REVIEW

New perspectives on enigmatic vanilloid receptors

Arpad Szallasi and Vincenzo Di Marzo In spite of the rapid advances in our understanding of vanilloid-receptor pharmacology in the PNS, the function of vanilloid receptors in the brain has remained elusive. Recently, the endocannabinoid anandamide has been proposed to function as an endogenous agonist at the vanilloid receptor VR1. This is an exciting hypothesis because the localization of VR1 overlaps with that of anandamide and its preferred cannabinoid receptor CB1 in various brain areas.The interaction of anandamide and/or related lipid metabolites with these two completely separate receptor systems in the brain clearly places VR1 in a much broader role than pain perception. At a practical level, the overlapping ligand recognition properties of VR1 and CB1 might be exploited by medicinal chemistry. For example, arvanil,a chimeric ligand that combines structural features of capsaicin and anandamide,promises to be an interesting lead for new drugs that interact at both vanilloid and cannabinoid receptors.
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HE BEST-KNOWN natural vanilloids are capsaicin (Fig. 1), which is responsible for the piquancy of hot chilli peppers, and its ultrapotent analog, resiniferatoxin (Fig. 1), which was originally isolated from the cactus-like plant Euphorbia resinifera1,2. Newly discovered vanilloids include the fungal terpenoid, isovelleral, as well as scutigeral, a triprenyl phenol isolated from the edible mushroom Albatrellus ovinus3. The cloning of a functional vanilloid receptor, VR1, in 1997, heralded the beginning of ground-breaking discoveries in the vanilloid field4. In 1999, two proteins with high homology to VR1 [a vanilloid receptor-like protein (VRL1) that is responsive to high temperatures (5253oC) and a stretch-inhibitable channel (SIC) with mechanosensitive properties] were identified5,6. Furthermore, a vanilloid receptor 5-splice variant (VR.5sv), which differs from VR1 by elimination of the majority of the intracellular N-terminal domain, was isolated7. VR1 and VRL1 are products of distinct genes, whereas VR1, VR.5sv and SIC appear to represent alternatively spliced variants of the same gene. Consistent with this hypothesis, VR1 and VRL1 have distinct tissue distributions5, whereas VR.5.sv and SIC genes are co-expressed with the gene for VR1 in most of the tissues examined7,8. Analysis of sequence databases suggests the existence of additional VR1-like receptors9. An exhaustive analysis of the tissue distribution of all potential VR1 splice variants and related VR1 sequences using molecular biology methods, such as ribonuclease protection assays, is essential to understand the precise expression of VR1 mRNA and associated protein production in relation to their biological functions. VR1 is activated not only by vanilloid ligands but also by noxious heat and low pH (acids) and thus can be viewed as a molecular integrator of noxious stimuli in peripheral terminals of primary sensory neurons10. Because heat can gate the channel directly, this could be viewed in one sense as an endogenous ligand of the VR1 channel. By contrast, decreased pH from the
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physiological pH potentiates both capsaicin and heatinduced currents and thus could be considered as an allosteric activator of the channel. However, if the temperature is high enough or if the pH is low enough, either one of these could gate the channel, arguing that they should be considered endogenous agonists of VR1. Cloning and functional expression of the cDNA for a human ortholog of rat VR1 has also been reported11, and it is probable that several pharmaceutical companies are actively screening their compound libraries for novel vanilloid-receptor ligands. In spite of these spectacular advances, there is still uncertainty as to whether an endogenous ligand for VR1, other than protons and elevated temperature, exists.

Heterogeneity of vanilloid actions

VRL1, VR.5sv and SIC are not activated by vanilloids57, thus, to date, VR1 is the only known functional vanilloid receptor. This is surprising because the diverse pharmacological actions of vanilloids are difficult to explain in the context of a single receptor2. For example, vanilloids have been shown to have bellshaped doseresponse curves (where the initial stimulation at lower doses is overcome by the response being blocked at higher doses) in several bioassays. Examples of this phenomenon include the release of calcitonin gene-related peptide (CGRP) in rat spinal-cord slices that contain central terminals of capsaicin-sensitive neurons12, and the biphasic oxygen-uptake response in the isolated rat hindpaw13. On the basis of these findings, the existence of two pharmacologically distinct vanilloid-receptor subtypes that mediate excitation or inhibition of capsaicin-sensitive neurons, respectively, was postulated14. Furthermore, consistent with this hypothesis, distinct structureactivity relationships for the induction of Ca2 -isotope uptake (traditionally used to detect the vanilloid-activated ion channel) in isolated dorsal-root-ganglion (DRG) neurons in culture and for the inhibition of specific [3H]resiniferatoxin binding were observed2,14. Generally, capsaicinoids
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Arpad Szallasi is at the Dept of Pathology, Washington University School of Medicine, St Louis, MO 63110, USA and Vincenzo Di Marzo is at the Istituto per la Chimica di Molecole di Interesse Biologico, CNR, 80072 Arco Felice (NA), Italy.

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AMT

O O H O

O C
OH

OCH3 O OH

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OCH3

Capsaicin
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++ Olvanil
O C NH OH OH

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R-type for binding and of the C-type for Ca2 mobilization18. Nevertheless, the concept of a single heatand acid-sensitive ion channel as the only target for vanilloids is inconsistent with the conflicting pharmacological actions of capsaicin and resiniferatoxin congeners1,2,14. In addition, the location of the VR1 receptor in brain regions such as the cortex, cerebellum, hippocampus and the locus ceruleus8 is unusual for a protein whose primary function is to integrate heat, low pH and other effects in the sensory response to tissue injury. In fact, two recent exciting findings could potentially solve some of the controversies surrounding vanilloid receptors: (1) VR1 and CB1 receptors show overlapping ligand-recognition properties19,20 and (2) VR1 co-exists with CB1, as well as with its endogenous ligand, anandamide, in brain nuclei and some sensory neurons8. The concept that anandamide acts as a full agonist at VR1 has resulted in heated debate, partly as a result of the underestimation of the capsaicin-like potency of anandamide in the initial report of its actions at VR1 receptors19. For a complete overview of the arguments for and against anandamide as an endogenous vanilloid receptor agonist, see Refs 2123.

++

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Capsaicin congeners and proteins of the endogenous cannabinoid system

In the early 1990s, two cannabinoid receptors with distinct tissue distribution, termed CB1 and CB2, were cloned24,25. Arachidonoyl-ethanolamide, better known as anandamide (Fig. 1), is thought to act as an endogenous CB1-receptor agonist27 because, similar to 9 ( ) tetrahydrocannabinol, the main psychoactive ingredient in marijuana, this agonist activates both CB1 and, to a minor extent, CB2 receptors28,29. Termination of the activity of anandamide by cells is achieved through a two-step process30: (1) re-uptake by intact cells via the anandamide membrane transporter and (2) hydrolysis of the amide bond, catalyzed by the enzyme fatty-acid amide hydrolase (FAAH). The chemical similarity between anandamide and the oleic acid homolog of capsaicin (better known as olvanil) (Fig. 1), suggests that certain vanilloids might interact with either of the two cannabinoid receptors, or with the anandamide transporter, or FAAH. Indeed, in binding assays carried out with the selective CB1 and VR1 highaffinity ligands, [3H]SR141716A and [3H]resiniferatoxin, respectively, olvanil exhibited an affinity for CB1 (Ki value of 1.6 M; Ref. 20), which is only slightly lower than that observed for its binding to VR1 receptors (Ki value of 0.4 M; Ref. 18). Moreover, olvanil behaved as a partial agonist in a functional assay of CB1 activity, that is, in the inhibition of forskolin-induced adenylyl cyclase20. Olvanil also inhibited the anandamide transporter in rat basophilic leukemia (RBL-2H3) cells, a widely used model of inflammatory mast cells, without influencing FAAH activity20. Interestingly, both capsaicin and its synthetic analog (pseudocapsaicin) were inactive or only weakly active in all these assays20. These data imply that olvanil, particularly at high doses, might activate cannabinoid receptors either directly or indirectly, that is, by raising the levels of endogenous anandamide through inhibition of its inactivation. Thus, in view of the widely documented analgesic and vasodilator actions of endocannabinoids31,32, these findings suggest that part of the pharmacological effects of olvanil in vivo might be a result of interactions with proteins of the endocannabinoid system.

AM404
O C NH OCH3

++ Arvanil
O C NH OH OH

++

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++

++

Anandamide
OH O C NH OH

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2-Arachidonoyl-glycerol
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Fig. 1. Chemical structure of ligands of the vanilloid receptor, cannabinoid receptor and anandamide membrane transporter. There is a partial overlap among the ligand recognition properties of vanilloid receptors VR1, cannabinoid receptors CB1, and the anandamide membrane transporter (AMT). The chemical structures of typical ligands of VR1 and CB1 receptors are shown in colors ranging from red to blue, depending on the relative affinity of these ligands, indicated with or signs, for VR1 and CB1 receptors. The relative affinity of these ligands for AMT are indicated with or signs in black. Both a polyunsaturated C20 chain and a vanillyl moiety are necessary for maximal interaction of these compounds with all three targets20,23,26. The affinity of 2-arachidonoylglycerol for AMT depends on experimental conditions29.

show higher potency for Ca2 uptake, whereas resiniferanoids have higher potency in the binding assay, hence the name R- and C-type vanilloid receptors14. It has been proposed that C-type vanilloid receptors are responsible for the excitatory actions of vanilloids, whereas R-type receptors predominantly mediate desensitization15. Further heterogeneity within C-type receptors was suggested by the multiple currents that capsaicin analogs evoke16,17. However, this model can no longer be maintained because the cloned rat VR1 receptor shows structureactivity relationships of the 492
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In an attempt to develop compounds with improved activity as CB1 ligands or as inhibitors of the anandamide membrane transporter that retain a high potency at vanilloid receptors, capsaicin homologs with alkyl chains of various length and saturation were synthesized26. This strategy led to the development of linvanil, the -linolenic acid derivative of capsaicin, which is weakly active as a CB1-receptor ligand but still capable of inhibiting the anandamide membrane transporter and activating VR1-mediated cation currents. Another compound, arvanil, whose chemical structure is a hybrid between anandamide and capsaicin (Fig. 1), is among the most-potent (IC50 3.6 M) inhibitors of the anandamide transporter discovered to date26. Furthermore, with a Ki value of 0.5 M, arvanil is moderately more potent than olvanil at CB1 receptors. Finally, arvanil retains the high affinity shown by olvanil for rat VR1 heterologously expressed in HEK293 cells (Ki values, 0.3 and 0.4 M for arvanil and olvanil, respectively)33 and is as efficacious as olvanil at inducing cation currents in Xenopus oocytes transfected with VR1 mRNA (Ref. 26). These actions might explain, in part, the potent in vivo analgesic, vasodilator, and anti-inflammatory activity of arvanil (Ref. 33 and V. Di Marzo et al. unpublished observations). Interestingly, not only capsaicin analogs (as exemplified by olvanil) can inhibit the anandamide transporter but the reverse also holds true: the anandamide transporter inhibitor N-(4-hydroxyphenyl)-arachidonylamide (better known as AM404; Ref. 34) is a full agonist at VR1 with kinetics similar to that of capsaicin23,35. These findings imply that the same substance can interact with both the anandamide transporter and VR1 provided it contains certain structural features (Fig. 1). This phenomenon might have great physiological significance because it appears that anandamide needs to be transported into cells in order to activate VR1 receptors (Di Marzo et al., unpublished observations).

Anandamide as an endogenous ligand for VR1 in sensory neurons

VR1 is found along the entire length of primary sensory neurons with somata in dorsal-root and trigeminal ganglia36. These neurons are of small to medium diameter and give rise to unmyelinated C fibers1. In addition, some neurons with A fibers are also vanilloid sensitive1. VR1-positive neurons with C fibers can be divided into two subdivisions: peptidergic and nonpeptidergic36. Among the neuropeptides found in vanilloid-sensitive neurons, substance P (SP) and CGRP are the best characterized37. Non-peptidergic vanilloidsensitive neurons characteristically possess the P2X3 purinoceptor36 and cross-desensitization between purinoceptors and vanilloid receptors has been described38. A subset of nodose ganglion neurons also contain VR1 (Ref. 39). As described above, on peripheral terminals, VR1 probably functions as a shared receptor for various noxious stimuli, including heat, acids and some plant toxins. In addition, during inflammation, endogenous substances released from activated immune cells might also target VR1, whose activation, apart from nociception, also leads to CGRPmediated local vasodilation1,2,37. In the gastrointestinal tract, this mechanism is believed to have a central role in mucosal protection40. By contrast, the role of VR1 in

the central terminals of primary sensory neurons (i.e., the dorsal horn of the spinal cord) and the endogenous activators of this receptor are unknown. As a general rule, vanilloids have a biphasic action on sensitive peripheral nerves, an initial excitatory phase (manifested as pain and/or neurogenic inflammation) followed by a lasting refractory state, traditionally known as desensitization1,2. However, numerous exceptions to this rule exist. Some vanilloids, such as piperine, the pungent compound in black pepper, are pungent but do not desensitize41; other vanilloids, as exemplified by olvanil, are, by contrast, potent analgesic agents that lack the initial pain response42. Thus, putative endogenous vanilloids could either activate or inhibit nociceptors. To date, no experimental evidence has been published in support of the existence of a specific endogenous VR1 ligand. An intriguing alternative is that an already known endogenous substance might also function as a vanilloid-receptor agonist. One attractive candidate for such a function is anandamide, for three reasons. First, anandamide exhibits structural similarity to long-chain capsaicin congeners (Fig. 1), which are capable of interacting with cannabinoid receptors and the anandamide transporter20. Second, arachidonic acid and arachidonate-containing diacylglycerols act as endogenous ligands for several members of the transient release-potential ion-channel family43,44, in which VR1 belongs4. Third, anandamide inhibits capsaicin-sensitive nerves45. In 1999, anandamide, but not the other putative endocannabinoids, palmitoyl-ethanolamide or 2-arachidonoyl glycerol28,29, was shown to activate rat VR1 expressed in Xenopus oocytes or HEK293 cells19. With regard to cation currents, anandamide behaved as a full agonist at rat VR1 and this observation was later confirmed using human VR1 (Ref. 11). In addition, the competitive vanilloid-receptor antagonist capsazepine prevented the activation of VR1 by anandamide11,19. In rat DRG neurons, at high concentrations, anandamide induced VR1-mediated inward cation currents11, whereas at much lower concentrations, it fully activated native vanilloid receptors on rat artery perivascular C fibers, thereby triggering the release of stored CGRP and causing vasodilation19. By contrast, at lower doses and in skin sensory afferents, anandamide had the opposite effect: it inhibited capsaicin-induced CGRP release, seemingly through the activation of CB1 receptors45. The low affinity of anandamide for VR1, relative to CB1 receptors, in transfected cells was used as an argument against anandamide being an endogen-ous vanilloid21. Moreover, unlike capsaicin, low pH did not potentiate the actions of anandamide on VR111. Therefore, it is essential to determine whether anandamide might have differing concentrationresponse curves in the presence of elevated assay temperatures or when VR1 is in a phosphorylated state. Furthermore, the EC50 for anandamide-induced Ca2 influx into cells over-expressing human VR1 can be decreased up to tenfold in the presence of FAAH inhibitors (Di Marzo et al., unpublished observations), thus suggesting that degradation might result in underestimate anandamide potencies at VR1. In the PNS, CB1 receptors appear to be restricted to DRGs (Ref. 46), where they are found in only 1013% of the CGRP- and SP-containing sensory neurons47. By contrast, VR1 is present along the entire length of the majority of these peptidergic sensory neurons36.
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Therefore, activation of sensory neurons by anandamide interacting at VR1 receptors might predominate over the inhibitory action via CB1 receptors. In the periphery, anandamide can derive from various sources, for example, sensory neurons themselves can synthesize anandamide and release it in a Ca2 dependent manner48. In addition, inflammatory cells (for example, macrophages and mast cells) can liberate anandamide when subjected to inflammatory stimuli4951. Anandamide can thus exert either pro- or antiinflammatory actions, depending on whether it activates VR1 or CB1 receptors. In the spinal cord, the situation is probably more complex because anandamide released from sensory nerve endings might be involved in several positive as well as negative feedback mechanisms via activation of CB1 and VR1, respectively. Although CB1-receptor activation by anandamide results in analgesia, in the case of activation of VR1, the end result might be either hyperalgesia followed by analgesia (as with capsaicin administration) or direct analgesia (characteristic of olvanil treatment). However, the contribution of VR1-dependent mechanisms to the analgesia observed after anandamide administration has not yet been supported by experimental data. Therefore, much work is required before concluding that anandamide functions as an endogenous activator or as a blocker of vanilloid-sensitive sensory neurons. The recent finding that lipoxygenase products of arachidonic acid can activate both native VR1 and VR1 in expression systems might also be relevant52.

Distribution of VR1 in the brain

In spite of several reports of biological responses to capsaicin microinjected into various brain nuclei5356, the existence of vanilloid receptors in the CNS remains elusive, mainly because, in addition to interacting at vanilloid receptors2, capsaicin can also perturb membranes57, induce the formation of pseudochannels58 or influence various enzymes59,60, all of which could account for its actions in the brain. Using PCR detection, VR1 mRNA appears to be present in the rat brain61. By contrast, [3H]resiniferatoxin autoradiography using sections of whole rat brain62 or northern-blot hybridization with mRNA isolated from whole brain10 failed to detect VR1. However, these methods would not identify VR1 mRNA if its levels in the brain were low compared with its levels in primary sensory neurons. To answer the question of whether or not vanilloid receptors exist in the brain, two antibodies raised against the N- and the C- terminus of VR1, and a complementary RNA probe for in situ hybridization histochemistry have been used to explore VR1 in the rat brain and specific areas of the human brain8. In the rat, VR1-positive neurons were found throughout the whole neuroaxis8, including all cortical areas (in layers three and five), several regions of the limbic system (e.g., hippocampus, central amygdala, and both medial and lateral habenula), striatum, hypothalamus, centromedian and paraventricular thalamic nuclei, reticular formation, locus ceruleus, cerebellum and inferior olive (Fig. 2). VR1-immunopositive cells were also found in the third and fifth layers of the human parietal cortex8. Double-labeling immunofluorescence showed a complete overlap between VR1-positive and tyrosine hydroxylase-positive cells in the substantia 494
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nigra, identifying vanilloid-sensitive nigral cells as monoaminergic8. To validate the authenticity of the rat VR1 mRNA found in CNS tissue, RT-PCR was performed with VR1-specific primers and nucleotidesequence analysis of the product from hypothalamus identified it as a fragment of VR1 mRNA (Ref. 8). With the exception of the anterior hypothalamus (preoptic area), which is firmly linked to the hypothermic action of capsaicin63,64, the biological role of VR1positive brain neurons is enigmatic. It is noteworthy that anandamide induces a drop in the body temperature of mice that is not antagonized by a selective CB1receptor antagonist65. Therefore, it is possible that anandamide, which is present in the hypothalamus66, exerts its hypothermic action via preoptic VR1-positive neurons. Interestingly, VR1 and anandamide overlap in several other brain areas (e.g., hippocampus, cortex, striatum and substantia nigra), which also have a high density of CB1 receptors67. Capsaicin (presumably via the activation of VR1) stimulates adenylate cyclase activity in the rat cerebral cortex in vitro68. This action contrasts with the negative coupling of CB1 to adenylate cyclase29,69. Thus, at least in theory, anandamide could either enhance or decrease cAMP levels in cortical neurons, depending on the receptors (CB1 or VR1) that these cells possess. In the hippocampus, thalamic nuclei and basal ganglia, anandamide, acting at the CB1 receptor, is thought to exert negative neuromodulatory actions by inhibiting transmitter release and action. Thus, LTP (and, consequently, learning and memory), motor behavior and sensory perception are depressed29. Conversely, if anandamide activated VR1-positive neurons in these areas, the resulting overall effect would be a facilitatory neuromodulation. This possibility might explain why anandamide exerts both stimulatory and inhibitory effects in an array of neuro-behavioral assays, ranging from spontaneous activity to anxiety28,70. Finally, anandamide and its biosynthetic precursors are present in intriguingly high levels in the brainstem and medulla71, areas in which the CB1-receptor is restricted to small nuclei, such as the periaqueductal gray and the rostral ventromedial medulla, and participates in the suppression of supraspinal nociception72,73. Therefore, it is possible that anandamide also acts as an agonist at VR1 receptors present in other nuclei of the brainstem, such as the inferior olive and locus ceruleus8.

Concluding remarks and future directions

A re-evaluation of the actions of anandamide and olvanil in the recently developed CB1-receptor knockout mice74,75 and VR1-receptor knockout mice76,77, respectively, should clarify the relative contribution of these two receptors to the pharmacologies of vanilloids and endocannabinoids. Furthermore, the dominant negative VR1 mutant78 also promises to be a useful tool. Similar to unsaturated dialdehydes, related terpenoids and triprenyl phenols3, anandamide represents a new addition to the list of novel vanilloids, that is, VR1-receptor ligands that lack any recognizable vanillyl motif. Several other candidates are also already in line to join this list, including ginsenosides79 and cocaine80. It is possible that anandamide is not the only endogenous VR1-receptor activator, and further analysis is required to establish the existence of other endogenous activators of vanilloid receptors that are more potent than this endocannabinoid.

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(a)

(f)

(b) (g)

(c)

(h)

(d)

(i)

(e) (j)

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Fig. 2. Distribution of mRNA for vanilloid receptor subtype 1 using dark field illumination. Vanilloid receptor subtype 1 (VR1) was detected by in situ hybridization histochemistry using a riboprobe in the central nervous system of the rat8. A strong positive signal is shown in all cortical areas including the olfactory (Ob, olfactory bulb; tu, olfactory tubercle) and parietal cortex (Pa), septum (S), hippocampus (HI) and dentate gyrus (GD), substantia nigra (snr, snc), cerebellum (Cb), and the inferior olive (io). A weaker but clear signal is present in the amygdala (Am), solitary tract nucleus (nts), nucleus of the spinal trigeminal tract (tsV), and several hypothalamic nuclei (Hth). Additional abbreviations: Aq, cerebral aqueduct; CCi, cingulate cortex; CF, frontal cortex; CI, inferior colliculus; CS, superior colliculus; cp, caudateputamen; DR, dorsal raph nucleus; FPC, frontopolar cortex; ip, interpeduncular nucleus; LR, linear raph nucleus; MB, mamillary body; MR, nucleus raph magnus; Pas, parasubiculum; po, pontine nuclei; Th, thalamus. Scale bar, 1 mm.

However, the partial overlap between the ligand recognition properties of CB1 and VR1 receptors and the anandamide transporter warrants caution when interpreting in vivo experiments. By contrast, this overlap can now be exploited by medicinal chemistry. The past four years have yielded more surprises in the vanilloid field than the previous four decades and it is likely that further unexpected results are yet to come.

Note added in proof

The predicted two-dimensional topology of VR1 includes six transmembrane spanning segments (S1 to S6) and a channel pore in the extracellular loop linking S5 to S6 (Ref. 4). Recent side-directed mutagenesis experiments suggest that potentiation by protons of heat-evoked VR1 activation and direct activation by protons of VR1 are mediated by distinct molecular recognition sites (E600 and E648, respectively) located

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in this pore region81. A structural determinant (D646) of ruthenium red blockade of VR1 was also identified82. The proposed architecture of the pore would place D646 at the entrance. This model is in agreement with the concept of ruthenium red being a capsaicin channel pore blocker. Selected references
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Acknowledgements
The authors thank James E. Krause for reading the manuscript and Eva Mezey for contributing Fig. 2.

Context, state and the receptive fields of striatal cortex cells

Florentin Wrgtter and Ulf T. Eysel Visual cortical cells are commonly characterized by their receptive-field structure. Originally, a visual receptive field was defined in a purely spatial way as that retinal area from which a change in spiking response of the regarded cell could be elicited by visual stimulation.The first attempts to understand receptive-field structure were based entirely on the anatomical connectivity of the primary visual pathway.More recently,however,it has been discovered that the spatial and temporal context in which a stimulus is presented to a cell can strongly influence its receptive field, and this in turn is dependent on the state of arousal and attention. Accordingly, new concepts recognize that cortical receptive fields are highly dynamic entities embracing more than the sum of the full spatial and temporal response properties of a cell.
Trends Neurosci. (2000) 23, 497503

NFORMATION PROCESSING in the brain relies on the coordinated activity of its individual single neurons. This led to the traditional physiological approach of recording from single cells, in order to decode functional mechanisms from their responses. To this end, a sensor organ (for example, the retina) is stimulated and its primary (or higher order) afferents are monitored. In this framework, cells were regarded as passive inputoutput systems that perform some kind of transformation. Accordingly, a visual receptive field was thought to be a spatially defined retinal area that reacted in a rather static way such that the same stimulus led to identical responses differing only because of stochastic variations (noise). However, the visual world at the level of a single cortical cell (outside an electrophysiology laboratory) is anything but predictable. Receptive fields of cortical cells often encounter new stimulus situations, owing to
0166-2236/00/$ see front matter 2000 Elsevier Science Ltd. All rights reserved.

fast (saccadic) eye movements, which occur at an average rate of 3/s, or to object motion in the viewed scene, or both. Even during fixation or smooth pursuit, retinal positioning errors induce target shifts that lead to a fast changing stimulation of the cortical cells. These effects can be interpreted as a constantly changing flow of information that enters the visual system. The cortical network has to react to these changes in order to create a reliable visual perception. As a direct consequence of the fast changing signals that arrive at any given cortical cell, a strongly varying activity pattern is observed as its output. Through lateral and feedback connectivity this activity re-enters the cortical network at all levels and is able to influence even those cells (and especially their receptive field structure) from which it initially originated. It now seems clear, therefore, that the (anatomical) structure of the connectivity, together with the ongoing activity in the network, defines the
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F. Wrgtter is at the Dept of Psychology, Center for Cognitive and Computational Neuroscience (CCCN), University of Stirling, Stirling UK FK9 4LA and U.T. Eysel is at the Institut fr Physiologie, RuhrUniversitt Bochum, D-44780 Bochum, Germany.

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