N-oleoyldopamine, a novel endogenous capsaicin-like lipid that produces hyperalgesia.
N-Arachidonoyldopamine (NADA) was recently identified as an endogenous ligand for the vanilloid type 1 receptor (VR1). Further analysis of the bovine striatal extract from which NADA was isolated indicated the existence of substances corresponding in molecular mass to N-oleoyldopamine (OLDA), N-palmitoyldopamine (PALDA), and N-stearoyldopamine (STEARDA). Quadrupole time-of-flight mass spectrometric analysis of bovine striatal extracts revealed the existence of OLDA, PALDA, and STEARDA as endogenous compounds in the mammalian brain. PALDA and STEARDA failed to affect calcium influx in VR1-transfected human embryonic kidney (HEK) 293 cells or paw withdrawal latencies from a radiant heat source, and there was no evidence of spontaneous pain behavior. By contrast, OLDA induced calcium influx (EC(50) = 36 nm), reduced the latency of paw withdrawal from a radiant heat source in a dose-dependent manner (EC(50) = 0.72 microg), and produced nocifensive behavior. These effects were blocked by co-administration of the VR1 antagonist iodo-resiniferatoxin (10 nm for HEK cells and 1 microg/50 micro;l for pain behavior). These findings demonstrate the existence of an endogenous compound in the brain that is similar to capsaicin and NADA in its chemical structure and activity on VR1. Unlike NADA, OLDA was only a weak ligand for rat CB1 receptors; but like NADA, it was recognized by the anandamide membrane transporter while being a poor substrate for fatty-acid amide hydrolase. Analysis of the activity of six additional synthetic and potentially endogenous N-acyldopamine indicated the requirement of a long unsaturated fatty acid chain for an optimal functional interaction with VR1 receptors.
Chu
Constance J
CJ
Department of Psychology, Brown University, Providence, Rhode Island 02912, USA.
Huang
Susan M
SM
De Petrocellis
Luciano
L
Bisogno
Tiziana
T
Ewing
Scott A
SA
Miller
Jeffrey D
JD
Zipkin
Robert E
RE
Daddario
Nives
N
Appendino
Giovanni
G
Di Marzo
Vincenzo
V
Walker
J Michael
JM
D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002211:Capsaicin / Q000737:chemistry* / Q000494:pharmacology; D002417:Cattle; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004224:Diterpenes / Q000494:pharmacology; D004298:Dopamine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D063388:Endocannabinoids; D006801:Humans; D006930:Hyperalgesia / Q000209:etiology*; D020128:Inhibitory Concentration 50; D007477:Ions; D008055:Lipids; D008297:Male; D013058:Mass Spectrometry; D008956:Models, Chemical; D053284:Polyunsaturated Alkamides; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D011955:Receptors, Drug / Q000037:antagonists & inhibitors; D050916:TRPV Cation Channels; D013696:Temperature; D013997:Time Factors
D001095:Arachidonic Acids; D002121:Calcium Channel Blockers; D004224:Diterpenes; D063388:Endocannabinoids; D007477:Ions; D008055:Lipids; D053284:Polyunsaturated Alkamides; D011955:Receptors, Drug; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; C468130:iodoresiniferatoxin; D002211:Capsaicin; D002118:Calcium; C078814:anandamide; D004298:Dopamine