Neutrophils are the earliest inflammatory cell to infiltrate tissue and dominate the acute inflammatory stage, playing an important role in early phagocytosis (Ainsworth et al., 1996; Hurley, 1983; Movat, 1985;). Neutro-phils release various inflammatory mediators, as well as chemotactic factors specific for monocytes and other inflammatory cells (Ainsworth et al., 1996; Antony etal., 1985; Levine etal., 1986; Pereira etal., 1990; Territo etal., 1989). Thus, neutrophils have the potential to amplify the cellular inflammatory response and are pivotal in its early onset (Ainsworth et al., 1996). Although neutrophils are generally replaced by macrophages as the primary cell type present in tissue as the acute inflammatory response progresses, abnormal chronic inflammatory states are usually pleomorphic, involving a variety of cell types, including neutrophils (Hurley, 1983; Movat, 1985). Under pathological conditions, the pro-inflammatory actions of neutrophils contribute to the development of inflammatory pain (Bennett etal., 1998; Levine andTaiwo, 1994; Levine et al., 1984, 1985; Schuligoi, 1998), unstable angina pectoris (Wysocka et al., 1997), inflammatory bowel disease (Kane, 2001), atheroscler-sosis (Cross et al., 2005) and also play a critical role in the development of arthritic inflammation (Ward, 1997). In addition, there is a growing body of evidence suggesting that neutrophils make a crucial contribution to a number of autoimmune, autoinflammatory, and neoplastic disorders (Nathan, 2006).
It is clear from the volume of empirical evidence contained in the literature that cell-surface receptors are an essential component of the majority of pro-migratory responses (Arai et al., 1997; Hwang et al., 2004; Neptune and Bourne, 1997; Wenzel-Seifert et al., 1998; Yokomizo et al., 2000). To date, few investigations regarding inhibitors of cell migration have been reported (Armstrong, 1995; De la Fuente et al., 1998; Garrido et al., 1996; Harvath et al., 1991; Mitsui et al., 1997; Okamoto et al., 2000); they include a m-opioid agonist, prostaglandin E, S1P and adenylyl cyclase-activating peptide, all of which act mainly on leukocytes, via cell-surface receptors. Together, the work of Kurihara et al. and McHugh et al. has revealed that certain endogenous cannabinoids and lipids are potent inhibitors ofinduced human neutro-phil migration. McHugh et al. implicate a novel SR141716A-sensitive pharmacological target distinct from cannabinoid CB1 and CB2 receptors, which is antagonized by the endogenous compound N-arachidonoyl-L-serine; and that, in neutrophils, the CB2 receptor exerts negative co-operativity upon this receptor. In addition, Kurihara et al. have demonstrated that, at least in the case of 2-AG, fMLP-induced RhoA activity is decreased following endocannabinoid pretreatment, disrupting the front/ rear polarization necessary for neutrophils to engage in chemotaxis. From this review, the therapeutic potential of exploiting endocannabinoids as neutrophilic chemorepellants is plain to see.
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