Control of excitatory synaptic transmission by capsaicin is unaltered in TRPV1 vanilloid receptor knockout mice

Neurochemistry International 52 (2008) 89–94
www.elsevier.com/locate/neuint
Control of excitatory synaptic transmission by capsaicin is
unaltered in TRPV1 vanilloid receptor knockout mice
Felix Benninger, Tama´s F. Freund, Norbert Ha´jos *
Department of Cellular and Network Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences,
Budapest H-1450, Hungary
Received 29 March 2007; received in revised form 14 June 2007; accepted 15 June 2007
Available online 21 June 2007
Abstract
Several studies have shown that capsaicin could effectively regulate excitatory synaptic transmission in the central nervous system, but the
assumption that this effect is mediated by TRPV1 vanilloid receptors (TRPV1Rs) has not been tested directly. To provide direct evidence, we
compared the effect of capsaicin on excitatory synapses in wild type mice and TRPV1R knockouts. Using whole-cell patch-clamp techniques,
excitatory postsynaptic currents (EPSCs) were recorded in granule cells of the dentate gyrus. First, we investigated the effect of capsaicin on EPSCs
evoked by focal stimulation of ?bers in the stratum moleculare. Bath application of 10 mM capsaicin reduced the amplitude of evoked EPSCs both
in wild type and TRPV1R knockout animals to a similar extent. Treatment of the slices with the TRPV1R antagonist capsazepine (10 mM) alone, or
together with the agonist capsaicin, also caused a decrease in the EPSC amplitude both in wild type and TRPV1R knockout animals. Both drugs
appeared to affect the ef?cacy of excitatory synapses at presynaptic sites, since a signi?cant increase was observed in paired-pulse ratio of EPSC
amplitude after drug treatment. Next we examined the effect of capsaicin on spontaneously occurring EPSCs. This prototypic vanilloid ligand
increased the frequency of events without changing their amplitude in wild type mice. Similar enhancement in the frequency without altering the
amplitude of spontaneous EPSCs was observed in TRPV1R knockout mice.
These data strongly argue against the hypothesis that capsaicin modulates excitatory synaptic transmission by activating TRPV1Rs, at least in
the hippocampal network.
# 2007 Elsevier Ltd. All rights reserved.
Keywords: Brain slices; Glutamate; Transmitter release; Dentate gyrus; Granule cell; Excitatory synapses
1. Introduction
capsaicin could also affect the operation of both voltage-gated
sodium and calcium channels (Balla et al., 2001; Lundbaek
Capsaicin, the pungent ingredient of red peppers, severely
et al., 2005; Kofalvi et al., 2006), indicating that some of the
affects pain sensation, in?ammation or hyperalgesia. Systema-
capsaicin effects might not be linked to TRPV1Rs.
tic studies aiming to elucidate the effects of capsaicin revealed
In contrast to the well-established function of TRPV1Rs in
that this alkaloid primarily targets sensory ?bers of the C type,
the periphery, its role is much less obvious in the central
where it activates a member of the transient receptor potential
nervous system. Using autoradiography or immunohistochem-
(TRP) channels, TRPV1 vanilloid receptors (TRPV1Rs)
istry, TRPV1Rs were shown to be present in several brain
(Szallasi and Blumberg, 1999; Szolcsanyi, 2004). These
regions, including cortical structures (Acs et al., 1996; Mezey
receptors, cloned by Caterina et al. (1997), are non-selective
et al., 2000; Roberts et al., 2004; Toth et al., 2005; Cristino
cation channels gated by heat, low pH or endogenous ligands,
et al., 2006). Importantly, the speci?city of signals in two of
such as anandamide (Tominaga et al., 1998; Zygmunt et al.,
these reports has been con?rmed in TRPV1R knockout mice
1999; Caterina et al., 1999; Smart et al., 2000). In addition,
(Roberts et al., 2004; Cristino et al., 2006), strongly arguing for
the existence of TRPV1Rs in the CNS, yet their subcellular
(synaptic or extrasynaptic) localization remains to be deter-
mined by high resolution electron microscopy. The functional
* Corresponding author. Tel.: +36 1 2109400x387; fax: +36 1 2109412.
E-mail address: hajos@koki.hu (N. Ha´jos).
role of TRPV1Rs in distinct brain regions was addressed by
0197-0186/$ – see front matter # 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.neuint.2007.06.008

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F. Benninger et al. / Neurochemistry International 52 (2008) 89–94
electrophysiological experiments. In the hippocampus, for
Marton Electronics, Canoga Park, CA). Patch electrodes were pulled from
example, an increase in paired-pulse depression of ?eld
borosilicate glass capillaries with an inner ?lament (1.5 mm o.d., 1.12 mm i.d.;
Hilgenberg, Germany) using a Sutter P-87 puller. Electrodes ($3–6 MV) were
potentials after application of capsaicin or anandamide has
?lled with a solution containing (in mM) 80 CsCl, 60 Cs-gluconate, 3 NaCl, 1
been noticed, and this effect was found to be sensitive to
MgCl2, 10 HEPES, 2 Mg-ATP, and 5 QX-314 (pH 7.2–7.3 adjusted with CsOH;
TRPV1R antagonists (Al-Hayani et al., 2001; Huang et al.,
osmolarity 275–290 mOsm). Excitatory postsynaptic currents (EPSCs) were
2002). In addition to the investigation of capsaicin effects on
recorded at a holding potential of À65 mV. Slices were perfused with ACSF
?eld potentials, other studies have examined the activation of
containing 70–100 mM picrotoxin to block inhibitory neurotransmission. The
solution was bubbled with carbogen gas at room temperature and perfused at a
putative TRPV1Rs on synaptic transmission more directly.
?ow rate of 2–3 ml/min in a submerged type chamber. To evoke EPSCs, the
These studies have found that in distinct parts of the brain,
stimulating electrode was placed in the stratum moleculare of the dentate gyrus.
glutamatergic, but not GABAegic synaptic communication
Pairs of electrical stimuli separated by 50 ms were delivered via a theta glass
could be controlled by capsaicin, an effect that was also
pipette (Sutter Instrument Company, Novato, CA) ?lled with ACSF at 0.1 Hz
antagonized by TRPV
using a Supertech timer and isolator (Supertech Ltd., Pe´cs, Hungary, http://
1R antagonists (Sasamura et al., 1998;
www.superte.ch). Access resistances (between 4 and 18 MV, compensated 65–
Ha´jos and Freund, 2002; Marinelli et al., 2002, 2003; Xing and
70%) were frequently monitored and remained constant (Æ20%) during the
Li, 2007). Interestingly, excitatory postsynaptic currents
period of analysis. Signals were recorded with an Axopatch 200B (Molecular
(EPSCs) evoked by electrical stimulation were found to be
Devices, Sunnyvale, CA), ?ltered at 2 kHz, digitized at 6 kHz (National
depressed after application of capsaicin, whereas the same
Instruments PCI-6024E A/D board, Austin, TX), and analyzed off-line with
treatment signi?cantly increased the occurrence of spontaneous
the EVAN program (courtesy of Prof. I. Mody, UCLA, CA).
The drugs were perfused until the maximal effect was reached (usually 3–
EPSCs without affecting their amplitude.
4 min). The effect of drugs on evoked EPSCs was calculated as follows: control
To reveal whether the effect of capsaicin on synaptic
EPSC amplitudes in a 2–3 min time window were compared to those measured
glutamate release is indeed mediated by TRPV1Rs, we
after 5–6 min drug application for the same period of time. Only those
investigated the properties of EPSCs in dentate granule cells
experiments were included that had stable amplitudes at least for 10 min before
after bath application of this prototypic vanilloid ligand both in
drug application. The paired-pulse ratio was calculated from the mean ampli-
tude of the second EPSCs divided by the mean amplitude of the ?rst EPSCs. For
wild type and TRPV1R knockout mice.
spontaneously occurring EPSCs, the amplitude and the inter-event interval for
individual events were calculated and medians of their distributions were
2. Experimental procedures
compared before and after 5 min of capsaicin application. After each experi-
ment, the tubing made of Te?on was washed with ethanol for 10 min and with
ACSF for 15 min. For comparison of data, Wilcoxon matched pairs test or
Experiments were carried out according to the guidelines of the institutional
Mann–Whitney U-test were used in STATISTICA 6.1 (Statsoft, Inc., Tulsa,
ethical code and the Hungarian Act of Animal Care and Experimentation (1998.
OK). Data are presented as mean ÆS.E.M.
XXVIII. section 243/1998). Wild type and TRPV1R knockout mice of both
Picrotoxin was purchased from Sigma–Aldrich, while (E)-capsaicin and
sexes (20–77 days old, C57BL/6J strain) (Davis et al., 2000) were used. Mouse
capsazepine were obtained from Tocris. Both drugs were dissolved in DMSO
genotyping was performed on tail DNA. Neo PCR primer sequences were the
giving a 100 mM stock solution, which were stored at 4 8C.
following: NeoF 50-CCGGCCGCTTGGGTGGAGAGG and NeoR 50-products
on 300 bp (targeted allele), and TRPV1Rs (VRF1 50-CATGGCCAGTGAGAA-
CACCATGG and VRR2 50-AGCCTTTTGTTCTTGGCTTCTCCT) products
3. Results
on 150 bp (wild type allele). Ampli?cation reactions were carried out in 25 ml
total volume with presence of 1% dimethyl-formamide, 0.2 mM primer each,
The effects of the prototypic TRPV
0.2 mM dNTP, 1.5 mM MgCl
1R agonist capsaicin on
2 (93 8C for 15 s, 58 8C for 15 s, 72 8C for 45 s, for
30 cycles). Ampli?cation products were analyzed by agarose gel electrophor-
EPSCs evoked by focal stimulation of ?bers in the stratum
esis on 1.2% agarose gels. An example for the results of genotyping of a litter is
moleculare were measured in dentate granule cells of wild type
shown in Fig. 1.
mice and TRPV1R knockouts. Similar to what we found earlier
The animals were deeply anaesthetized with iso?urane followed by decap-
(Ha´jos and Freund, 2002), bath application of 10 mM capsaicin
itation. After opening the skull, the brain was quickly removed and immersed
signi?cantly reduced the amplitude of EPSCs (by 36.6 Æ 6.1%
into ice-cold cutting solution containing (in mM: NaCl 126, KCl 2.5, NaHCO3
26, CaCl
of control) in wild type mice (control: 143.8 Æ 19.3 pA;
2 0.5, MgCl2 5, NaH2PO4 1.25, glucose 10) bubbled with 95% O2/5%
CO
capsaicin: 88.6 Æ 12.1 pA; n = 6; p < 0.02; Fig. 2A and B). In
2 (carbogen gas). Thick horizontal slices (300–350 mm from mice) were
prepared using a Leica VT1000S Vibratome. The slices were stored in an
TRPV1R knockout mice, a similar signi?cant reduction was
interface type chamber containing ACSF (in mM: 126 NaCl, 2.5 KCl, 26
observed after capsaicin application, the amplitude of EPSCs
NaHCO3, 2 CaCl2, 2 MgCl2, 1.25 NaH2PO4, and 10 glucose) at room
was suppressed by 31.6 Æ 4.1% of control (control: 146.9 Æ
temperature for at least 1 h before recording.
Whole-cell patch-clamp recordings were obtained at 34–36 8C from granule
34.2 pA; capsaicin: 103.8 Æ 26.9 pA; n = 6; p < 0.02; Fig. 2A
cells in the dentate gyrus visualized by infrared videomicroscopy (Versascope,
and B). The inhibitory effect of capsaicin on the amplitude of
EPSCs was indistinguishable in wild type mice and TRPV1R
knockouts ( p > 0.1).
Next, we tested the effect of 10 mM capsazepine, a TRPV1R
antagonist, on excitatory synapses. We found that bath
application of this drug also signi?cantly reduced the EPSC
amplitude (by 34.9 Æ 5.4% of control) in wild type animals
(control: 165.1 Æ 35.5 pA, capsazepine: 112.4 Æ 28.2 pA;
Fig. 1. Results of genotyping a litter. Presence of a 150 bp length fragment
n = 5; p < 0.05; Fig. 3A and B). When we co-applied
indicates wild type allele, 300 bp PCR fragment shows targeted allele.
10 mM capsaicin together with 10 mM capsazepine, the
TRPV1Rs (+/+, wild type;+/À, heterozygote; À/À, knockout). Controls (ctr)
for +/+ and À/À are also indicated.
amplitude of evoked EPSCs was similarly decreased (by

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F. Benninger et al. / Neurochemistry International 52 (2008) 89–94
91
of control after capsazepine treatment; control: 205.2 Æ
7.3 pA;
capsazepine:
143.2 Æ 6.4 pA;
n = 4;
p < 0.05;
Fig. 3A and B). Similarly, the treatment of slices with a
mixture of capsaicin and capsazepine reduced the EPSC
amplitude by 38.1 Æ 6.2% of control (control: 211.8 Æ 4.4 pA,
capsaicin + capsazepine: 131.3 Æ 13.5 pA; n = 3; p < 0.05),
just like in the wild types. These results suggest that
capsazepine, as well as capsaicin alone can reduce the
amplitude of EPSCs independent of TRPV1Rs, and their
effects are not additive.
By a comparison of the paired-pulse ratios of evoked EPSCs,
we next examined whether capsaicin and capsazepine affect
excitatory synapses presynaptically or postsynaptically. If
glutamate release is altered, then the paired-pulse ratio should
change. If the reduction in EPSC amplitude is not accompanied
by changes in the paired-pulse ratio, then the conductivity of
glutamate receptors should be modi?ed by the drug treatment.
Therefore, we ?rst investigated the effect of capsaicin on
Fig. 2. The suppression of excitatory postsynaptic currents by capsaicin in
paired-pulse ratio in wild type mice and TRPV1R knockouts.
dentate granule cells recorded in wild type (WT) or TRPV1R knockout (KO)
After drug application, the ratio signi?cantly increased to
mice. (A): Representative averaged recordings of six to eight consecutive
121.3 Æ 3.2% of control in wild types and to 132.5 Æ 9.9% of
EPSCs taken before (black) and after application of 10 mM capsaicin (gray)
control in knockouts (n = 6 each, p < 0.02). Comparable to
in wild type mice (WT) or in TRPV1R knockouts. Scale bars are 25 pA and
10 ms. (B): Individual values (open circles) and averaged data (solid circles) for
these ?ndings, capsazepine treatment also caused a signi?cant
the capsaicin-induced suppression of EPSCs in wild type and TRPV1R knock-
increase in the paired-pulse ratio both in wild types
out mice are shown.
(129.7 Æ 10.1%; n = 5; p < 0.05) and knockouts (126.4 Æ
8.8; n = 4; p < 0.05). Thus, the effects of both capsaicin and
33.3 Æ 9.4% of control; control: 149.5 Æ 21.2 pA; capsai-
capsazepine appear to be presynaptic, reducing glutamate
cin + capsazepine:
99.6 Æ 19.6 pA;
n = 4;
p < 0.05).
In
release from excitatory terminals both in wild type and
TRPV1R knockouts, suppression of the EPSC amplitude was
TRPV1R knockout mice.
comparable to that seen in wild type mice (i.e., by 30.2 Æ 1.5%
In further experiments, we investigated how capsaicin alters
the properties of spontaneous EPSCs (sEPSCs). In wild type
mice, bath application of capsaicin signi?cantly increased the
occurrence of spontaneous events (i.e., reduced the inter-event
interval by 32.5 Æ 11.8% of control, control: 0.43 Æ 0.23 s;
capsaicin: 0.2 Æ 0.05 s; n = 5; p < 0.04, Fig. 4A and B) without
changing their amplitude (control: 16.6 Æ 2.1 pA; capsaicin:
16.1 Æ 2.7 pA; n = 5; p > 0.1; Fig. 4A and B). Similarly,
capsaicin also elevated the frequency of sEPSCs in TRPV1R
knockouts, since the inter-event interval was reduced by
29.3 Æ 7.4% of control (control: 0.16 Æ 0.04 s; capsaicin:
0.12 Æ 0.04 s; n = 6; p < 0.02; Fig. 4A and B). Similar to those
observed in wild types, the amplitude of synaptic events did not
change (control: 19.2 Æ 3.6 pA; capsaicin: 17.7 Æ 3.3 pA;
n = 6; p > 0.1; Fig. 4A and B). The comparison of the
decrease in the inter-event interval of sEPSCs between wild
type mice and TRPV1R knockouts showed no difference
( p > 0.1). These results provided further evidence that
capsaicin affected synaptic glutamate release in wild type
and TRPV1R knockout mice to a similar degree, in a similar
manner.
Fig. 3. The reduction of excitatory postsynaptic currents by capsazepine (CZ)
in dentate granule cells recorded in wild type (WT) or TRPV1R knockout (KO)
4. Discussion
mice. (A): Representative averaged recordings of 8–10 consecutive EPSCs
taken before (black) and after application of 10 mM capsazepine (gray) in wild
Electrophysiological data presented here strongly suggest
type mice (WT) or in TRPV1R knockouts. Scale bars are 25 pA and 10 ms. (B):
that capsaicin actions on excitatory synaptic transmission are
Individual values (open circles) and averaged data (solid circles) for the
not mediated by TRPV
capsazepine-induced suppression of EPSCs in wild type and TRPV
1Rs, at least in the dentate gyrus. Our
1R knockout
mice are shown.
previous observations already raised this possibility (Ha´jos and

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F. Benninger et al. / Neurochemistry International 52 (2008) 89–94
Fig. 4. The occurrence of spontaneous EPSCs in dentate granule cells is increased by capsaicin both in wild type and TRPV1R knockout mice. (A): Representative
raw recordings before and after bath application of 10 mM capsaicin. Scale bars are 10 pA and 100 ms. (B): Median of individual experiments (open circles) and
averaged values (?lled circles) for the inter-event interval (IEI) and the amplitude of spontaneous EPSCs in control and after drug application are shown. Capsaicin
induced a signi?cant reduction in the inter-event intervals of synaptic events (i.e., increased the frequency) without changing their amplitude both in wild type and
TRPV1R knockout mice.
Freund, 2002), as we have shown that the suppression of the
sharp contrast observed in adult animals (present study; Kofalvi
amplitude of EPSCs after the second application of capsaicin
et al., 2003). Thus, it seems likely that during development the
was indistinguishable from that seen after the ?rst application.
molecular target of capsazepine changes its effect on synaptic
This observation was not consistent with the known desensi-
transmission, or the binding site(s) of capsazepine might alter.
tization properties of TRPV1Rs upon repeated capsaicin
We therefore propose that, in the hippocampus of young rats,
application (Dray et al., 1989; Docherty et al., 1991; Caterina
the suppression of EPSC amplitude by capsaicin is counter-
et al., 1997). Our results seem to contradict those pharmaco-
balanced by the enhancement caused by capsazepine, therefore
logical data, where the effect of capsaicin on synaptic
no reduction in glutamate release can be observed.
transmission has been found to be fully blocked by antagonists
As to the presynaptic mechanism of capsaicin actions, a
speci?c for TRPV1Rs (e.g., capsazepine or iodo-resinifera-
recent study showed that iodo-resiniferatoxin as well as
toxin) (Al-Hayani et al., 2001; Marinelli et al., 2003). Here we
capsaicin (both applied in mM concentrations) could markedly
found that, in adult mice, capsazepine also effectively reduced
reduce the high K+-induced Ca2+ entry (Kofalvi et al., 2006).
the amplitude of EPSCs, similar to that seen after capsaicin
Since transmitter release is highly sensitive to Ca2+ entry, one
application. In line with these data, a study by Kofalvi et al.
might assume that glutamate release from excitatory terminals
(2003) has shown that glutamate release from synaptosomes
in the dentate gyrus could be affected with a similar
prepared from the hippocampus of adult rats could be
mechanism. In the present study we found that capsaicin,
signi?cantly suppressed by capsazepine. These ?ndings are
capsazepine, or co-application of the two, reduce the
in contrast with our published results (Ha´jos and Freund, 2002),
amplitude of EPSCs to a similar extent, suggesting that
where capsazepine could antagonize the effect of capsaicin on
capsazepine might also decrease Ca2+ entry at the same site,
EPSC amplitude recorded in slices from rats of P15-22. We
where capsaicin acts.
repeated the experiments with capsazepine in young rats and
Data from other laboratories, as well as our own results,
found that this drug on its own could substantially enhance the
showed that capsaicin could reduce the amplitude of evoked
amplitude of EPSCs (unpublished observations), which is in
EPSCs, while it increased the frequency of spontaneous EPSCs

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F. Benninger et al. / Neurochemistry International 52 (2008) 89–94
93
without changing their amplitude (Ha´jos and Freund, 2002;
Caterina, M.J., Rosen, T.A., Tominaga, M., Brake, A.J., Julius, D., 1999. A
Marinelli et al., 2002, 2003). These unconventional effects
capsaicin-receptor homologue with a high threshold for noxious heat.
Nature 398, 436–441.
seem to suggest that the target molecule of capsaicin regulating
Cristino, L., de Petrocellis, L., Pryce, G., Baker, D., Guglielmotti, V., Di Marzo,
glutamatergic transmission could be located at the presynaptic
V., 2006. Immunohistochemical localization of cannabinoid type 1 and
axon terminals, an assumption that is also supported by the
vanilloid transient receptor potential vanilloid type 1 receptors in the mouse
observed increase in the paired-pulse ratio (present study). If
brain. Neuroscience 139, 1405–1415.
capsaicin modulated postsynaptic glutamate receptors, the
Davis, J.B., Gray, J., Gunthorpe, M.J., Hatcher, J.P., Davey, P.T., Overend, P.,
Harries, M.H., Latcham, J., Clapham, C., Atkinson, K., Hughes, S.A.,
amplitude of sEPSCs should have also been altered, which was
Rance, K., Grau, E., Harper, A.J., Pugh, P.L., Rogers, D.C., Bingham,
not the case (present study; Marinelli et al., 2003). The question
S., Randall, A., Sheardown, S.A., 2000. Vanilloid receptor-1 is essential for
arises how capsaicin could reduce the amplitude of evoked
in?ammatory thermal hyperalgesia. Nature 405, 183–187.
EPSCs, while in the same time increases the frequency of
Docherty, R.J., Robertson, B., Bevan, S., 1991. Capsaicin causes prolonged
sEPSCs. One explanation might be that if capsaicin triggers
inhibition of voltage-activated calcium currents in adult rat dorsal root
ganglion neurons in culture. Neuroscience 40, 513–521.
release of retrograde messengers from postsynaptic neurons
Dray, A., Bettaney, J., Forster, P., 1989. Capsaicin desensitization of peripheral
that directly promote fusion of vesicles irrespective of Ca2+
nociceptive ?bres does not impair sensitivity to other noxious stimuli.
concentration within the terminals, this could enhance the
Neurosci. Lett. 99, 50–54.
action potential-independent glutamate release (i.e., the
Gavva, N.R., Bannon, A.W., Surapaneni, S., Hovland Jr., D.N., Lehto, S.G.,
majority of sEPSCs under our circumstances). Although
Gore, A., Juan, T., Deng, H., Han, B., Klionsky, L., Kuang, R., Le, A.,
Tamir, R., Wang, J., Youngblood, B., Zhu, D., Norman, M.H., Magal, E.,
TRPV1Rs have been shown to be located in the dendrites
Treanor, J.J., Louis, J.C., 2007. The vanilloid receptor TRPV1 is tonically
and somata of hippocampal principal cells (Cristino et al.,
activated in vivo and involved in body temperature regulation. J. Neurosci.
2006), these receptors are unlikely to be involved in the
27, 3366–3374.
enhancement of sEPSC frequency, since the same effect was
Ha´jos, N., Freund, T.F., 2002. Pharmacological separation of cannabinoid
observed in the TRPV
sensitive receptors on hippocampal excitatory and inhibitory ?bers. Neu-
1R knockout mice. Further studies should
ropharmacology 43, 503–510.
clarify the possible mechanisms underlying the capscaicin-
Huang, S.M., Bisogno, T., Trevisani, M., Al-Hayani, A., De Petrocellis, L.,
induced changes in excitatory neurotransmission.
Fezza, F., Tognetto, M., Petros, T.J., Krey, J.F., Chu, C.J., Miller, J.D.,
In summary, our data presented here suggest that TRPV1Rs
Davies, S.N., Geppetti, P., Walker, J.M., Di Marzo, V., 2002. An endogenous
may not be the target molecules for capsaicin regulating
capsaicin-like substance with high potency at recombinant and native
glutamatergic synapses in the hippocampal network, although
vanilloid VR1 receptors. Proc. Natl. Acad. Sci. U.S.A. 99, 8400–8405.
Kofalvi, A., Vizi, E.S., Ledent, C., Sperlagh, B., 2003. Cannabinoids inhibit
they might have a function during pathological conditions like
the release of [3H]glutamate from rodent hippocampal synaptosomes via
fever or osmotic changes in extracellular space (Caterina et al.,
a novel CB1 receptor-independent action. Eur. J. Neurosci. 18, 1973–
1997; Gavva et al., 2007; Liu et al., 2007).
1978.
Kofalvi, A., Oliveira, C.R., Cunha, R.A., 2006. Lack of evidence for functional
Acknowledgements
TRPV1 vanilloid receptors in rat hippocampal nerve terminals. Neurosci.
Lett. 403, 151–156.
Liu, L., Chen, L., Liedtke, W., Simon, S.A., 2007. Changes in osmolality
TRPV1R knockout mice were generously provided by Dr.
sensitize the response to capsaicin in trigeminal sensory neurons. J.
John B. Davis (GSK R&D Ltd., UK). We are also grateful to
Neurophysiol. 97, 2001–2015.
Zsuzsanna Erde´lyi and Ferenc Erde´lyi for genotyping the
Lundbaek, J.A., Birn, P., Tape, S.E., Toombes, G.E., Sogaard, R., Koeppe II,
animals. This work was supported by the Howard Hughes
R.E., Gruner, S.M., Hansen, A.J., Andersen, O.S., 2005. Capsaicin regulates
voltage-dependent sodium channels by altering lipid bilayer elasticity. Mol.
Medical Institute, by EU(LSHM-CT-2004-005166), NKFP 1A/
Pharmacol. 68, 680–689.
002/2004, OTKA Hungary (T46820), and NIH (NS30549).
Marinelli, S., Vaughan, C.W., Christie, M.J., Connor, M., 2002. Capsaicin
N.H. is the recipient of a Wellcome Trust International Senior
activation of glutamatergic synaptic transmission in the rat locus coeruleus
Research Fellowship. The excellent technical assistance of
in vitro. J. Physiol. 543, 531–540.
Katalin Lengyel, Emo?ke Simon and Katalin Iva´nyi is also
Marinelli, S., Di Marzo, V., Berretta, N., Matias, I., Maccarrone, M., Bernardi,
G., Mercuri, N.B., 2003. Presynaptic facilitation of glutamatergic synapses
gratefully acknowledged.
to dopaminergic neurons of the rat substantia nigra by endogenous stimula-
tion of vanilloid receptors. J. Neurosci. 23, 3136–3144.
References
Mezey, E., Toth, Z.E., Cortright, D.N., Arzubi, M.K., Krause, J.E., Elde, R.,
Guo, A., Blumberg, P.M., Szallasi, A., 2000. Distribution of mRNA for
Acs, G., Palkovits, M., Blumberg, P.M., 1996. Speci?c binding of [3H]resini-
vanilloid receptor subtype 1 (VR1), and VR1-like immunoreactivity, in the
feratoxin by human and rat preoptic area, locus ceruleus, medial hypotha-
central nervous system of the rat and human. Proc. Natl. Acad. Sci. U.S.A.
lamus, reticular formation and ventral thalamus membrane preparations.
97, 3655–3660.
Life Sci. 59, 1899–1908.
Roberts, J.C., Davis, J.B., Benham, C.D., 2004. [3H]Resiniferatoxin autoradio-
Al-Hayani, A., Wease, K.N., Ross, R.A., Pertwee, R.G., Davies, S.N., 2001. The
graphy in the CNS of wild-type and TRPV1 null mice de?nes TRPV1 (VR-1)
endogenous cannabinoid anandamide activates vanilloid receptors in the rat
protein distribution. Brain Res. 995, 176–183.
hippocampal slice. Neuropharmacology 41, 1000–1005.
Sasamura, T., Sasaki, M., Tohda, C., Kuraishi, Y., 1998. Existence of
Balla, Z., Szoke, E., Czeh, G., Szolcsanyi, J., 2001. Effect of capsaicin on
capsaicin-sensitive glutamatergic terminals in rat hypothalamus. Neurore-
voltage-gated currents of trigeminal neurones in cell culture and slice
port 9, 2045–2048.
preparations. Acta Physiol. Hung. 88, 173–196.
Smart, D., Gunthorpe, M.J., Jerman, J.C., Nasir, S., Gray, J., Muir, A.I.,
Caterina, M.J., Schumacher, M.A., Tominaga, M., Rosen, T.A., Levine, J.D.,
Chambers, J.K., Randall, A.D., Davis, J.B., 2000. The endogenous lipid
Julius, D., 1997. The capsaicin receptor: a heat-activated ion channel in the
anandamide is a full agonist at the human vanilloid receptor (hVR1). Br. J.
pain pathway. Nature 389, 816–824.
Pharmacol. 129, 227–230.

---

94
F. Benninger et al. / Neurochemistry International 52 (2008) 89–94
Szallasi, A., Blumberg, P.M., 1999. Vanilloid (capsaicin) receptors and mechan-
vanilloid receptor 1 (TRPV1) in the adult rat brain. Brain Res. 135,
isms. Pharmacol. Rev. 51, 159–212.
162–168.
Szolcsanyi, J., 2004. Forty years in capsaicin research for sensory pharmacol-
Xing, J., Li, J., 2007. TRPV1 receptor mediates glutamatergic synaptic input to
ogy and physiology. Neuropeptides 38, 377–384.
dorsolateral periaqueductal gray (dl-PAG) neurons. J. Neurophysiol. 97,
Tominaga, M., Caterina, M.J., Malmberg, A.B., Rosen, T.A., Gilbert, H., Skinner,
503–511.
K., Raumann, B.E., Basbaum, A.I., Julius, D., 1998. The cloned capsaicin
Zygmunt, P.M., Petersson, J., Andersson, D.A., Chuang, H., Sorgard, M., Di
receptor integrates multiple pain-producing stimuli. Neuron 21, 531–543.
Marzo, V., Julius, D., Hogestatt, E.D., 1999. Vanilloid receptors on
Toth, A., Boczan, J., Kedei, N., Lizanecz, E., Bagi, Z., Papp, Z., Edes, I.,
sensory nerves mediate the vasodilator action of anandamide. Nature
Csiba, L., Blumberg, P.M., 2005. Expression and distribution of
400, 452–457.

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Document Outline

• Control of excitatory synaptic transmission by capsaicin is unaltered in TRPV1 vanilloid receptor knockout mice
  • Introduction
  • Experimental procedures
  • Results
  • Discussion
  • Acknowledgements
  • References

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