammatory actions of neutrophils contribute to the development of various inflammatory diseases. Gi protein-coupled cell-surface receptors are an essential component of pro-migratory responses in leukocytes; however, few investigations regarding inhibitors of cell migration have been reported. Kurihara etal. (2006) and McHugh etal. (2008) have revealed that certain endogenous cannabinoids and lipids are potent inhibitors ofinduced human neutrophil migration. McHugh et al. implicate a novel SR141716A-sensitive pharmacological target distinct from cannabinoid CB1 and CB2 receptors, which is antagonized by N-arachidonoyl-L-serine; and that the CB2 receptor exerts negative

* Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana, USA { Institute of Medical Sciences, University of Aberdeen, Aberdeen, Scotland, United Kingdom

Vitamins and Hormones, Volume 81 © 2009 Elsevier Inc.

ISSN 0083-6729, DOI: 10.1016/S0083-6729(09)81013-3 All rights reserved.

co-operativity upon this receptor. Kurihara et al. demonstrate that fMLP-induced RhoA activity is decreased following endocannabinoid pretreatment, disrupting the front/rear polarization necessary for neutrophils to engage in chemotaxis. The therapeutic potential of exploiting endocannabinoids as neutrophilic chemorepellants is plain to see.

I. Cellular Motility and Neutrophils

Cellular motility is a critical feature of many different processes at various stages of human development. For instance, the correct positioning of differentiated cells during embryogenesis is entirely dependent upon effective cell migration. As a human matures toward adulthood, most cells switch off their motile capability, leaving only a few specialized cells able to migrate autonomously in order to fulfill their ongoing functions, such as stem cells in tissue regeneration (Kayali et al., 2003; Thiele et al., 2004), fibroblasts in wound healing (Gillitzer and Goebeler, 2001; Senior et al., 1983), and leukocytes in the immune response. In fact, the coordinated migration of leukocyte subsets is a prerequisite for effective host immunity, that is, lymphocytes continuously patrol the body for pathogenic invaders (Moser and Ebert, 2003), dendritic cells migrate into the secondary lymphatic organs after antigen uptake (Sallusto et al., 1998) and neutrophils are quickly recruited to sites of inflammation (Imhof and Dunon, 1997; Kucharzik and Williams, 2003).

Neutrophils are the most abundant type of white blood cell present in humans, and because they are much more numerous than the longer-lived monocytes or macrophages, the first phagocyte a pathogen is likely to encounter is a neutrophil. In healthy human blood, neutrophils normally exist in a quiescent state with an average half-life of 12 h; however, upon interaction with extracellular chemical cues, they undergo activation and become highly motile phagocytic cells able to pass through the walls of capillaries and enter tissue spaces to engulf and destroy disease-producing bacteria. Antibacterial and digestive enzymes within their cytoplasmic granules subsequently digest the phagocytosed particles. As a result of this action, neutrophils form the first line of defense against infection and are transported rapidly to specific areas of inflammation, where they have the ability to move through the tissues by an amoeboid action at speeds of up to 40 mm min-1 (Stevens and Lowe, 1996). To actually reach an area of infection or tissue damage, neutrophils marginate (position themselves adjacent to the blood vessel endothelium) and undergo selectin-dependent capture followed by, in most cases, integrin-dependent adhesion after which they move through the endothelium and basement membrane to the tissue of interest where they survive for 1—2 days. Once in the support tissue, neutrophils respond with chemotaxis, the process whereby cells sense soluble molecules and follow them along a concentration gradient to their source. Despite the variety of different chemotactic molecules, for example, sugars, peptides, cell metabolites, or membrane lipids, the migratory signals they deliver are transduced into the generation of locomotory force via G protein-coupled receptors (GPCRs). GPCRs are coupled on the cytosolic side of the neutrophil plasma membrane to heterotrimeric G proteins (Neer, 1995), which in turn activate a complex and as yet not fully defined array of signaling cascades, culminating in the assembly and disassembly of cellular actin filaments; generating cell motility (Hwang et al., 2004; Neptune and Bourne, 1997; Wenzel-Seifert et al., 1998; Yokomizo et al., 2000). Studies involving chemotaxis ofHEK293 cells, as well as those from a lymphocyte cell line (300-19), stably transfected with GPCRs that coupled exclusively to Gq, G^ and Gs G proteins, found that cells expressing receptors coupled to G^ but not to Gq or Gs proteins migrated in response to a concentration gradient of the appropriate agonist. This prompted the hypothesis that many Gi-coupled receptors share the ability to mediate cell migration (Arai et al., 1997; Neptune and Bourne, 1997). The two most prominent groups of ligands for the Grcoupled GPCRs involved in migratory processes are the chemokines and the neurotransmitters; the latter includes the endogenous cannabinoids.

II. The Endogenous Cannabinoid System

In the early 1990s, molecular cloning identified two distinct G proteincoupled cannabinoid receptors, which were given the nomenclature CB1 and CB2 receptors (Matsuda et al., 1990; Munro et al., 1993). The existence in mammalian cells of specific membrane receptors for plant-derived cannabinoids triggered a search for an endogenous ligand, which culminated in 1992 in the identification of N-arachidonylethanolamide or anandamide (AEA) (Devane, 1992). Three years later, a second endogenous cannabinoid, 2-arachidonylgly-cerol (2-AG), was isolated from gut (Mechoulam et al., 1995) and brain tissue (Sugiura et al., 1995). By definition cannabinoids are molecules that are able to bind and activate cannabinoid receptors. They encompass a wide range of compounds, which can be categorized, according to chemical structure, into the following groups: classical, nonclassical, aminoalkylindole, and eicosa-noid cannabinoids. Alternative categorization groups the cannabinoids into three main classes according to their source. The first, the endocannabinoids are endogenous long-chain fatty acid derivatives, for example, AEA and 2-AG. Other putative members of this class include noladin ether, virodhamine, oleamide, N-arachidonoyldopamine (NADA), N-oleoyldopa-mine, N-homo-g-linoenylethanolamide, and N-docosatetraenylethanolamide;

however, their activity has not yet been well characterized (Fezza et al., 2002; Hanus et al., 1993; Walker et al, 2002). The second, the phytocannabinoids comprise more than 60 compounds derived from the Cannabis plant family, for example, the psychoactive principle of Cannabis sativa, D9-tetrahydrocannabi-nol (D9-THC), and the primary nonpsychoactive constituent, cannabidiol (CBD). The third, the synthetic cannabinoids were developed from various SAR-based studies, for example, CP55940, WIN55212-2,JWH-133, AM630, and so on.

CB1 receptors are predominantly expressed by neurons in the brain, spinal cord, and peripheral nervous system; however, distribution is not homogenous. CB1 expression is greater in the cerebral cortex, hippocampus, basal ganglia, and cerebellum than the hypothalamus and spinal cord, where receptor numbers are significantly lower (Howlett et al., 2002). With regard to the peripheral nervous system, CB1 mRNA transcripts have been detected in the following tissues: pituitary gland, immune cells, reproductive tissues, gastrointestinal tract, superior cervical ganglion, heart, lung, urinary bladder, and adrenal gland (Pertwee, 1997). On balance, CB1 receptor levels are considerably lower in the peripheral tissues compared with the central nervous system, although some tissues contain high concentrations of CB1 receptors localized in discreet regions, for example, nerve terminals, which form a small percentage of the total mass (Pertwee, 2001).

Current opinion holds that the CB2 receptor is less widely expressed than CB1, having been only confidently detected outwith the central nervous system (Galiegue et al., 1995; Munro et al., 1993). The CB2 receptor is present principally in the immune system where mRNA transcripts are 10-100-fold more abundant than those of CB1 (Galiegue et al., 1995; Kaminski et al., 1992; Massi et al., 1997). Moreover, CB2 receptors have been located in tonsils, thymus, bone marrow, adrenal glands, heart, lung, prostate gland, uterus, pancreas, ovary, and testis (Galiegue et al., 1995; Howlett et al., 2002). CB2 receptor protein has also been identified in the retina of adult rats (Lu et al., 2000), and FACS analysis has indicated CB2 receptor protein in the dorsal root; however, immunohistochemistry failed to detect CB2 receptors on DRG neurones, implying the receptors may be present on non-neuronal cells such as microglia and fibroblasts ganglia (Ross et al., 2001). It is thought that CB2 receptors are largely involved in the modulation of the immune system, including antigen processing by macrophages, helper T cell activation and the migratory response of certain immunocompetent cells (Howlett et al., 2002).

In addition to the cannabinoid receptors discussed above, evidence is accumulating that cannabinoids, and endocannabinoids in particular, are capable of acting via additional sites that remain yet to be cloned. Firstly, GPR55, an orphan GPCR that AstraZenaca plc and GlaxoSmithKline, Inc.

have independently demonstrated to be activated by endogenous, phyto and synthetic cannabinoids, as well as by lysophophatidylinositol (LPI) (Brown and Wise, 2001; Drmota et al., 2004). Secondly, evidence for a putative CB2-like cannabinoid receptor has been obtained from experiments involving inhibition of electrically evoked contractions of the mouse vas deferens; and from others with palmitoylethanolamide (PEA), an endogenous lipid that does not bind CB1 or CB2 receptors yet exhibits antinociceptive activity in various animal pain models that can be blocked by the CB2-selective inverse agonist SR144528 (Bisogno et al., 2001; Petitet et al., 1998; Wiley and Martin, 2002). Thirdly, aputative non-CB1, non-CB2 GPCR for AEA and WIN55212-2 has been reported from GTPgS binding in wild type and CB1_/_ mice (Breivogel etal., 1997; Di Marzo et al., 2000). Fourthly, experiments involving mouse and rat mesenteric arteries from double CB1_/_/CB2_/_ knockout animals, and also from studies of microglial cell migration, indicate a novel cannabinoid receptor that is activated by AEA and two CBD analogues, abnormal canna-bidiol (Abn-CBD) and 0-1602, neither of which bind appreciably to CB1 or CB2 receptors (Bukoski et al., 2002; jarai et al., 1999; Kunos et al., 2000; Offertaler et al., 2003; Showalter et al., 1996; Wagner et al., 1999; Walter et al., 2003). CBD and N-arachidonoyl-L-serine (ARA-S) are thought to behave as partial agonists at the Abn-CBD receptor, while another CBD analogue, 0-1918 and SR141716A, act an antagonists (McHugh et al., 2008; Milman et al., 2006; Offertaler et al., 2003; Pertwee, 2004; Zhang et al., 2005). Fifthly, studies with isolated segments of rat mesenteric and hepatic arteries have yielded evidence for a novel cannabinoid receptor on capsaicin-sensitive perivascular sensory neurons that can be equipotently activated by D9-THC and cannabinol (CBN; another nonpsychoactivephytocannabinoid) to induce calcitonin gene-related peptide (CGRP) release and the relaxation of phenylephrine-precontractedvessels (Zygmunt etal., 2002). Sixthly, evidence has been obtained that cannabinoids can interact with and modulate non-cannabinoid receptors via allosteric binding sites. The primary binding site on receptors recognized by an endogenous agonist is referred to as the orthosteric site, while a distinct site on a receptor protein that modulates the binding properties of the orthosteric site, via conformational change, is termed an allosteric site (Christopoulos and Kenakin, 2002). Therefore, an allosteric modulator is a compound that interacts with this secondary site to modulate the affinity of a distinct ligand for the orthosteric site and can result in positive or negative modulation (Lee and El-Fakahany, 1991). Evidence has been obtained that the 5-HT3 receptor contains an allosteric site with which CP55940, WIN55212-2, and AEA can interact (Barann et al., 2002). Other reports indicate there may be allosteric sites for cannabinoids on other receptors, including M1 and M4 muscarinic receptors (Christopoulos and Wilson, 2001) and ionotropic AMPA, GLUA1, and GLUA3 receptors (Akinshola etal., 1999a,b).

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