title: Actions of 3-methyl-N-oleoyldopamine, 4-methyl-N-oleoyldopamine and N-oleoylethanolamide on the rat TRPV1 receptor in vitro and in vivo.
abstract: N-oleoyldopamine (OLDA) has been identified as an agonist of the transient receptor potential vanilloid type 1 (TRPV1) receptor. A related fatty acid amide, N-oleoylethanolamide (OEA), was found to excite sensory neurons and produce visceral hyperalgesia via activation of the TRPV1 receptor, however, a recent study described this agent as an antinociceptive one. The aim of the present paper was to characterize two newly synthesized derivatives of N-oleoyldopamine, 3-methyl-N-oleoyldopamine (3-MOLDA) and 4-methyl-N-oleoyldopamine (4-MOLDA) as well as OEA with regard to their effects on the TRPV1 receptor. Radioactive 45Ca2+ uptake was measured in HT5-1 cells transfected with the rat TRPV1 receptor and intracellular Ca2+ concentration was monitored by fura-2 microfluorimetry in cultured trigeminal sensory neurons. Thermonociception was assessed by determining the behavioral noxious heat threshold in rats. 3-MOLDA induced 45Ca2+ uptake in a concentration-dependent manner, whereas 4-MOLDA and OEA were without effect. 4-MOLDA and OEA, however, concentration-dependently reduced the 45Ca2+ uptake-inducing effect of capsaicin. In trigeminal sensory neurons, 3-MOLDA caused an increase in intracellular Ca2+ concentration and this effect exhibited tachyphylaxis upon repeated application. Again, 4-MOLDA and OEA failed to alter intracellular Ca2+ levels. Upon intraplantar injection, 3-MOLDA caused an 8-10 degrees C drop of the noxious heat threshold in rats which was inhibited by the TRPV1 receptor antagonist iodo-resiniferatoxin. 4-MOLDA and OEA failed to alter the heat threshold but inhibited the threshold drop induced by the TRPV1 receptor agonist resiniferatoxin. These data show that 3-MOLDA behaves as an agonist, whereas 4-MOLDA and OEA appear to be antagonists, at the rat TRPV1 receptor.
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Pécs, Szigeti u. 12, H-7624 Pécs, Hungary.
authors.forename: Róbert
authors.initials: R
authors.lastname: Almási
authors.forename: Eva
authors.initials: E
authors.lastname: Szoke
authors.forename: Kata
authors.initials: K
authors.lastname: Bölcskei
authors.forename: Angelika
authors.initials: A
authors.lastname: Varga
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Riedl
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Sándor
authors.forename: János
authors.initials: J
authors.lastname: Szolcsányi
authors.forename: Gábor
authors.initials: G
authors.lastname: Petho
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002132:Calcium Radioisotopes / Q000378:metabolism; D002211:Capsaicin / Q000378:metabolism; D002478:Cells, Cultured; D004298:Dopamine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D063388:Endocannabinoids; D015394:Molecular Structure; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D009829:Oleic Acids / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D018689:Sensory System Agents / Q000378:metabolism; D050916:TRPV Cation Channels / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012668:Trigeminal Ganglion / Q000166:cytology
chemical_list: C528577:3-methyl-N-oleoyldopamine; C528576:4-methyl-N-oleoyldopamine; D002132:Calcium Radioisotopes; D063388:Endocannabinoids; D009829:Oleic Acids; D018689:Sensory System Agents; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; C488250:oleoylethanolamide; D002211:Capsaicin; D002118:Calcium; C488796:N-oleoyldopamine; D004298:Dopamine