In mammals, specific lipids and amino acids serve as crucial signaling molecules. In bacteria, conjugates of lipids and amino acids (referred to as lipoamino acids) have been identified and found to possess biological activity. Here, we report that mammals also produce lipoamino acids, specifically the arachidonyl amino acids. We show that the conjugate of arachidonic acid and glycine (N-arachidonylglycine (NAGly)) is present in bovine and rat brain as well as other tissues and that it suppresses tonic inflammatory pain. The biosynthesis of NAGly and its degradation by the enzyme fatty acid amide hydrolase can be observed in rat brain tissue. In addition to NAGly, bovine brain produces at least two other arachidonyl amino acids: N-arachidonyl ␥-aminobutyric acid (NAGABA) and N-arachidonylalanine. Like NAGly, NAGABA inhibits pain. These findings open the door to the identification of other members of this new class of biomolecules, which may be integral to pain regulation and a variety of functions in mammals.Molecules found in bacteria that consist of a lipid moiety conjugated to an amino acid have been termed lipoamino acids (1-3). Burstein et al. (4) found that the lipoamino acid Narachidonylglycine (NAGly) 1 causes hot plate analgesia in mice, indicating its possible biological relevance in mammals. NAGly was first synthesized (5) as a structural analog of the endogenous cannabinoid anandamide (6), and it was found to lack affinity for the cannabinoid CB1 receptor. We hypothesized that NAGly may be produced by mammalian tissues because it is composed of the naturally occurring compounds glycine and arachidonic acid. Herein we show that at least three arachidonyl amino acids are natural constituents in mammalian brain: NAGly, N-arachidonyl ␥-aminobutyric acid (NAGABA), and N-arachidonylalanine (NAAla). One member of this group, NAGly, is characterized in detail here. It is synthesized in situ in rat brain tissue from the precursors arachidonic acid and glycine, and it is hydrolyzed by the enzyme fatty acid amide hydrolase (FAAH). NAGly is widely distributed among mammalian tissues, implying multiple functions. One possible physiological function of NAGly is pain suppression, indicated by its marked suppression of formalininduced pain behavior in rats, confirming a previous report of analgesic activity in mice (4). EXPERIMENTAL PROCEDURESTissue Extraction and Purification-The procedure comprised a liquidliquid extraction modified from that described by Folch et al. (7) followed by a series of solid-phase separations. Fresh bovine brain and rat organs were homogenized in the methanol fraction of 20 volumes of 2:1 chloroform:methanol and centrifuged for 15 min at 31,000 ϫ g at 4°C. Chloroform was then added to the supernatant. NaCl (0.2 volume, 0.73%) was mixed with the crude homogenate, and the solution was allowed to separate overnight at 4°C or centrifuged at 1,000 ϫ g for 15 min. The upper phase was discarded and the interphase washed twice. The lower phase was then applied to diethylaminopropyl silica-based...

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RECENT QUALITATIVE SYSTEMatic review of the effectiveness of cannabinoids in the management of pain advised against their widespread introduction into clinical practice because of limited relative efficacy in acute pain and common adverse effects. 1 However, it was suggested that cannabinoids may have some beneficial effect in spasticity and in neuropathic pain, for which a therapeutic need is greater than in postoperative pain. In addition, the authors stated that new safe and effective agonists at the cannabinoid receptors may dissociate therapeutic effects from psychotropic effects, which makes randomized comparisons in neuropathic pain and spasticity worthwhile. 1 1Ј,1ЈDimethylheptyl-⌬ 8 -tetrahydrocannabinol-11-oic acid (CT-3) potentially possesses the efficacy to treat neuropathic pain and spasticity without the psychotropic liabilities of cannabis. CT-3 is a synthetic analog of tetrahydrocannabinol (THC)-11-oic acid, one of the endogenous transformation products of THC, in which a dimethylheptyl side chain is substituted for the pentyl side chain. 2 In preclinical studies, CT-3 was found to be a potent anti-inflammatory, analgesic, and antiallodynic agent

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