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An Endogenous Capsaicin-Like Substance with High Potency at Recombinant and Native Vanilloid VR1 Receptors

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An Endogenous Capsaicin-Like Substance with High Potency at Recombinant and Native Vanilloid VR1 Receptors An endogenous capsaicin-like substance with high potency at recombinant and native vanilloid VR1 receptors Susan M. Huang*†, Tiziana Bisogno†‡, Marcello Trevisani†§, Abdulmonem Al-Hayani¶, Luciano De Petrocellis‡, Filomena Fezza‡, Michele Tognetto§, Timothy J. Petros*, Jocelyn F. Krey*, Constance J. Chu*, Jeffrey D. Millerʈ, Stephen N. Davies¶, Pierangelo Geppetti§, J. Michael Walker*, and Vincenzo Di Marzo‡** *Departments of Psychology and Neuroscience, Brown University, Providence, RI 02912; ‡Endocannabinoid Research Group, Institutes of Biomolecular Chemistry and Cybernetics, National Research Council, 80078 Pozzuoli, Napoli, Italy; §Department of Experimental and Clinical Medicine, University of Ferrara, 44100 Ferrara, Italy; ¶Department of Biomedical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, United Kingdom; and ʈApplied Biosystems, Framingham, MA 01701 Edited by L. L. Iversen, University of Oxford, Oxford, United Kingdom, and approved April 18, 2002 (received for review April 3, 2002) The vanilloid receptor VR1 is a nonselective cation channel that is optimal functional interaction with the binding site (17, 18). Ac- most abundant in peripheral sensory fibers but also is found in cordingly, anandamide and lipoxygenase products (12–14) contain several brain nuclei. VR1 is gated by protons, heat, and the pungent the requisite acyl chain but lack the vanillyl group, hence their ingredient of ‘‘hot’’ chili peppers, capsaicin. To date, no endoge- relatively low potency at VR1. The only two metabolites found in nous compound with potency at this receptor comparable to that mammals that are similar structurally to vanillyl-amine are dopa- of capsaicin has been identified. Here we examined the hypothesis, mine and its 3-O-methyl derivative, homovanillyl-amine. Thus, based on previous structure-activity relationship studies and the unsaturated N-acyl-dopamines and N-acyl-homovanillyl-amines availability of biosynthetic precursors, that N-arachidonoyl-dopa- might behave as VR1 agonists. The existence in mammals of mine (NADA) is an endogenous ‘‘capsaicin-like’’ substance in mam- N-acyl-dopamines was hypothesized in earlier studies (19) but never malian nervous tissues. We found that NADA occurs in nervous investigated. Among them, N-arachidonoyl-dopamine (NADA) tissues, with the highest concentrations being found in the stria- was synthesized and shown to bind to cannabinoid but not dopa- tum, hippocampus, and cerebellum and the lowest concentrations mine receptors (20), making it a good candidate endovanilloid by in the dorsal root ganglion. We also gained evidence for the analogy with anandamide. Therefore, in the present study we existence of two possible routes for NADA biosynthesis and synthesized NADA and N-arachidonoyl-homovanillyl-amine (3-O- mechanisms for its inactivation in rat brain. NADA activates both methyl-NADA; Fig. 1) and tested their activity in human embryonic human and rat VR1 overexpressed in human embryonic kidney kidney (HEK)293 cells transfected with human or rat VR1 cDNAs. Ϸ (HEK)293 cells, with potency (EC50 50 nM) and efficacy similar to More importantly, by exploiting high-sensitivity and -accuracy mass those of capsaicin. Furthermore, NADA potently activates native spectrometric (MS) techniques, we looked for NADA in both rat vanilloid receptors in neurons from rat dorsal root ganglion and and bovine nervous tissue. We report that NADA is a naturally hippocampus, thereby inducing the release of substance P and occurring substance similar to capsaicin not only with regard to its calcitonin gene-related peptide (CGRP) from dorsal spinal cord chemical structure but also to its potency at VR1 receptors. slices and enhancing hippocampal paired-pulse depression, respec- tively. Intradermal NADA also induces VR1-mediated thermal hy- Methods ␮ ؎ ؍ peralgesia (EC50 1.5 0.3 g). Our data demonstrate the Chemical Synthesis. NADA and O-methyl-NADA were synthesized existence of a brain substance similar to capsaicin not only with from the corresponding amines and arachidonoylchloride (Sigma) respect to its chemical structure but also to its potency at VR1 as described (18, 20). The compounds were purified by column receptors. chromatography, and their chemical structure was confirmed by proton NMR and infrared spectroscopy. [3H]NADA [1 mCi͞mol (1 anilloid receptors of type 1 (VR1) are nonselective cation Ci ϭ 37 GBq)] was synthesized from arachidonoylchloride and Vchannels, expressed in peripheral sensory C and A␦ fibers and [3H]dopamine (NEN, 53.6 Ci͞mmol) by using the same procedure. gated by nociceptive stimuli such as low pH, heat, and some plant toxins, of which capsaicin, the pungent principle of chili peppers, is Intracellular Ca2؉ Concentration Assays with HEK293 Cells Transfected the best known example (1–4). Evidence obtained by several with VR1. HEK293 cells transfected with either rat VR1 or human laboratories and using different techniques (5–10) showed that VR1 VR1 cDNA (10, 13) were kindly provided by John Davis, Glaxo is present also in the central nervous system, where it is unlikely to SmithKline, and grown as monolayers in minimum essential me- be the target of noxious heat and low pH, thus suggesting the dium supplemented with nonessential amino acids͞10% FCS͞0.2 ͞ ͞ existence of brain endogenous agonists for this receptor (11). mM glutamine and maintained under 95% 5% air CO2 at 37°C. 2ϩ Indeed, lipid mediators previously known to serve other functions The effect of the substances on [Ca ]i was determined by using in the brain, i.e., the endocannabinoid anandamide and some Fluo-3, a selective intracellular fluorescent probe for Ca2ϩ. Cells lipoxygenase derivatives, activate VR1, albeit with a potency con- (50–60,000 per well) were loaded for2hat25°C with 4 ␮M Fluo-3 siderably lower than that of capsaicin (12–14). The antinociceptive effects of VR1 blockers in two models of inflammatory hyperal- gesia (15, 16) suggest that ‘‘endovanilloids’’ might be produced also This paper was submitted directly (Track II) to the PNAS office. by peripheral tissues and act in concert with locally enhanced Abbreviations: VR1, vanilloid receptor of type 1; NADA, N-arachidonoyl-dopamine; HEK, ͞ temperature and acidity during inflammation. human embryonic kidney; DRG, dorsal root ganglion ganglia; CGRP-LI, calcitonin gene- related peptide-like immunoreactivity; SP-LI, substance P-like immunoreactivity; PS, pop- If an endovanilloid did exist, what would be the structural ulation spike. prerequisites that would allow for an optimal interaction with †S.M.H., T.B., and M.T. contributed equally to this work. vanilloid receptors? Structure-activity relationship studies for va- **To whom reprint requests should be addressed at: Institute of Biomolecular Chemistry, nilloid receptors have indicated that both the vanillyl-amine moiety National Research Council, Via Campi Flegrei 34, Comprensorio Olivetti, 80078 Pozzuoli, and a long, unsaturated acyl chain are necessary to achieve an Napoli, Italy. E-mail: [email protected]. 8400–8405 ͉ PNAS ͉ June 11, 2002 ͉ vol. 99 ͉ no. 12 www.pnas.org͞cgi͞doi͞10.1073͞pnas.122196999 Downloaded by guest on September 27, 2021 ϭ vol, solvent B). NADA mobility in the two cases was Rf 0.45 and ϭ Rf 0.8. In the case of incubations with tyrosine, in one set of experiments the catechol-O-methyltransferase inhibitor OR-486, at a concentration (30 ␮M) active also against tyrosine ␤-hydroxylase (21), was included. The metabolism of [3H]NADA to [3H]dopamine or O-methyl- [3H]NADA was studied by incubating 10,000 ϫ g pellets (mito- chondria), 100,000 ϫ g pellets (microsomes), or cytosolic fractions from rat brain or liver homogenates in phosphate buffer at pH 7.0 or 9.0 with [3H]NADA (5 ␮M)for1hat37°C. After the incubation, the mixtures were extracted with 2 vol of chloroform͞methanol (2:1). The aqueous phase containing [3H]dopamine was counted directly, whereas the organic phase, containing unreacted [3H]NADA and O-methyl-[3H]NADA, was lyophilized and puri- fied by thin layer chromatography developed with solvent B (the Rf of O-methyl-NADA was 0.95). The formation of O-methyl-NADA also was confirmed by analysis of the lipid extract by atmospheric ͞ Fig. 1. Chemical structures of capsaicin, NADA, and O-methyl-NADA. pressure chemical ionization liquid chromatography MS. In some experiments the catechol-O-methyltransferase inhibitor OR-486 (1 ␮M) (21) was included in the incubation mixture and inhibited the methylester (Molecular Probes) and transferred to the cuvette of formation of O-methyl-NADA by 55 Ϯ 9% (mean Ϯ SD, n ϭ 3). the fluorescence detector (Perkin–Elmer LS50B) under continuous The uptake of [3H]NADA by intact C6 glioma cells was ␭ ϭ ␭ stirring. Fluorescence was measured at 25°C( EX 488 nm, EM studied as described (22). Nonspecific uptake was determined by ϭ 540 nm) before and after the addition of the test compounds at incubating the cells at 4°Corat37°C in the presence of 50 ␮M various concentrations. In some experiments cells were pretreated anandamide, both of which reduced the uptake of [3H]NADA by Ϸ for 5 min with phorbol 12,13-dibutyrate (100 nM, Sigma) in the 45%. presence or absence of bis-indolmaleimide (0.2 ␮M, Sigma). (Ca2؉ Fluorescence Measurements in Dorsal Root Ganglion (DRG Isolation, Identification, and Quantification of Endogenous NADA. Neurons. DRG were removed from rats (1–3 days old) as reported Striata were removed from fresh bovine brains and stored at previously (23). Cells were plated on poly-L-lysine and laminin- ␮ Ϫ80°C until extraction. The tissue was homogenized in 20 vol of coated glass coverslips and loaded with Fura-2 methylester (3 M). 2ϩ 2ϩ ice-cold methanol for 45 s to 1 min and centrifuged at 44,000 ϫ Ca ([Ca ]i) fluorescence measurements were performed at 37°C with a Nikon eclipse TE300 microscope. Fura-2 methylester was g for 30 min. Acetone and basified water (20 mM ammonium 2ϩ excited at 340 and 380 nM to indicate relative [Ca ]i changes by the hydroxide pH-adjusted to 9.14 with acetic acid) were added to ͞ the supernatant in the ratio of 1:2:1, and the mixture was F340 F380 ratio recorded with a dynamic image-analysis system NEUROBIOLOGY centrifuged at 44,000 ϫ g for 30 min.
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