Associate editor: D. SpinaBiochemistry and pharmacology of endovanilloids
Introduction
The transient receptor potential (TRP) vanilloid type 1 (TRPV1) channel is a nonselective cation channel that belongs to the TRP family of proteins. TRP encompass at least 3 classes of ion channels that mediate the “receptor”-induced response of a cell to external “transient” stimuli, such as light, temperature, mechanical and osmotic stimuli, electrical charge, and xenobiotic substances, thereby increasing or decreasing its selective permeability to particular ions and subsequently modifying the cell membrane “potential.” In particular, TRP ion channels are named after the role of these proteins in the Drosophila phototransduction mutant that shows a transient instead of a sustained response to bright light (Montell, 2005). TRP are encoded by at least 21 channel subunit genes and are divided into 3 subfamilies: TRPC (canonical), TRPV (vanilloid), and TRPM (melastatin). The heat-activated TRPV1 (vanilloid receptor 1) was the first to be cloned among a group of 6 temperature-activated TRP ion channels (Caterina et al., 1997, Patapoutian et al., 2003). In fact, 4 heat-activated TRP channels (TRPV1–4) and 2 cold-activated channels (TRPM8 and TRPA1; Caterina and Julius, 2001, Patapoutian et al., 2003) have been identified to date. Repeated thermal stimulation may either evoke sensitization (TRPV3 and TRPV2) or desensitization (TRPV4 and TRPA1) of these receptors, as well as distinct intracellular signaling mechanisms within the family of TRP channels (for details, see Caterina et al., 1999, Guler et al., 2002, Peier et al., 2002, Smith et al., 2002, Watanabe et al., 2002, Xu et al., 2002, Story et al., 2003).
TRPV1 was first identified due to its responsiveness to the pungent compound capsaicin isolated from hot chili peppers. TRPV1 also responds to other plant toxins, the most potent of which is resiniferatoxin (RTX) (Szallasi & Blumberg, 1999), and to temperatures in the noxious range (> 43 °C) and acid (Caterina et al., 1997, Tominaga et al., 1998), suggesting that the “capsaicin receptor” may mediate both thermal and chemical pain. Consistent with the hypothesis of its involvement in pain and nociception, TRPV1 expression has been confirmed in small to medium diameter primary afferent fibers (Caterina et al., 1997), which are characteristic peptidergic sensory neurons of unmyelinated nociceptive Aδ and C fibers (Caterina et al., 1997, Tominaga et al., 1998). As mentioned above, TRPV1, being a nociceptor, can also become activated by low pH and inflammatory factors, such as nerve growth factor, bradykinin, lipids, prostaglandins, protein kinases A (PKA) and C (PKC), and ATP (Tominaga and Caterina, 2004, De Petrocellis and Di Marzo, 2005). Also non-neuronal cells, such as keratinocyes (Southall et al., 2003), bladder urothelium, and smooth muscle (Birder et al., 2001), liver (Reilly et al., 2003), polymorphonuclear granulocytes (Heiner et al., 2003), pancreatic β cells (Akiba et al., 2004), endothelial cells (Golech et al., 2004), lymphocytes (Saunders et al., 2007), and macrophages (Chen et al., 2003) express TRPV1, whose physiological role in these cells still remains to be fully understood. Interestingly, TRPV1 has been found also in the brain, such as in dopaminergic neurons of the substantia nigra, hippocampal pyramidal neurons, hypothalamic neurons, and neurons in the locus coeruleus and various layers of the cortex, where it might be involved in the modulation of synaptic plasticity (Mezey et al., 2000, Roberts et al., 2004). More recently TRPV1 has been localized in the rodent hippocampus, cortex, cerebellum, olfactory bulb, mesencephalon, and hindbrain by means of immunohistochemistry (Toth et al., 2005, Cristino et al., 2006a), and its presence in several mouse brain areas was conclusively confirmed by the lack of immunoreactivity in the corresponding brain areas of TRPV1 null mice (Cristino et al., 2006a). The role of brain TRPV1 is not well defined and will be discussed below, although further studies are needed in order to establish its function. Recently, Kofalvi and colleagues (2006) reported no evidence for functional TRPV1 in rat hippocampal neurons, where inconsistent data between ex vivo and in vitro data on the neurochemical and physiological functions of TRPV1 were obtained. Others have recently reviewed the role of TRPV1 in the brain (Steenland et al., 2006).
In the central nervous system or under normal physiological conditions, TRPV1 is unlikely to be activated by heat or low pH. Therefore, the existence of endogenous ligands using this ion channel for inter- or intracellular signaling, the endovanilloids, was suggested (Di Marzo et al., 2001, van der Stelt and Di Marzo, 2004). The recognition of the chemical similarity between the endogenous ligand of cannabinoid receptors N-arachidonoyl-ethanolamine (anandamide, AEA) and capsaicin and, more remarkably, between potent N-acyl-vanillylamide agonists at vanilloid receptors and the prototypic inhibitor of AEA cellular uptake, AM404 (see below), marked the beginning of a large number of studies correlating the endocannabinoid and vanilloid signaling systems (Di Marzo et al., 1998a). Thus, AEA, first, (Zygmunt et al., 1999, Smart et al., 2000) and, later, other derivatives of long-chain unsaturated fatty acids, such as the N-acyldopamines (Huang et al., 2002, Chu et al., 2003), were shown to act as endogenous activators for TRPV1 (van der Stelt & Di Marzo, 2004) (Fig. 1). N-arachidonoyl-dopamine (NADA), but not its potential metabolite, O-methyl-NADA, was found to potently activate TRPV1 in the hippocampus (Huang et al., 2002). Other endogenous agonists of TRPV1 were described by Hwang et al. (2000), who reported that several products of lipoxygenases (LOX) were able to activate the capsaicin-activated channel in isolated membrane patches of sensory neurons. Of these compounds, 12-(S)-hydroperoxyeicosatetraenoic acid [12-(S)-HPETE], 15-(S)-hydroperoxyeicosatetraenoic acid [15-(S)-HPETE], and leukotriene B4 (LTB4) exhibited the highest efficacy.
In this article we review the current knowledge of (1) the regulation of the tissue levels of the endovanilloids and, hence, of the activity of their receptor targets, (2) their main pharmacological actions in vitro and in vivo, and (3) their potential physiological and pathological role.
Section snippets
Biosynthetic pathways for anandamide
AEA was originally isolated from porcine brain as the first endogenous cannabinoid (Devane et al., 1992), and its biosynthesis has subsequently been demonstrated in neurons (Di Marzo et al., 1994), macrophages (Di Marzo et al., 1996), and many other tissues and cell types. By activating the CB1 receptor, AEA reduces adenylate cyclase activity, inhibits the activity of voltage-gated Ca2+ currents and activates inwardly rectifying K+ currents (Mackie and Hille, 1992, Felder et al., 1993, Vogel et
Biosynthesis and degradation
NADA was identified as an endogenous compound that possesses medium to high nanomolar potency for both TRPV1 and cannabinoid CB1 receptors (Bisogno et al., 2000, Huang et al., 2002) and found at the highest concentrations (max, ∼ 6 pmol/g wet tissue weight) in 2 rat brain regions, the striatum and hippocampus. NADA was also found in cerebellum, thalamus, and DRG (Huang et al., 2002). Being most abundant in the striatum, the brain region with the highest amounts of DA, NADA was suggested to be
Anandamide and N-arachidonoyl-dopamine congeners as endovanilloids or “entourage” compounds
Among long-chain, linear fatty acid dopamides, also N-oleoyl-dopamine, was shown to potently activate TRPV1 (Chu et al., 2003). This compound was much more selective than NADA versus CB1 receptors. Two other congeners, N-palmitoyl- and N-stearoyl-dopamine (PALDA and STEARDA), though inactive per se on TRPV1, acted, in both HEK293 cells overexpressing the human TRPV1 and in in vivo experiments, as ‘entourage’ compounds, that is, they enhanced the stimulatory effects on TRPV1 exerted by other
Biosynthesis and degradation
In addition to AEA, NADA, and their congeners, also LOX products of AA have been proposed as candidates for the role of endovanilloids. 12-(S)-HPETE, 15-(S)-HPETE, and LTB4 were shown to be more efficacious than AEA as vanilloid receptor agonists when monitoring TRPV1-mediated currents in isolated membrane patches of sensory neurons and in HEK cells (Hwang et al., 2000). The structural similarity between capsaicin and 12-(S)-HPETE was demonstrated by modelling studies and might explain why
3-Hydroxy-eicosatetraenoic acid and 3-hydroxy-anandamide: 2 new endovanilloids?
We recently investigated the possibility that 3-hydroxy-eicosatetraenoic acid (3-HETE), a fungal metabolite of AA produced by Candida albicans and related fungi via a fatty acid β-oxidation-related pathway (van Dyk et al., 1991), is capable to activate human recombinant TRPV1 receptors and, hence, to act as an endovanilloid. We found that in HEK293 cells overexpressing the human TRPV1, but not in wild-type HEK293 cells, 3-HETE dose-dependently elevated the intracellular Ca2+ concentration, this
Physiological and pathological processes potentially involving the endovanilloids as suggested by studies in which transient receptor potential vanilloid type 1 function is impaired
An idea of the potential physiological and pathological roles of endovanilloids can be gained also from studies in which TRPV1 receptors are impaired either genetically, as in TRPV1−/− mice, or by means of RNA interference techniques or following treatment with selective antagonists. In agreement with the proposed role of TRPV1 in the processing of multiple pain producing stimuli (Tominaga et al., 1998, Tominaga and Julius, 2000), it was first noted that TRPV1−/− mice exhibit an impaired
Concluding remarks
From the published evidence described in this article, it is possible to conclude that endovanilloids and TRPV1 receptors play important physiological and, particularly, pathological roles not only in the peripheral sensory nervous system but also in the brain and in non-nervous tissues. This conclusion opens the way to the development of synthetic compounds targeting either TRPV1 receptors or the enzymes responsible for endovanilloid biosynthesis and degradation as potential new therapeutic
Acknowledgments
KS and VDM are grateful to the Volkswagenstiftung for supporting their work on TRPV1 receptors in the brain, and to Dr. Luigia Cristino, Institute of Cybernetics, CNR, for preparing Fig. 3.
References (239)
- et al.
Cannabinoid 1 receptors are expressed by nerve growth factor- and glial cell-derived neurotrophic factor-responsive primary sensory neurones
Neuroscience
(2002) - et al.
Cannabinoid 1 receptors are expressed in nociceptive primary sensory neurons
Neuroscience
(2000) - et al.
Transient receptor potential vanilloid subfamily 1 expressed in pancreatic islet beta cells modulates insulin secretion in rats
Biochem Biophys Res Commun
(2004) - et al.
Local inflammation increases vanilloid receptor 1 expression within distinct subgroups of DRG neurons
Brain Res
(2003) - et al.
4 clinically useful vanilloid receptor TRPV1 antagonists: just around the corner (or too early to tell)?
Prog Med Chem
(2006) - et al.
Vanilloid receptor 1 expression in the rat urinary tract
Neuroscience
(2002) - et al.
Attenuation of experimental arthritis in TRPV1R knockout mice
Exp Mol Pathol
(2006) - et al.
Modulation of human TRPV1 receptor activity by extracellular protons and host cell expression system
Eur J Pharmacol
(2006) - et al.
Investigation of the role of TRPV1 receptors in acute and chronic nociceptive processes using gene-deficient mice
Pain
(2005) - et al.
Peripheral capsaicin receptors increase in the inflamed rat hindpaw: a possible mechanism for peripheral sensitization
Neurosci Lett
(2001)
Sensory fibres expressing capsaicin receptor TRPV1 in patients with rectal hypersensitivity and faecal urgency
Lancet
Antinociceptive effect of antisense oligonucleotides against the vanilloid receptor VR1/TRPV1
Neurochem Int
Silencing of vanilloid receptor TRPV1 by RNAi reduces neuropathic and visceral pain in vivo
Biochem Biophys Res Commun
N-oleoyldopamine, a novel endogenous capsaicin-like lipid that produces hyperalgesia
J Biol Chem
Arachidonyl ethanolamide induces apoptosis of uterine cervix cancer cells via aberrantly expressed vanilloid receptor-1
Gynecol Oncol
Immunohistochemical localization of cannabinoid type 1 and vanilloid transient receptor potential vanilloid type 1 receptors in the mouse brain
Neuroscience
Involvement of vanilloid-like receptors in the effects of anandamide on motor behavior and nigrostriatal dopaminergic activity: in vivo and in vitro evidence
Brain Res
UCM707, an inhibitor of the anandamide uptake, behaves as a symptom control agent in models of Huntington's disease and multiple sclerosis but fails to delay/arrest the progression of different motor-related disorders
Eur Neuropsychopharmacol
Lipids as regulators of the activity of transient receptor potential type V1 (TRPV1) channels
Life Sci
Overlap between the ligand recognition properties of the anandamide transporter and the VR1 vanilloid receptor: inhibitors of anandamide uptake with negligible capsaicin-like activity
FEBS Lett
The activity of anandamide at vanilloid VR1 receptors requires facilitated transport across the cell membrane and is limited by intracellular metabolism
J Biol Chem
Palmitoylethanolamide enhances anandamide stimulation of human vanilloid VR1 receptors
FEBS Lett
Highly selective CB(1) cannabinoid receptor ligands and novel CB(1)/VR(1) vanilloid receptor "hybrid" ligands
Biochem Biophys Res Commun
Interactions between synthetic vanilloids and the endogenous cannabinoid system
FEBS Lett
Anandamide receptors
Prostaglandins Leukot Essent Fatty Acids
Endocannabinoids: endogenous cannabinoid receptor ligands with neuromodulatory action
Trends Neurosci
Comparative analysis of fatty acid amide hydrolase and cb(1) cannabinoid receptor expression in the mouse brain: evidence of a widespread role for fatty acid amide hydrolase in regulation of endocannabinoid signaling
Neuroscience
Cannabinoid CB1 receptor expression in rat spinal cord
Mol Cell Neurosci
Molecular determinants of vanilloid sensitivity in TRPV1
J Biol Chem
Human brain endothelium: coexpression and function of vanilloid and endocannabinoid receptors
Brain Res Mol Brain Res
Identification and characterisation of SB-366791, a potent and selective vanilloid receptor (VR1/TRPV1) antagonist
Neuropharmacology
Capsaicin-like effects or N-arachidonoyl-dopamine in the isolated guinea pig bronchi and urinary bladder
Eur J Pharmacol
Characterization of the kinetics and distribution of N-arachidonylethanolamine (anandamide) hydrolysis by rat brain
Biochim Biophys Acta
TRPV1 and the gut: from a tasty receptor for a painful vanilloid to a key player in hyperalgesia
Eur J Pharmacol
Early painful diabetic neuropathy is associated with differential changes in the expression and function of vanilloid receptor 1
J Biol Chem
Identification of a new class of molecules, the arachidonyl amino acids, and characterization of one member that inhibits pain
J Biol Chem
Voltage-dependent priming of rat vanilloid receptor: effects of agonist and protein kinase C activation
J Physiol
Extracellular cations sensitize and gate capsaicin receptor TRPV1 modulating pain signaling
J Neurosci
Anandamide regulates neuropeptide release from capsaicin-sensitive primary sensory neurons by activating both the cannabinoid 1 receptor and the vanilloid receptor 1 in vitro
Eur J Neurosci
Vanilloid type 1 receptors (VR1) on trigeminal sensory nerve fibres play a minor role in neurogenic dural vasodilatation, and are involved in capsaicin-induced dural dilation
Br J Pharmacol
Anandamide acts as a vasodilator of dural blood vessels in vivo by activating TRPV1 receptors
Br J Pharmacol
Mechanisms underlying tissue selectivity of anandamide and other vanilloid receptor agonists
Mol Pharmacol
Halogenation of a capsaicin analogue leads to novel vanilloid TRPV1 receptor antagonists
Br J Pharmacol
The endogenous TRPV1 ligand anandamide increases in the rat inflamed urinary bladder and may contribute to inflammatory pain
Soc Neurosci
The Bezold-Jarisch reflex. A historical perspective of cardiopulmonary reflexes
Ann N Y Acad Sci
Cannabinoid antagonist SR-141716 inhibits endotoxic hypotension by a cardiac mechanism not involving CB1 or CB2 receptors
Am J Physiol Heart Circ Physiol
Functional role of high-affinity anandamide transport, as revealed by selective inhibition
Science
Capsaicin receptor (TRPV1) and non-erosive reflux disease
Eur J Gastroenterol Hepatol
Vanilloid receptor expression suggests a sensory role for urinary bladder epithelial cells
Proc Natl Acad Sci U S A
N-acyl-dopamines: novel synthetic CB(1) cannabinoid-receptor ligands and inhibitors of anandamide inactivation with cannabimimetic activity in vitro and in vivo
Biochem J
Cited by (338)
CB2 receptor in the CNS: From immune and neuronal modulation to behavior
2023, Neuroscience and Biobehavioral ReviewsInhibiting degradation of 2-arachidonoylglycerol as a therapeutic strategy for neurodegenerative diseases
2023, Pharmacology and TherapeuticsParkinson's disease related alterations in cannabinoid transmission
2022, Brain Research Bulletin