Anandamide and Vanilloid TRPV1 Receptors: Mini Review

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British Journal of Pharmacology (2003) 140, 790–801 & 2003 Nature Publishing Group All rights reserved 0007

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MINI REVIEW
Anandamide and vanilloid TRPV1 receptors
*,1Ruth A. Ross
1
Department of Biomedical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD,
Scotland

A large body of evidence now exists to substantiate that the endocannabinoid, anandamide, activates
TRPV1 receptors. It is a low intrinsic efficacy TRPV1 agonist that behaves as a partial agonist in
tissues with a low receptor reserve, while in tissues with high receptor reserve and in circumstances
associated with certain disease states, it behaves as a full agonist. The efficacy of anandamide as a
TRPV1 agonist is influenced by a succession of factors including receptor reserve, phosphorylation,
metabolism and uptake, CB1 receptor activation, voltage, temperature, pH and bovine serum
albumin. There are indications that the endocannabinoid system may play a role in the modulation of
TRPV1 receptor activation. The activation of TRPV1 receptors by anandamide has potential
implications in the treatment of inflammatory, respiratory and cardiovascular disorders. The relative
importance of anandamide as a physiological and/or pathophysiological TRPV1 receptor agonist in
comparison to other potential candidates has yet to be revealed.
British Journal of Pharmacology (2003) 140, 790–801. doi:10.1038/sj.bjp.0705467
Keywords: Anandamide; vanilloid; TRPV1; cannabinoid; endocannabinoid; endovanilloid; lipoxygenase
Abbreviations: Anandamide, (arachidonyl ethanolamide); capsaicin, (3-methoxy-4-hydroxy)benzyl-8-methyl-6-nonenamide; CB1,
cannabinoid receptor; DRG, dorsal root ganglion; HETE, hydroxyeicoatetraenoic acids; HPETE, hydroperoxy-
eicosatetraenoic acids; PDBu, phorbol 12,13 dibutyrate; PKC, protein kinase C; RTX, resiniferatoxin; TRP,
transient receptor potential

Introduction
The vanilloid VR1 or TRPV1 receptor is part of a family cells (see Parolaro et al., 2002). This article will focus on the
of transient receptor potential (TRP) channels (see Benham most recent findings and, in particular, those aspects relating
et al., 2002), whose expression is largely associated with small to the pharmacology of anandamide.
diameter primary afferent fibres. This receptor is a nonselec-
tive cation channel that integrates multiple noxious stimuli The basics: affinity, potency and efficacy
and is associated with the pathophysiology of various major
diseases (Szallasi, 2002). It is activated by the naturally There is ample evidence that the interaction of anandamide
occurring vanilloids, capsaicin and resiniferatoxin (RTX), with TRPV1 receptors is specific: TRPV1 actions are blocked
noxious heat and acid (see Szallasi, 2002). Anandamide (N- by receptor-specific antagonists and not by antagonists of CB1
arachidonoyl-ethanolamide) is an ‘endocannabinoid’, as and CB2 receptors; desensitisation of TRPV1 via capsaicin
defined by its ability to bind to and activate cannabinoid pretreatment abrogates the effects of anandamide; neonatal
CB1 and CB2 receptors (see Pertwee & Ross, 2002); however, capsaicin treatment prevents anandamide activation of
the pharmacology of this compound is complex (see Di Marzo, TRPV1; anandamide-mediated TRPV1 effects are absent from
2002; Di Marzo et al., 2002b). The search for endogenous untransfected cells that do not express TRPV1 receptors;
TRPV1 receptor activators or ‘endovanilloids’ is ongoing anandamide displaces radiolabelled RTX from specific binding
and recent advances suggest that anandamide may be one sites (Zygmunt et al., 1999; Smart et al., 2000; Ross et al.,
such compound (Di Marzo et al., 2001). Since the first 2001b).
revelations of the structural similarity of anandamide to It seems appropriate to begin this article by reviewing the
capsaicin and of its ability to activate TRPV1 receptors literature relating to the pharmacology of anandamide and
(Melck et al., 1999; Zygmunt et al., 1999; Smart et al., 2000), TRPV1. Traditionally, the foundations of the pharmacological
this topic has been the focus of exciting and sometimes analysis of any compound are the three basic parameters of
controversial debate. affinity, potency and efficacy. Numerous studies confirm that
Various reviews cover the interaction of anandamide with anandamide activates TRPV1 receptors; those that specifically
TRPV1 receptors in pain pathways (see Di Marzo et al., 2002a; measure the affinity, efficacy or potency at native and
Iversen & Chapman, 2002; Rice et al., 2002; Walker & Huang, recombinant TRPV1 receptors are shown in Tables 1 and 2.
2002), the cardiovascular system (see Högestätt & Zygmunt,
2002; Ralevic et al., 2002; Randall et al., 2002) and immune
Affinity

*Author for correspondence; E-mail: r.ross@abdn.ac.uk Radioligand displacement assays in recombinant cell lines
Advance online publication: 29 September 2003 using the high-affinity TRPV1 agonist [3H]RTX demonstrate
R.A. Ross Anandamide and vanilloid receptors 791

Table 1 Studies measuring the affinity, potency and efficacy of anandamide at recombinant TRPV1 receptors
Cell line Affinity (Ki) Measured response pH Potency (pEC50) Efficacy Reference
(Emax) (%)a

HEK Inward current 7.4 5.3170.06 B30 – 50 Zygmunt et al. (1999)


293(rat)
[Ca2+]i (FLIPR) 7.4 5.7370.04 100 Ralevic et al. (2001)
6.4 5.7670.04 F Ralevic et al. (2001)
[Ca2+]i (FLIPR) F 5.8570.01 100 Jerman et al. (2002)
[Ca2+]i (Fura-2) F 5.8570.12 63 Sprague et al. (2001)
(221C)
5.1570.04 72 Sprague et al. (2001)
(371C)
o4 (501C) 120 Sprague et al. (2001)

HEK 293 [Ca2+]i (FLIPR) 7.4 5.9470.06 100 Smart et al. (2000)
(human)
6.4 5.7670.04 100 Smart et al. (2000)
7.4 5.6070.10 100 Ralevic et al. (2001)
7.4 6.66 (with LEA)b F Smart et al. (2000)
7.4 5.74 (no LEA) F Smart et al. (2002)
F [Ca2+]i (Fluro-3 7.4 6.20 100 De Petrocellis et al. (2001a)
imaging)
5.40 (with PEA) 7.4 6.66 (with PEA)c F De Petrocellis et al. (2001b)
4.72 (no PEA) 6.36 (no PEA) F De Petrocellis et al. (2001b)

CHO (rat) 5.7870.06 (with PMSF) [Ca2+]i ([45Ca2+] 7.4 5.8070.04 100 Ross et al. (2001b)
uptake) (with PMSF)d
o5 (no PMSF) 7.4 o5 (no PMSF) F Ross et al. (2001b)

CHO 2+
[Ca ]i 7.5 5.01 B22 Savidge et al. (2002)
(guinea-pig)
NIH 3T3 [Ca2+]i ([45Ca2+] 5.5 4.85 F Olah et al. (2001)
(rat) uptake)
6.0 4.60 F Olah et al. (2001)
6.5 4.20 F Olah et al. (2001)
a
Relative to that of capsaicin (100%).
b
Lauroylethanolamide (LEA) is an N-acylethanolamide.
c
Palmitoylethanolamide (PEA) is an N-acylethanolamide.
d
Phenylmethylsulphonyl fluoride (PMSF) is an inhibitor of FAAH.

Table 2 Studies measuring the affinity, potency and efficacy of anandamide at native TRPVI receptors
Tissue Measured response Potency (pEC50) Efficacy (Emax) (%)a Reference

Guinea-pig basilar artery Relaxation 6.0270.11 10071 Zygmunt et al. (1999)


Rat hepatic artery Relaxation 6.4570.11 9273 Zygmunt et al. (1999)
Rat mesenteric artery Relaxation 6.170.1 9871 Andersson et al. (2002)
Rat mesenteric bed Relaxation 6.3270.04 B100% Ralevic et al. (2001)
Guinea-pig bronchi Contraction 5.2370.1 (with PMSF)b 46.576.0 Tucker et al. (2001)
5.2670.05 (no PMSF) 41.675.8 Tucker et al. (2001)
5.1870.11 (with PMSF) 49.573.9 Craib et al. (2001)
4.1570.64 (no PMSF) F Craib et al. (2001)

o5.470.1 42876 Andersson et al. (2002)

Guinea-pig ileum [3H]Ach release 6.3 F Mang et al. (2001)


Increased muscle tone 6.3 F

Mouse trigeminal neurones Outward current 5.370.1 3872 Roberts et al. (2001)
Rat DRG Inward current F 10 – 50 Smart et al. (2001)
Single channel currents 4.93 F Hwang et al. (2001)
(inside-out patches)
[Ca2+]i ([5Ca2+ ] uptake) 5.15 (pH 5.5) F Olah et al. (2001)
5 (pH 6) B23% Olah et al. (2001)
Inactive (pH 6.6) F Olah et al. (2001)
[Ca2+]i (FLIPR) F B63% Jerman et al. (2002)
a
Relative to that of capsaicin (100%).
b
Phenylmethylsulphonyl fluoride (PMSF) is an inhibitor of FAAH.

British Journal of Pharmacology vol 140 (5)


792 R.A. Ross Anandamide and vanilloid receptors

that anandamide has a low affinity for the receptor. While the (1999) estimate the efficacy of anandamide to be 30 – 50% that
Ki value of B2 mM for anandamide is high, it is similar to that of capsaicin. In the same cells, Sprague et al. (2001) find that,
of the established receptor agonist capsaicin (De Petrocellis at 22 and 371C, the Emax value for anandamide is 63 and 72%
et al., 2001b; Ross et al., 2001b). This assay is, of course, of the response to capsaicin. In CHO cells expressing guinea-
reliant on RTX binding to the same site on TRPV1 as other pig TRPV1, anandamide has a significantly lower efficacy
agonists. It has been observed that RTX has a significantly (22%) than that of capsaicin (Savidge et al., 2002). Similar
lower Ki/EC50 ratio than capsaicin as measured in radioligand differences are found in tissues expressing native TRPV1
binding and functional Ca2 þ uptake assays (see Di Marzo receptors and the efficacy of anandamide appears to be tissue
et al., 2002a) in both native and recombinant TRPV1 dependent (Table 2). Thus, it is a full agonist in blood vessels
expression systems. Such findings can be explained on the and mesenteric arterial bed; it is a partial agonist in the
basis that RTX has a lower intrinsic efficacy than capsaicin. bronchus, dorsal root ganglion (DRG) and trigeminal
Indeed, there is direct evidence that RTX is a lower efficacy neurones (Table 2). In the substantia gelatinosa neurones of
agonist at TRPV1 than capsaicin (Wardle et al., 1997; Ross the dorsal horn, anandamide activates TRPV1 receptors to
et al., 2001b; Andersson et al., 2002). However, it is possible increase the frequency of mEPSPs and stimulate neuropeptide
that RTX and capsaicin bind to different domains on the release, but only at high concentrations of 10 and 50 mM (see
receptor. There is now evidence that RTX behaves differently Morisset et al., 2001).
from capsaicin: the activation of TRPV1 by RTX leads to a The differences in the efficacy of anandamide between
Ca2 þ -independent Ca2 þ mobilisation that is not observed with tissues and as measured using different pharmacological end
capsaicin (Marshall et al., 2003). Such data question the points can be accounted for by a low intrinsic efficacy. Agonist
usefulness of [3H]RTX as a radioligand for the direct potency is a function of both affinity and efficacy. The ratio of
measurement of the TRPV1 receptor ‘affinity’ of anandamide Ki (inhibition constant) to EC50 value is indicative of the
and capsaicin: the inhibition of binding of [3H]RTX does not relative intrinsic efficacy of a compound. In CHO cells
necessarily imply a direct competition and may be explained by expressing rTRPV1, Ross et al. (2001b) found that, although
allosteric binding sites on the TRPV1 receptor. anandamide and AM404 have Emax values of 100%, they
There is good evidence that the structural determinants for display a low Ki/EC50 ratio as determined from radioligand
capsaicin binding and sensitivity are also essential for the binding and [45Ca2 þ ] uptake data. This is indicative of a low
interaction of anandamide with the receptor (Jordt & Julius, intrinsic efficacy. As a consequence of the low intrinsic efficacy
2002). Consequently, in mutant receptors rendered insensitive of anandamide at TRPV1, the Emax value will vary with the
to capsaicin, anandamide is also inactive, even at low pH. pharmacological end point that is measured. Thus, while the
While the wild-type VRL-1 receptor does not normally bind elevation of [Ca2 þ ]i has a high degree of signal amplification,
either capsaicin or anandamide; VRL-1 receptor mutants, in measurement of the TRPV1 current has no downstream
which capsaicin displaces the specific binding of [3H]RTX, also amplification. Accordingly, analyses of TRPV1 currents in
have an affinity for anandamide (Jordt & Julius, 2002). sensory neurones reveal that anandamide is a partial agonist
(Zygmunt et al., 1999; Roberts et al., 2002). When the response
Potency in the elevation in [Ca2 þ ]i is measured, anandamide is found to
be either a partial or a full agonist depending on the tissue used
While anandamide has a similar affinity for TRPV1 to that of (see Tables 1 and 2).
capsaicin, it has a significantly lower potency. In high The low intrinsic efficacy of anandamide at the TRPV1
expression recombinant cell lines using various methods, the receptor has important physiological implications. A low
potency (EC50) of anandamide has been measured in the range intrinsic efficacy agonist will attenuate the effects of a full
of 0.7 – 5 mM (Table 1). In native systems, the potency of agonist. Indeed, in trigeminal neurones, coapplication of
anandamide ranges from 0.3 to 0.8 mM in blood vessels anandamide with capsaicin significantly reduces the currents
(relaxation) compared with 6 – 10 mM in bronchus (contrac- produced by capsaicin (Roberts et al., 2002). If endogenous
tion) and DRG neurones ([Ca2 þ ]i and inward current) activators of TRPV1 exist that are full agonists, then
(Table 2). compounds such as anandamide may have an inhibitory role
and serve as anti-inflammatory and analgesic compounds.
Efficacy: full or partial agonist? Indeed, a high efficacy TRPV1 agonist, N-arachidonoyl-
dopamine (NADA), has recently been isolated from the
While it is clear that anandamide can activate TRPV1 central nervous system (Huang et al., 2002).
receptors, significant differences emerge when comparisons
are made of the efficacy of anandamide in native and
recombinant receptor systems. There are also significant Factors influencing the efficacy and potency of
differences between tissues. Using the measurement of [Ca2 þ ]i anandamide at TRPV1
in high expression recombinant cell lines expressing either rat
or human TRPV1, anandamide appears to be a full agonist as The intrinsic efficacy of anandamide at TRPV1 is relatively
defined by an Emax value that is not significantly different from low in comparison to that observed for this compound at
that of capsaicin (De Petrocellis et al., 2001a; Smart et al., the CB1 receptor (see Pertwee & Ross, 2002) and as a
2000; Ralevic et al., 2001; Ross et al., 2001b; Sprague et al., result, the physiological relevance of anandamide as an
2001; Jerman et al., 2002). Some authors find the Emax value of endogenous TRPV1 receptor agonist is controversial.
anandamide to be less than 100% in recombinant expression Recently, however, a succession of factors have been shown
systems. Measurements of inward current using whole-cell to influence the efficacy and potency of anandamide at TRPV1
patch-clamp electrophysiology in HEK 293 cells Zygmunt et al. significantly.

British Journal of Pharmacology vol 140 (5)


R.A. Ross Anandamide and vanilloid receptors 793

Receptor reserve receptor-mediated component of anandamide-induced vasor-


elaxation in the mesenteric arterial bed is attenuated by the
The receptor reserve in a given tissue or cell line will influence nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl
the efficacy of a low intrinsic efficacy agonist, whereby such a ester (L-NAME) (Harris et al., 2002). A recent study by
compound may behave as a full agonist or a partial agonist/ Andersson et al. (2002) provides evidence that primary afferent
antagonist in situations of high or low receptor reserve, fibres express the AMT and that variability in the expression
respectively. Thus, although anandamide and AM404 may levels of the transporter affects the potency of anandamide.
behave as full agonists in certain systems, one would predict Thus the AMT inhibitor, VDM13, causes a 2.3-fold rightward
that they may behave as partial agonists in tissues with a low shift in the log concentration – response curve for vasodilata-
receptor reserve. Andersson et al. (2002) performed computer tion of mesenteric arteries by anandamide, but does not affect
simulations of the impact of the receptor reserve on the the contractile response to anandamide in the bronchus.
concentration – response curves for various TRPV1 agonists, However, even in the presence of the uptake inhibitor,
their hypothesis being that the bronchus has a significantly anandamide is still a full agonist at TRPV1 in mesenteric
lower receptor reserve than mesenteric vessels. The simulations arteries as compared to a partial agonist in the bronchi. As
accurately modelled the experimental data from these tissues. discussed earlier, the authors demonstrate that the remaining
Thus, while capsaicin is equally potent in both tissues, RTX, tissue differences are due to a lower receptor reserve in the
olvanil and anandamide are less potent in the bronchi. bronchus. It should be noted that the existence of the AMT is
The low intrinsic efficacy of anandamide indicates that its controversial (see Glaser et al., 2003). A number of AMT
efficacy is significantly affected by changes in the receptor inhibitors are also inhibitors of fatty acid amide hydrolase
reserve in a given tissue. Circumstances that increase TRPV1 (FAAH) and as such, may increase the intracellular ananda-
expression levels will conspire to increase the efficacy of mide levels by inhibiting hydrolysis.
anandamide such that it behaves as a full agonist. In vitro, the
nerve growth factor (NGF) and glial-derived neurotrophic Fatty acid amide hydrolase (FAAH) Inside the cell,
factor regulate DRG neurone responses to capsaicin (Winter anandamide is rapidly metabolised by FAAH to yield
et al., 1988) and the treatment of DRG neurones with NGF arachidonic acid and ethanolamide. There is evidence that
increases the levels of TRPV1 mRNA (Winston et al., 2001). FAAH inhibitors enhance, attenuate or have no effect on
This has two important implications for the activation of TRPV1 activation by anandamide. Thus, as has been
TRPV1 by anandamide. Firstly, the levels of NGF used in demonstrated for CB1 receptors (Cravatt et al., 2001), the
cultures of DRG neurones may vary between labs and this affinity and potency of anandamide at TRPV1 is enhanced by
may affect the efficacy and potency of anandamide measured the inhibition of FAAH in certain tissues including CHO cells
by different research groups. Secondly, alterations in the levels (Ross et al., 2001b), HEK 293 (De Petrocellis et al., 2001a), rat
of these growth factors may be associated with the develop- ileum (McVey et al., 2002) and neuroblastoma cells (Maccar-
ment of chronic pain (for review see Di Marzo et al., 2002a) rone et al., 2000c). On the other hand, in the mesenteric bed,
and any associated changes in the TRPV1 receptor expression FAAH inhibitors attenuate the TRPV1 receptor-mediated
will alter the efficacy of anandamide. relaxation by anandamide (Orliac et al., 2003). In the
The TRPV1 receptor is associated with the pathophysiology bronchus, however, the potency of anandamide as a TRPV1
of various major diseases (Szallasi, 2002). Alterations in the agonist is unaffected by FAAH inhibitors (Tucker et al., 2001;
expression and sensitivity of TRPV1 receptors is concurrent Andersson et al., 2002).
with the development of chronic pain (see Di Marzo et al., The intraluminal administration of anandamide causes
2002a) and inflammation (Amaya et al., 2003). The expression inflammation of the rat ileum resulting in enteritis. The effect
of TRPV1 is dramatically increased in colonic nerve fibres of involves stimulation of substance P release from sensory fibres
patients with active inflammatory bowel disease (Yiangou et al., and is antagonised by capsazepine (McVey et al., 2002). It is
2001). Patients with asthma show a significantly enhanced more potent in the presence of FAAH inhibitors. Inflamma-
sensitivity to capsaicin as compared to normal subjects (see tion of the ileum by Clostridium diffificle toxin A is known to
Spina & Page, 2002), and TRPV1 may be a key mediator in the involve the TRPV1 receptor activation and McVey et al.
pathophysiology of asthma (see Hwang & Oh, 2002). Hudson (2002) have also demonstrated that toxin A stimulates the
et al. (2001) demonstrate that in an animal model of release of anandamide. Moreover, FAAH inhibitors signifi-
neuropathic pain, VR1 immunoreactivity increases significantly cantly increase the inflammatory effects of this toxin,
in both C and A fibres in undamaged DRG neurones. indicating that endocannabinoids may mediate its inflamma-
tory actions. In endotoxaemic rats in which LPS has been used
Anandamide uptake and metabolism to mimic Gram-negative sepsis, anandamide causes a reduc-
tion in the contractile responses of mesenteric beds to
Anandamide membrane transporter The agonist binding noradrenaline (Orliac et al., 2003). In this case, the effect of
site on TRPV1 is thought to be intracellular (Jung et al., 1999) anandamide is inhibited by capsazepine and an FAAH
and consequently the potency of exogenously added ananda- inhibitor and thus appears to involve a metabolite of
mide is affected by its ability to enter the cell. The anandamide anandamide that is as a TRPV1 receptor agonist.
membrane transporter (AMT) is responsible for the uptake of
extracellular anandamide and compounds that alter the Lipoxygenase
function of the AMT modulate the potency of anandamide
in HEK cells expressing TRPV1 (De Petrocellis et al., 2001a; The lipoxygenase metabolites of arachidonic acid, particularly
and see Di Marzo et al., 2002a). The AMT is activated by 12-(S)-hydroperoxyeicosatetraenoyl acid (12-(S)-HPETE), 5-
nitric oxide (Maccarrone et al., 2000a) and the TRPV1 (S)HETE and leukotriene B4 (LTB4), are agonists of the

British Journal of Pharmacology vol 140 (5)


794 R.A. Ross Anandamide and vanilloid receptors

TRPV1 receptor (Hwang et al., 2001; Piomelli, 2001). Recent by TRPV1 receptor activation leads to the release of
studies of the action of the potent inflammatory mediator arachidonic acid and/or anandamide, whose hydroxylation
bradykinin, provide more compelling evidence for the role of by lipoxygenase may lead to the formation of compounds that
lipoxygenase metabolites in the activation of TRPV1. Thus, are themselves vanilloid agonists. Indeed, mass spectrometric
bradykinin activation of TRPV1 receptors in both cultured analysis shows that capsaicin and depolarisation (KCl) induce
DRG neurones and the skin is significantly attenuated by a significant release of anandamide in DRG cultures (Ahlu-
lipoxygenase inhibitors (Shin et al., 2002). Of the neurones that walia et al., 2003). It is perhaps notable that the capsaicin-
respond electrophysiologically to bradykinin, 75% coexpress evoked release of anandamide is significantly attenuated when
mRNAs encoding the TRPV1, B2 receptor and 12-lipoxy- the FAAH inhibitor, MAFP, is excluded from the buffer,
genase. Furthermore, extracellular recording from C fibre demonstrating that anandamide is rapidly metabolised in
receptive fields in guinea-pig isolated airways reveals that DRG neurones. Metabolic products of anandamide have also
lipoxygenase inhibitors dramatically inhibit bradykinin-in- been implicated in anandamide-induced depolarisation of the
duced action potentials that are TRPV1 receptor mediated guinea-pig isolated vagus nerve that is TRPV1 receptor
(Carr et al., 2002): the nonselective lipoxygenase inhibitor, mediated (Kagaya et al., 2002). In this preparation, depolar-
ETYA, and the 12-lipoxygenase inhibitor, baicalein, reduce isation by anandamide, but not capsaicin, is inhibited by
the effect of bradykinin by 76 and 60%, respectively. It is lipoxygenase inhibitors, but only in the presence of calcium. It
known that 15-HPETE is synthesised by bronchial epithelial is not clear, however, whether these active metabolites are
cells and induces persistent airway hyper-responsiveness that is produced via direct lipoxygenase metabolism of anandamide
sensitive to pretreatment with capsaicin (see Spina & Page, or via the metabolism of arachidonic acid, because these
2002). In addition, protease-activated receptor 2 causes experiments did not include FAAH inhibitors.
TRPV1 receptor-mediated coronary vasodilation that involves Potent FAAH inhibitors have recently been synthesised,
a lipoxygenase-derived product (McLean et al., 2002). which enhance the levels of anandamide significantly, and
In addition to hydrolysis by FAAH, anandamide can also be these compounds may be of considerable therapeutic benefit
metabolised by a range of oxygenase enzymes that are already (Boger et al., 2000). In the event of inhibition of FAAH
known to convert arachidonic acid into potent biologically metabolism of anandamide, increased levels of endogenous
active compounds (see Kozak & Marnett, 2002; Ross et al., anandamide may lead to the production of significant levels of
2002). These include cyclooxygenase-2, lipoxygenase and P450 the HPETE ethanolamides. It is also notable that specific
enzymes. In vitro, 12- and 15-lipoxygenase convert ananda- inhibitors of 5-lipoxygenase markedly enhance the level of
mide into 12- and 15-HPETE ethanolamide (HPETEE), hydrolysis of anandamide by FAAH in human mast cells
respectively, the reaction rates being similar to those for (Maccarrone et al., 2000b). Thus, Maccarrone et al. hypothe-
arachidonic acid (see Kozak & Marnett, 2002). Thus, the sise that 5-lipoxygenase metabolites of anandamide may be
pharmacology of anandamide may be directed by tissue- acting as endogenous inhibitors of FAAH. To complement the
specific differences in the balance of metabolic enzymes. For hypothesis, they have demonstrated that various HPETE and
example in platelets, which lack significant expression of COX- HETE ethanolamides are potent endogenous inhibitors of
2 or FAAH, the primary metabolism of anandamide is by FAAH (Maccarrone et al., 2000d; van der Stelt et al., 2002).
lipoxygenase (Edgemond et al., 1998). As an alternative Consequently, lipoxygenase metabolism of anandamide may
substrate for lipoxygenase enzymes, anandamide may attenu- enhance TRPV1 receptor activation by increasing the levels of
ate the production of metabolites of arachidonic acid that are available anandamide.
TRPV1 receptor agonists. Alternatively, anandamide may
activate TRPV1 via lipoxygenase metabolites of arachidonic Entourage effects
acid formed subsequent to its metabolism by FAAH. A further
possibility is that anandamide lipoxygenase metabolites may Anandamide is one of a group of N-acylethanolamides that
themselves activate TRPV1 receptors (Figure 1). In the include palmitoylethanolamide (PEA). PEA is cosynthesised
bronchus, the TRPV1 receptor-mediated contractile action of with anandamide and acts as an ‘entourage’ compound to
anandamide is little affected by FAAH inhibitors, but is inhibit the degradation of anandamide and thereby increase
significantly attenuated by lipoxygenase inhibitors (Craib et al., the available levels. PEA enhances both the affinity and the
2001). These data suggest that, in this tissue, anandamide may potency of anandamide at TRPV1 receptors (De Petrocellis
be metabolised to hydroperoxyeicosatetraenoyl ethanolamides et al., 2001b), an effect shared by other N-acylethanolamides
(HPETEEs) and LTB4 ethanolamides that, like the hydro- (e.g. lauroylethanolamide) (Smart et al., 2002) (see Table 1).
peroxy derivatives of arachidonic acid (HPETEs) and LTB4, The enhancement of anandamide-induced TRPV1 receptor
may be vanilloid receptor agonists. In hTRPV1-HEK cells, the activation by these compounds does not correlate with their
anandamide lipoxygenase metabolites, 11(S)-HPETEE and ability to inhibit anandamide metabolism by FAAH (Smart
5(S)-HPETEE, do not induce an increase in [Ca2 þ ]i and 15(S)- et al., 2002). This suggests that these compounds enhance the
HPETEE has only a modest effect at concentrations above action of anandamide by a mechanism other than the
10 mM (De Petrocellis et al., 2001a). However, it is feasible that inhibition of enzymatic degradation. Therefore, in circum-
these compounds and related molecules are more potent as stances that increase the synthesis of N-acylethanolamides, the
TRPV1 agonists if produced intracellularly via the metabolism actions of anandamide at TRPV1 may be enhanced.
of arachidonic acid and/or anandamide close to the intracel-
lular TRPV1 agonist binding site. Phosphorylation
In the bronchus, lipoxygenase inhibitors modestly attenuate
the contractile action of capsaicin (Craib et al., 2001), raising Phosphorylation of TRPV1 by protein kinase C (PKC) and
the possibility that the increase in intracellular calcium elicited protein kinase A (PKA) sensitises TRPV1 receptors to

British Journal of Pharmacology vol 140 (5)


R.A. Ross Anandamide and vanilloid receptors 795

Figure 1 Metabolic pathways of anandamide and arachidonic acid related to the TRPV1 receptor. Anandamide (AEA) is rapidly
hydrolysed by FAAH to yield arachidonic acid and ethanolamide. Arachidonic acid (AA) is oxygenated by lipoxygenase enzymes:
the products include 12-(S)- and 15-(S)-HPETE, 5-(S)HETE and LTB4 that are TRPV1 agonists (Hwang et al., 2001). Anandamide
is also a substrate for lipoxygenase (see Kozak & Marnett, 2002), yielding equivalent HPETE ethanolamides (HPETEE) and HETE
ethanolamides (HETEE) that may also be TRPV1 agonists (Craib et al., 2001). The lipoxygenase products of anandamide are
potent inhibitors of FAAH (Maccarrone et al., 2000d). PKC can activate the TRPV1 receptor directly (Premkumar & Ahern, 2000;
Olah et al., 2002), and it will also sensitise the receptor to other agonists (Vellani et al., 2001). Anandamide can activate PKC directly
(De Petrocellis et al., 1995; Premkumar & Ahern, 2000). CB1 receptor activation is coupled to the stimulation of PLC, hydrolysis of
PIP2 and release of the TRPV1 receptor from the tonic inhibitory effect of this compound (see Hermann et al., 2003). Anandamide
formation occurs through phosphodiesterase-mediated cleavage of a phospholipid precursor, N-arachidonoyl-phosphatidyletha-
nolamine (NAPE), and its production in and release from neurones is calcium dependent (Di Marzo et al., 1994). In cultured
neurones, anandamide is synthesised in response to TRPV1 receptor activation (Ahluwalia et al., 2003).

vanilloids, anandamide, heat and protons (see Di Marzo et al., et al., 2002). In cultured DRG neurons, the PKC activator,
2002a). Premkumar & Ahern (2000) report that the repeated phorbol 12,13 dibutyrate (PBDu), induces TRPV1 receptor
application of anandamide evokes progressively larger TRPV1 activation; in cultures treated chronically with PBDu, there is a
currents in oocytes and that anandamide treatment enhances significant downregulation of the PKCa isoform (and only a
proton-evoked currents. The potentiation by anandamide is partial downregulation of PKC b, d, e isoforms) with
significantly attenuated by compounds that inhibit PKC, concomitant loss of TRPV1 receptor activation (Olah et al.,
and the authors suggest that anandamide stimulates PKC to 2002). While anandamide activates TRPV1 receptors in
enhance agonist-evoked responses (Figure 1). These experi- cultures in which PKCa is downregulated, it is four-fold less
ments were performed in an oocyte expression system injected potent and this may implicate PKCa in modulating the
with TRPV1, thus anandamide actions are presumably potency of anandamide (Olah et al., 2002).
cannabinoid receptor independent. Indeed, there is evidence Phosphorylation of TRPV1 is likely to be associated with
that by binding directly to the diacylglycerol site, anandamide inflammation (Cesare et al., 1999). A comparative study of
has a dual modulatory effect on PKC in the rat brain in vitro: PKCg immunoreactivity in the dorsal horn before and after
while anandamide increases phosphatidylserine-induced the induction of inflammation in the rat hind paw reveals that
PKC activation, it also inhibits dioleylglycerol-induced poten- there are persistent alterations that parallel the time course of
tiation of Ca2 þ -induced PKC activation (De Petrocellis et al., allodynia (Martin et al., 1999). Kamei et al. (2001) have
1995). produced evidence that allodynia and hyperalgesia in diabetic
PKC is a series of isozymes that are specific for different mice may be due to the sensitisation of VR1 receptors in
substrates and there is controversy as to which isozyme is primary sensory neurones and there is evidence of an
responsible for PKC-mediated enhancement of TRPV1 upregulation of certain isoforms of PKC in diabetes (Borghini
responses (see Cesare et al., 1999; Numazaki et al., 2002; Olah et al., 1994; Koya & King, 1998). Furthermore, PKC

British Journal of Pharmacology vol 140 (5)


796 R.A. Ross Anandamide and vanilloid receptors

inhibitors have been shown to have beneficial effects on in which CB1 receptors are not coupled to PI-PLC or PI-3-K
diabetic neuropathy (Cameron et al., 1999). or in which the TRPV1 receptor is phosphorylated by cyclic
As discussed above, PKC and PKA facilitate the activation AMP-dependent PKA activation.
of TRPV1 by anandamide. In contrast, PKC-mediated
phosphorylation of the CB1 receptor prevents cannabinoid- CB1 receptor activation
mediated activation of Kir currents and the inhibition of P/Q-
type Ca2 þ channels (Garcia et al., 1998). The CB1 receptor Within the DRG, there is a heterogeneous population of cells
inhibits adenylyl cyclase via the a-subunit of Gi resulting in the containing small, intermediate and large diameter neurones
inhibition of PKA activation. Thus, one may anticipate that that give rise to C, Ad or Ab fibre axons. Both in culture and in
PKC and PKA are pivotal in regulating the balance of CB1 situ, DRG neurones express both CB1 and TRPV1 receptors.
and TRPV1 activation by anandamide (see Di Marzo et al., The localisation of CB1 and TRPV1 receptor is controversial
2002a; Hermann et al., 2003) (Figure 1). (see Rice et al., 2002); some studies suggest a high degree of
colocalisation (Ahluwalia et al., 2000; 2002) and others suggest
Phosphatidyl-inositol-bis phosphate little colocalisation (Farquhar-Smith et al., 2000; Khasabova
et al., 2002). Anandamide has a dual effect on neuropeptide
The TRPV1 receptor is under the inhibitory control of release from cultured DRG neurones: at low concentrations,
phosphatidyl-inositol-bis phosphate (PIP2); both antibody anandamide induces a CB1 receptor-mediated inhibition of
sequestration of plasma membrane PIP2 and phospholipase electrically stimulated neuropeptide release, presumably by the
C (PLC) hydrolysis of PIP2 potentiate the TPRV1 channel inhibition of voltage-gated Ca2 þ channels (Ross et al., 2001a),
activation (Chuang et al., 2001). The potent inflammatory while at higher concentrations anandamide evokes a TRPV1
mediators, bradykinin and NGF, activate PLC signalling receptor-mediated release (Tognetto et al., 2001). Anandamide
pathways in DRG neurones leading to the hydrolysis of PIP2 also attenuates capsaicin-evoked neuropeptide release from
to inositol-tris-phosphate and diacylglycerols (DAGs) DRG neurones and isolated paw skin (Richardson et al., 1998;
(Chuang et al., 2001). The authors suggest that, in addition Nagy et al., 2002). Furthermore, in the presence of a CB1
to sensitisation via a PKC-dependent mechanism, TRPV1 is receptor antagonist, anandamide becomes equipotent with
also sensitised by a PKC-independent mechanism consequent capsaicin as a TRPV1 receptor agonist (Nagy et al., 2002).
to the hydrolysis of PIP2. Similarly, in the guinea-pig ileum, anandamide increases
In HEK-293 cells overexpressing both the CB1 and TRPV1 acetylcholine release in a capsazepine-sensitive manner and
receptors, pretreatment with a cannabinoid receptor agonist this effect is enhanced in the presence of the CB1 receptor
significantly enhances capsaicin-evoked increases in [Ca2 þ ]i antagonist, SR141716A (Mang et al., 2001). Finally, in human
(Hermann et al., 2003). This effect is inhibited by SR141716A neuroblastoma cells, cannabinoid receptor antagonists po-
and is absent from cells that express TRPV1 only, indicating tentiate the TRPV1 receptor-mediated cell death induced by
that CB1 receptor activation leads to an enhanced activation of anandamide (Maccarrone et al., 2000c). The implication of
TRPV1. Furthermore, anandamide produces a significantly such data is that the activation of the CB1 receptor by
greater increase in intracellular calcium in CB1-TRPV1-HEK as anandamide may attenuate its TRVP1 receptor-mediated
compared to TRPV1-HEK cells. The CB1 receptor-mediated action. In the spinal cord, superfusion of the CB1 receptor
enhancement of TRPV1 activation is attenuated by the antagonist significantly enhances the release of neuropeptide
inhibitors of phosphoinositide-3-kinase (PI-3-K) and PLC. PI- evoked by capsaicin (Lever & Malcangio, 2002). The activa-
3-K is responsible for the formation of PIP2, while PI-PLC tion of the TRPV1 receptor may evoke the release of
catalyses PIP2 hydrolysis and the result of inhibition of these endocannabinoids that subsequently activate CB1 receptors
enzymes will be the attenuation of the turnover and hydrolysis to attenuate the TRPV1 receptor-mediated release of neuro-
of PIP2. CB1 receptor activation is coupled to the stimulation of peptide. This hypothesis is supported by the finding that
PLC and PI-3-K (Ho et al., 1999; Netzeband et al., 1999; Gomez capsaicin induces a significant release of anandamide in DRG
Del Pulgar et al., 2002) and hence may release TRPV1 from cultures (Ahluwalia et al., 2003). Cannabinoid receptors are
tonic inhibition by PIP2. PKC is also activated as a consequence constitutively active and there are numerous examples of the
of the hydrolysis of PIP2 to DAG. Hermann et al. (2003) suggest CB1 receptor antagonist, SR141716A, producing inverse
that these mechanisms may underlie the CB1 receptor-mediated cannabimimetic effects (see Pertwee, 2003; Hurst et al.,
enhancement of TRPV1 receptor activation (Figure 1). 2002). In DRG neurons, a cannabinoid agonist inhibits and
Hermann et al. (2003) also found that if cAMP-mediated antagonist enhances voltage-gated Ca2 þ currents (Ross et al.,
signalling is activated, CB1 agonists mediate the inhibition and 2001a). It is possible that in DRG neurones and the spinal
not the enhancement of TRPV1 receptor activation: when cord, constitutively active CB1 receptors may exert a tonic
PKA is activated via forskolin stimulation of adenylyl cyclase, inhibitory effect on the TRPV1 receptor by attenuating
CB1 receptor agonists inhibit TRPV1 receptor activation by cAMP-dependent PKA activation. In this scenario, inverse
capsaicin. In cells in which there is coexpression of these agonists may enhance TRPV1 receptor activation.
receptors, the findings of Hermann et al. (2003) raise two Ellington et al. (2002) find that the CB1 receptor agonist,
possibilities for CB1 receptor influence on the activation of CP55940, inhibits capsaicin-evoked calcitonin gene-related
TRPV1. Firstly, CB1 receptor activation may lead to an peptide (CGRP) release from the paw skin of both the control
enhanced TRPV1 receptor activation. One may predict such and diabetic animals. While anandamide inhibits CGRP
an outcome in cells in which the CB1 receptor couples to release from the paw skin of control animals, it produces a
pathways that facilitate that gating of TRPV1. Alternatively, small stimulation of CGRP release in diabetic animals. This
CB1 receptor activation may lead to an inhibition of TRPV1 demonstrates that there is an alteration in the pharmacology of
receptor activation. Such an outcome may be observed in cells anandamide in the disease state that may be associated with

British Journal of Pharmacology vol 140 (5)


R.A. Ross Anandamide and vanilloid receptors 797

changes in TRPV1 receptor expression and/or sensitivity in CA3 regions of the hippocampus (Mezey et al., 2000). When
sensory fibres of diabetic animals. paired-pulse stimulation is applied to hippocampal slices, there
Anandamide also has bidirectional effects on cough in is a depression of the second population spike evoked at
conscious guinea-pigs (Jia et al., 2002). When given by aerosol, interpulse intervals of 5 – 200 ms. The inhibitory feedback is
anandamide induces cough, an effect that is prevented by due to the release of GABA following the first stimulation. Al-
pretreatment with capsazepine and not CB1 or CB2 receptor Hayani et al. (2001) demonstrate that the TRPV1 receptor
antagonists. When airways are pretreated with the ligand for a agonists RTX, capsaicin and anandamide increase paired-
longer time in experimental conditions, anandamide inhibits pulse depression in the CA1 region of the rat hippocampal
cough through CB1 receptors. slice. The effect is blocked by the TRPV1 receptor antagonist,
capsazepine. In contrast, the CB1 receptor agonist, WIN55212,
Voltage and the endocannabinoid 2-arachidonoyl glycerol, reduce
paired-pulse depression, an effect that is blocked by the CB1
Voltage-dependent priming of TRPV1 receptors is yet another receptor antagonist AM251 and is consistent with the CB1
mechanism by which the activation by anandamide may be receptor-mediated inhibition of GABA release (see Davies
enhanced. Ahern & Premkumar (2002) demonstrate that et al., 2002). In view of the low intrinsic efficacy of
depolarisation acts synergistically with agonists to enhance anandamide at TRPV1 as compared to CB1, it is unexpected
the TRPV1 current in both oocytes expressing TRPV1 and that anandamide should preferentially activate the TRPV1
cultured DRG neurones. Hence, voltage modulates the receptor in this preparation. An interesting possibility is that
TRPV1 currents activated by anandamide, protons, heat and anandamide activation of the CB1 receptor leads to an
PKC (PBDu treatment). Intriguingly, voltage evokes a enhancement of TRPV1 activation by liberating TRPV1 from
significantly larger current rise with anandamide and PKC as tonic inhibition by PIP2 (see Hermann et al., 2003). The
compared to that observed with capsaicin. Furthermore, the experiments were performed in the absence of an FAAH
extent of the activation of TRPV1 receptors by voltage is inhibitor and another explanation may be the rapid conversion
inversely related to the agonist concentration. Consequently, of anandamide to an active metabolite. Other possibilities
this mechanism is significantly more pronounced for low include those discussed earlier, in particular receptor reserve
efficacy agonists such as anandamide. and the phosphorylation states of TRPV1 and CB1 in the CA1
region of the hippocampus. A further possibility is that,
Temperature, pH, BSA, ethanol despite displaying the characteristics of TRPV1, this may be a
novel site at which anandamide has a higher potency.
Heat is known to enhance the TRPV1 receptor-mediated Additional effects of vanilloids have been noted in the
responses. Accordingly, the pEC50 values for the elevation of hippocampus. Hájos & Freund (2002a) found that the CB1/
[Ca2 þ ]i in HEK293 cells by anandamide are significantly lower CB2 receptor agonists (WIN55212 and CP55940) and capsaicin
at 371C compared to 221C (Sprague et al., 2001). Hence, modulate excitatory transmission, an effect that is antagonised
temperature may contribute to the low efficacy of anandamide by capsazepine. The results suggest the existence of a novel site
in experiments that are conducted at room temperature, on the hippocampal excitatory axons at which both cannabi-
including patch-clamp electrophysiology. Olah et al. (2001) noids and vanilloids act to suppress glutamatergic transmis-
found that in both cultured DRG neurones and an NIH3T3 sion (see Davies et al., 2002; Hájos & Freund, 2002b).
cell line stably expressing TRPV1 receptors, low acidic pH (6.0 Vanilloid effects have also been reported in the brain stem:
and 5.5) markedly enhances the stimulation of [45Ca2 þ ] uptake microinjection of capsaicin into the sensory nerve terminals of
by anandamide. However, in TRPV1-transfected HEK 293 the commissural nucleus of the solitary tract (cNTS),
cells, lowering the pH of the buffer from 7.4 to 6.4 does not significantly reduces the respiration rate (Geraghty & Maz-
affect the potency of anandamide (Ralevic et al., 2001; Smart zone, 2002). The finding that RTX is significantly more potent
et al., 2001). De Petrocellis et al. (2001c) demonstrate that the than capsaicin and that the effects are blocked by capsazepine
potency of anandamide at TRPV1 is markedly reduced in the suggest that this is TRPV1 receptor-mediated. While ananda-
presence of bovine serum albumin (BSA): 1 mM elevates [Ca2 þ ]i mide and olvanil do not inhibit respiration in this preparation,
by B65, B10 and B2% in the presence of 0, 0.1 and 0.2% these compounds significantly attenuate the effect of RTX in a
BSA, respectively. The authors suggest that BSA prevents the concentration-dependent manner. TRPV1 receptor activation
uptake of anandamide, interfering with the carrier-mediated in the cNTS is desensitised by very low concentrations of RTX
internalisation of this compound, and the subsequent activa- and the authors suggest that anandamide may be desensitising
tion of intracellular TRPV1. Ethanol (0.1 – 3%) enhances the receptor. Alternatively, anandamide may be behaving as a
TRPV1 receptor activation by capsaicin, heat, protons and partial agonist to antagonise RTX in this preparation.
anandamide as measured using either FLIPR or electrophy- Marinelli et al. (2002) demonstrate that capsaicin causes an
siology (Trevisani et al., 2002). It is conceivable that TRPV1 increase in miniature excitatory postsynaptic currents in the rat
receptor activation by anandamide may be greater if ethanol is locus coeruleus, an effect that is mediated by presynaptic TRPV1
used as the vehicle as opposed to DMSO. receptors that potentiate glutamate and adrenaline/noradrena-
line release. Similarly, there is evidence that the substantia nigra
Central nervous system pars compacta (SNc) contains presynaptic TRPV1 receptors on
glutamatergic synapses to dopaminergic neurones. Spontaneous
TRPV1 receptors have been thought to be primarily associated EPSCs (sEPSCs) are increased and inhibited by a TRPV1
with the peripheral nervous system and in particular, primary agonist and antagonist respectively (Marinelli et al., 2003). The
afferent fibres, yet PCR studies show that TRPV1 mRNA is tissue contains high levels of endogenous anandamide and the
present in brain tissue and is especially high in the CA1 and authors suggest that the stimulation of TPRV1 in the SNc by

British Journal of Pharmacology vol 140 (5)


798 R.A. Ross Anandamide and vanilloid receptors

endocannabinoids may effect tonic facilitation of glutamate efficacy TRPV1 agonist behaving as a partial agonist in tissues
release. In the presence of the CB1 receptor antagonist AM281, with a low receptor reserve, while in tissues with high receptor
anandamide increases the frequency of sEPSCs, albeit at the reserve and in circumstances associated with certain disease
high concentration of 30 mM. At the lower concentration of states, it behaves as a full agonist. Furthermore, there are
10 mM, anandamide is only active when PKA is stimulated by the indications that the endocannabinoid system may play a role
adenylyl cyclase activator, forskolin. in the modulation of TRPV1 receptor activation. The
activation of TRPV1 receptors by anandamide has potential
implications in the treatment of inflammatory, respiratory and
Conclusions cardiovascular disorders. The relative importance of ananda-
mide as a physiological and/or pathophysiological TRPV1
A large body of evidence now exists to substantiate that receptor agonist in comparison to other potential candidates,
anandamide activates TRPV1 receptors. It is a low intrinsic such as 15-HPETE and NADA, has yet to be revealed.

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