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Endogenous activators of the pain receptor TRPV1 From cell to man

Movahed Rad, Pouya LU (2005)
Abstract (Swedish)
Popular Abstract in Swedish

N-acyletanolaminer (NAE) tillhör en växande grupp av kroppsegna lipider, som påverkar en mängd olika receptorer och jonkanaler. En sådan substans är anandamid, som finns i hjärnan och många andra organ. 1992 visade en grupp forskare att anandamid aktiverar receptorn för ?9-tetrahydrocannabinol (cannabinoidreceptorn) i centrala nervsystemet. Anandamid och andra NAE bildas vid receptor aktivering eller då celler utsatta för stress. Anandamidnivåerna ökar under många patologiska tillstånd, såsom vävnadsskada, ischemi och inflammation. Fettsyraamidhydrolas är ett enzym, som svarar för nedbrytningen av anandamid och andra NAE. Både in vivo studier genomförda på försöksdjur och in vitro experiment... (More)
Popular Abstract in Swedish

N-acyletanolaminer (NAE) tillhör en växande grupp av kroppsegna lipider, som påverkar en mängd olika receptorer och jonkanaler. En sådan substans är anandamid, som finns i hjärnan och många andra organ. 1992 visade en grupp forskare att anandamid aktiverar receptorn för ?9-tetrahydrocannabinol (cannabinoidreceptorn) i centrala nervsystemet. Anandamid och andra NAE bildas vid receptor aktivering eller då celler utsatta för stress. Anandamidnivåerna ökar under många patologiska tillstånd, såsom vävnadsskada, ischemi och inflammation. Fettsyraamidhydrolas är ett enzym, som svarar för nedbrytningen av anandamid och andra NAE. Både in vivo studier genomförda på försöksdjur och in vitro experiment utförda på isolerade vävnader visar att anandamid har olika effekter på det kardiovaskulära systemet såsom hypotension, bradykardi och vasodilatation. Makrofager, monocyter, kärlendotelceller och sensoriska nerver har förmåga att bilda anandamid och andra NAE. Mekanismerna bakom de kadiovaskulära effekterna av anandamid är inte helt kartlagda, men verkar vara beroende av de experimentella förutsättningar, som till exempel administrationssättet.



Anandamid kan vidga isolerade blodkärl genom att aktivera den så kallade kapsaicinreceptorn (TRPV1), som är belägen på sensoriska nerver i kärlväggen. Aktivering av TRPV1 leder till en frisättning av neuropeptiden kalcitoningenrelated peptid, som är en mycket effektiv vasodilator. TRPV1 är en oselektiv katjonkanal tillhörande familjen transientreceptorpotentialkanaler (TRP). Denna kanal aktivares bland annat av kapsaicin, som är den brännande substansen i chilipeppar.



I den här avhandlingen visar vi att metanandamid, som är en syntetisk analog till anandamid, ger upphov till en vasodilatation i mesenterialkärlbädden på råtta genom att aktivera TRPV1 på sensoriska nerver. Anandamid orsakar också en vasodilatation i huden på människa och denna effekt, som är känslig för den selektiva TRPV1 antagonisten kapsazepin, kan reproduceras av andra TRPV1 agonister, såsom kapsaicin och olvanil.



De kroppsegna lipiderna N-linolenoyletanolamin (18:3 NAE), N-linoleoyletanolamin (18:2 NAE), N-oleoyletanolamin (18:1 NAE) and N-stearoyletanolamin (18:0 NAE) uppvisar strukturella likheter med anandamid, men till skillnad från denna kan de inte aktivera cannabinoidreceptorn. Vi kan nu visa att dessa lipider förekommer i både kärlvävnad och sensoriska nervganglier i mängder, som i vissa fall vida överskrider nivåerna av anandamid. 18:3 NAE, 18:2 NAE and 18:1 NAE, men inte 18:0 NAE and oleinsyra, aktiverar TRPV1 i blodkärl från råtta och motsvarande jonkanal från människa när den uttryckts artificiellt i eukaryota celler.



Den här studien visar tydligt att metanandamid kan orsaka vasodilatation i den isolerade mesenterialkärlbädden från råtta genom att aktivera TRPV1 på primärsensoriska nerver. Dessutom visar vi att anandamid genom att aktivera TRPV1 kan öka blodflödet i huden på människa. Detta är den första gången någon visar en biologisk effekt av anandamid på människa. Vi har även identifierat flera endogena substanser, tillhörande den kemiska gruppen NAE, som kan aktivera TRPV1. Dessa omättade lipider, som alla saknar aktivitet på cannabinoidreceptorer, skulle kunna verka tillsammans med andra kroppsegna TRPV1 modulatorer såsom anandamid och lipoxygenasprodukter vid olika tillstånd förknippade med aktiveringen av kapsaicinkänsliga sensoriska nerver. Smärta, inflammation, vävnadsischemi och blåsfunktionsrubbningar är exempel på sådana tillstånd. (Less)
Abstract
N-acylethanolamines (NAEs) belong to a growing family of endogenous signalling molecules acting on a variety of receptors and ion channels. In 1992, it was reported that the N-acylethanolamine anandamide is present in the brain and activates the central cannabinoid (CB) receptor. Anandamide and other NAEs are considered to be generated on demand following receptor activation or cell stress. The tissue level of anandamide increases during ischemic tissue injury and inflammation. Hydrolytic cleavage of the amide bond by fatty acid amide hydrolase is responsible for the elimination of anandamide and other N-acylethanolamines.



Studies on whole animals or isolated tissues have shown that anandamide induces a variety of... (More)
N-acylethanolamines (NAEs) belong to a growing family of endogenous signalling molecules acting on a variety of receptors and ion channels. In 1992, it was reported that the N-acylethanolamine anandamide is present in the brain and activates the central cannabinoid (CB) receptor. Anandamide and other NAEs are considered to be generated on demand following receptor activation or cell stress. The tissue level of anandamide increases during ischemic tissue injury and inflammation. Hydrolytic cleavage of the amide bond by fatty acid amide hydrolase is responsible for the elimination of anandamide and other N-acylethanolamines.



Studies on whole animals or isolated tissues have shown that anandamide induces a variety of effects in the cardiovascular system, including vasodilatation, bradycardia and hypotension. Macrophages and monocytes, endothelial cells and sensory nerves are possible cellular sources of anandamide in the vascular system. The mechanisms behind the cardiovascular effects of anandamide are not fully understood, but seem to depend on the bioassay and the mode of administration of anandamide. In isolated arterial segments, anandamide produces vasorelaxation via activation of transient receptor potential vanilloid 1 (TRPV1) on perivascular sensory nerves and the subsequent release of the potent vasodilator calcitonin gene-related peptide. TRPV1 is a nonselective cation channel, belonging to the transient receptor potential ion channel superfamily, and the receptor for the pungent ingredient in hot chilli peppers. In this work, we show that anandamide and its metabolically stable analogue methanandamide are able to cause vasodilatation in intact vascular beds by a similar TRPV1-dependent mechanism. The vasodilator response to methanandamide in rat isolated perfused mesenteric arterial bed is inhibited by the TRPV1 antagonist ruthenium red. More importantly, anandamide together with well known plant-derived or synthetic TRPV1 agonists are able to cause vasodilatation in vivo in human skin, an effect inhibited by the selective TRPV1 antagonist capsazepine.



The endogenous C18 NAEs N-linolenoylethanolamine (18:3 NAE), N-linoleoylethanolamine (18:2 NAE), N-oleoylethanolamine (18:1 NAE) and N-stearoylethanolamine (18:0 NAE) are structurally related to anandamide, but these lipids are poor ligands at cannabinoid CB1 receptors. Here we show that these lipids are present in rat sensory ganglia and vascular tissue in levels that may substantially exceed those of anandamide. 18:3 NAE, 18:2 NAE and 18:1 NAE, but not 18:0 NAE and oleic acid, activate rat TRPV1 on perivascular sensory nerves and human TRPV1 expressed in eukaryotic cells.



In conclusion, this study clearly show that, in the rat isolated mesenteric arterial bed, the vasodilator response to methanandamide is mediated predominantly via activation of TRPV1 on sensory nerves. We also demonstrate for the first time that anandamide has biological activity in man, causing vasodilatation in human skin microcirculation via activation of TRPV1. We also identify novel endogenous TRPV1 ligands, belonging to the C18 NAE family of lipids. These unsaturated C18 NAEs, which are poor ligands at the cannabinoid CB1 receptor, may act in concert with anandamide as endogenous TRPV1 modulators in conditions associated with activation of capsaicin-sensitive sensory nerves, including pain, inflammation, ischemia and bladder instability. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Professor Fowler, Christopher, Institutionen för farmakologi och klinisk neurovetenskap Umeå universitet
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Medicin (människa och djur), Medicine (human and vertebrates), cannabinoids, capsazepine, N-acylethanolamines, anandamide, blood Circulation, vasodilation, humans, calcitonin Gene-related Peptide, capsaicin, neurogenic inflammation, nociceptors, TRPV1 protein, pain
publisher
Divison of Clinical Chemistry and Pharmacology, Lund University
defense location
Föreläsningssal 1 (F1)Centralblocket, Universitetssjukhuset I Lund
defense date
2005-09-16 13:00
ISSN
1652-8220
ISBN
91-85439-69-X
language
English
LU publication?
yes
id
9ef53404-2e01-44a0-a10b-170f133eaa3b (old id 545264)
date added to LUP
2007-09-23 10:59:39
date last changed
2016-09-19 08:44:56
@phdthesis{9ef53404-2e01-44a0-a10b-170f133eaa3b,
  abstract     = {N-acylethanolamines (NAEs) belong to a growing family of endogenous signalling molecules acting on a variety of receptors and ion channels. In 1992, it was reported that the N-acylethanolamine anandamide is present in the brain and activates the central cannabinoid (CB) receptor. Anandamide and other NAEs are considered to be generated on demand following receptor activation or cell stress. The tissue level of anandamide increases during ischemic tissue injury and inflammation. Hydrolytic cleavage of the amide bond by fatty acid amide hydrolase is responsible for the elimination of anandamide and other N-acylethanolamines.<br/><br>
<br/><br>
Studies on whole animals or isolated tissues have shown that anandamide induces a variety of effects in the cardiovascular system, including vasodilatation, bradycardia and hypotension. Macrophages and monocytes, endothelial cells and sensory nerves are possible cellular sources of anandamide in the vascular system. The mechanisms behind the cardiovascular effects of anandamide are not fully understood, but seem to depend on the bioassay and the mode of administration of anandamide. In isolated arterial segments, anandamide produces vasorelaxation via activation of transient receptor potential vanilloid 1 (TRPV1) on perivascular sensory nerves and the subsequent release of the potent vasodilator calcitonin gene-related peptide. TRPV1 is a nonselective cation channel, belonging to the transient receptor potential ion channel superfamily, and the receptor for the pungent ingredient in hot chilli peppers. In this work, we show that anandamide and its metabolically stable analogue methanandamide are able to cause vasodilatation in intact vascular beds by a similar TRPV1-dependent mechanism. The vasodilator response to methanandamide in rat isolated perfused mesenteric arterial bed is inhibited by the TRPV1 antagonist ruthenium red. More importantly, anandamide together with well known plant-derived or synthetic TRPV1 agonists are able to cause vasodilatation in vivo in human skin, an effect inhibited by the selective TRPV1 antagonist capsazepine.<br/><br>
<br/><br>
The endogenous C18 NAEs N-linolenoylethanolamine (18:3 NAE), N-linoleoylethanolamine (18:2 NAE), N-oleoylethanolamine (18:1 NAE) and N-stearoylethanolamine (18:0 NAE) are structurally related to anandamide, but these lipids are poor ligands at cannabinoid CB1 receptors. Here we show that these lipids are present in rat sensory ganglia and vascular tissue in levels that may substantially exceed those of anandamide. 18:3 NAE, 18:2 NAE and 18:1 NAE, but not 18:0 NAE and oleic acid, activate rat TRPV1 on perivascular sensory nerves and human TRPV1 expressed in eukaryotic cells.<br/><br>
<br/><br>
In conclusion, this study clearly show that, in the rat isolated mesenteric arterial bed, the vasodilator response to methanandamide is mediated predominantly via activation of TRPV1 on sensory nerves. We also demonstrate for the first time that anandamide has biological activity in man, causing vasodilatation in human skin microcirculation via activation of TRPV1. We also identify novel endogenous TRPV1 ligands, belonging to the C18 NAE family of lipids. These unsaturated C18 NAEs, which are poor ligands at the cannabinoid CB1 receptor, may act in concert with anandamide as endogenous TRPV1 modulators in conditions associated with activation of capsaicin-sensitive sensory nerves, including pain, inflammation, ischemia and bladder instability.},
  author       = {Movahed Rad, Pouya},
  isbn         = {91-85439-69-X},
  issn         = {1652-8220},
  keyword      = {Medicin (människa och djur),Medicine (human and vertebrates),cannabinoids,capsazepine,N-acylethanolamines,anandamide,blood Circulation,vasodilation,humans,calcitonin Gene-related Peptide,capsaicin,neurogenic inflammation,nociceptors,TRPV1 protein,pain},
  language     = {eng},
  publisher    = {Divison of Clinical Chemistry and Pharmacology, Lund University},
  school       = {Lund University},
  title        = {Endogenous activators of the pain receptor TRPV1 From cell to man},
  year         = {2005},
}