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The interactive role of cannabinoid and vanilloid systems in hippocampal synaptic plasticity in rats
European Journal of Pharmacology 757 (2015) 68–73
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European Journal of Pharmacology journal homepage: www.elsevier.com/locate/ejphar
Molecular and cellular pharmacology
The interactive role of cannabinoid and vanilloid systems in hippocampal synaptic plasticity in rats Lida Tahmasebi, Alireza Komaki n,1, Ruhollah Karamian, Siamak Shahidi, Abdolrahman Sarihi, Iraj Salehi, Ali Nikkhah Neurophysiology Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
art ic l e i nf o
a b s t r a c t
Article history: Received 30 September 2014 Received in revised form 23 March 2015 Accepted 25 March 2015 Available online 2 April 2015
Long-term potentiation (LTP) has been most thoroughly studied in the hippocampus, which has a key role in learning and memory. Endocannabinoids are one of the endogenous systems that modulate this kind of synaptic plasticity. The activation of the vanillioid system has also been shown to mediate synaptic plasticity in the hippocampus. In addition, immunohistochemical studies have shown that cannabinoid receptor type 1 (CB1) and vanilloid receptor 1 (TRPV1) are closely located in the hippocampus. In this study, we examined the hippocampal effects of co-administrating WIN55-212-2 and capsaicin, which are CB1 and TRPV1 agonists, respectively, on the induction of LTP in the dentate gyrus (DG) of rats. LTP in the hippocampal area was induced by high-frequency stimulation (HFS). Our results indicated that the cannabinoid agonist reduced both field excitatory post-synaptic potential (fEPSP) slope and population spike (PS) amplitude after HFS with respect to the control group, whereas the vanilloid agonist increased these parameters along with the increased induction of LTP as compared to the control group. We also showed that the co-administration of cannabinoid and vanilloid agonists had different effects on fEPSP slope and PS amplitude. It seems that agonists of the vanilloid system modulate cannabinoid outputs that cause an increase in synaptic plastisity, while in contemporary consumption of two agonist, TRPV1 agonist can change production of endocannabinoid, which in turn result to enhancement of LTP induction. These findings suggest that the two systems may interact or share certain common signaling pathways in the hippocampus. & 2015 Elsevier B.V. All rights reserved.
Keywords: Cannabinoid Vanilloid Capsaicin WIN55-212-2 Long-term potentiation Hippocampus Rat
1. Introduction Long-term potentiation (LTP) of synaptic activity is the most popular and widely researched model of synaptic plasticity that occurs during learning and memory (Hölscher, 1999). Neuromodulators are involved in most forms of synaptic plasticity ranging from the short- to long-term (Lovinger, 2010; Pawlak et al., 2010). Neurotransmitters and their receptors play important roles in synaptic plasticity (Swope et al., 1992). Moreover, it has been reported that neuromodulators are involved in most forms of synaptic plasticity ranging from the short- to long-term (Lovinger, 2010; Pawlak et al., 2010).
n Correspondence to: Departement of Physiology, School of Medicine, Hamadan University of Medical Sciences, Shahid Fahmideh Street, Hamadan, Iran. Tel.: þ 98 81 38380267; fax: þ 98 81 38380131. E-mail addresses: [email protected], [email protected] (A. Komaki). 1 URL: umsha.ac.ir
http://dx.doi.org/10.1016/j.ejphar.2015.03.063 0014-2999/& 2015 Elsevier B.V. All rights reserved.
Endocannabinoids and their receptors play a modulatory role in several physiological processes, mainly in the brain (Fernández‐ Ruiz et al., 2010). Cannabinoid receptors are distributed throughout the brain and cannabinoid receptor type 1 (CB1) are particularly well represented in the cortex (entorhinal and cingulate), hippocampus, lateral septum, nucleus accumbens, amygdala, and periaqueductal gray area (PAG) (Millan, 2003). Nevertheless, there are controversies regarding the effects of cannabinoids on synaptic plasticity. For instance, administration of CB1 receptor agonists has been found to exert inhibitory effects on LTP induction (Collins et al., 1994; Nowicky et al., 1987; Terranova et al., 1995). On the other hand, investigations of the induction of LTP in CA1 pyramidal neurons of hippocampal slices has shown that AM281 (a CB1 antagonist) impairs the induction of LTP (de Oliveira Alvares et al., 2006; Lin et al., 2011). Furthermore, CB1 receptor agonists are reported to induce biphasic effects, with lower doses being LTP enhancers and higher doses being LTP suppressers (Abush and Akirav, 2010). Transient receptor potential vanilloid 1 (TRPV1) has been shown to influence different types of synaptic plasticity in the
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hippocampus by altering synaptic calcium levels and neurotransmitter release (Chávez et al., 2010; Gibson et al., 2008; Marsch et al., 2007). The TRPV1 channel can be activated exogenously by various ligand-like agents including capsaicin (the compound responsible for producing the hotness of red chili peppers) (Huang et al., 2002; Montell et al., 2002). Recently reported functions for TRPV1 in the CNS include improved spatial memory retrieval in response to TRPV1 activation under stressful conditions (Li et al., 2008). It has been demonstrated that TRPV1 is required for certain types of synaptic plasticity, although there are controversies regarding the effects of the vanilloid system on synaptic plasticity. For example, research using TRPV1 knockout mice demonstrated reduced CA1 LTP in knockout animals as compared to wild type controls (Marsch et al., 2007). On the other hand, studies indicate that following ether anesthesia, capsaicin (a TRPV1 agonist) has a suppressive effect on lateral amygdala (LA) LTP both in patch clamp and in extracellular recordings (Zschenderlein et al., 2011). Despite these data indicating TRPV1 involvement in hippocampal synaptic plasticity, the mechanism by which it modulates this plasticity has not been identified (Al-Hayani et al., 2001; Huang et al., 2002). Functional interactions between cannabinoid and vanilloid systems have been described. Immunohistochemical studies suggest a similar distribution of TRPV1 and its extensive co-localization with CB1 in areas such as the hippocampus, basal ganglia, hypothalamus, thalamus (Cristino et al., 2006), ventrolateral PAG (Casarotto et al., 2011), dorsolateral PAG (Cristino et al., 2006), and prefrontal cortex (Micale et al., 2008). Although CB1 and TRPV1 receptors are expressed in several overlapping brain regions, they may have opposite roles in the regulation of neural activity (Di Marzo, 2010). It is likely that anandamide may interact with CB1 and TRPV1 receptors to inhibit and promote anxiety-like behaviors, respectively (Hakimizadeh and Oryan, 2012). Unlike established data about the individual effects of cannabinoid system and the vanilloid system on synaptic plasticity and neural function, the simultaneous stimulation effect of these two systems on synaptic plasticity has not been studied in the dentate gyrus (DG) of hippocampus. The DG is part of the hippocampus which is thought to contribute to mechanisms of learning and memory via activity of dentate granule cells (Jedlicka et al., 2011). The DG is one of the few areas of the rat brain which continues to generate new nerve cells well after birth (Blaise and Arnett, 2006; Nakashiba et al., 2012). In the DG, electrical stimuli delivered to perforant pathway (PP) elicit field excitatory postsynaptic potentials (fEPSPs) (Andersen et al., 1971). This area is one of few sites in the adult brain at which synaptic plasticity are induced (Jedlicka et al., 2015). Therefore, in this study, we test the hypothesis that a part of effects of the cannabinoid system on synaptic plasticity are the result of its effects on vanilloid system. The interactions of these two systems in the modulation of synaptic plasticity could have important therapeutic implications in clinical settings. In this study, we examined the effects of co-administration of intrahippocampal injections of cannabinoid and vanilloid agonists on the induction of LTP in the DG of rats.
2. Materials and methods 2.1. Animals Thirty-five experimentally naive, male Wistar rats (weighing 250–300 g) were obtained from the Pasteur Institute, Tehran, Iran. The animals were housed in an air-conditioned room at 22 72 1C under 12 h light/dark cycles (light turned on at 07:00 and turned off at 19:00). The animals were maintained in cages with five rats
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in each cage. Water and food were given ad libitum. After one week of adaptation, subjects were randomly separated into control, DMSO, WIN55-212-2, Capsaicin, and WIN þCapsaicin groups. There were 10 rats in each group. All research and animal care procedures were approved by the Veterinary Ethics Committee of this University and were performed in accordance with the National Institutes of Health Guide for Care and Use of Laboratory Animals (NIH Publication no. 85-23, revised 1985). 2.2. Drugs The synthetic full CB1/2-receptor agonist, WIN55,212-2 [R-(þ)-(2,3dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl)(1-naphthalenyl) methanonemesylate] (Sigma, USA), and the TRPV1 receptor agonist, capsaicin [8-Methyl-N-vanillyl-trans-6nonenamide] (Wako, Japan) were initially dissolved in DMSO [dimethylsulfoxide] (Sigma, USA) and further diluted in saline (0.9% NaCl). DMSO concentration in both drugs waso10%. This DMSO and saline solution was also used as the vehicle. Drug concentrations were based on previous studies: WIN55-212-2: 0.5 mg/0.5 ml (Abush and Akirav, 2010) and capsaicin: 0.03 mg/0.5 ml (Hakimizadeh and Oryan, 2012). Drugs were microinjected into DG approximately 20 min prior to HFS. 2.3. Surgical procedures, electrophysiological recordings, and LTP induction Rats were anesthetized intraperitoneally with urethane [Ethyl carbamate (Sigma, USA)] (1.5 g/kg with supplemental injections as required) (Karimi et al., 2013; Komaki et al., 2014) and fixated in a stereotaxic apparatus for surgery. A heating pad was used to maintain the animals' body temperature. After incision of the skin and obtaining the position of the dentate gyrus (DG) according to the Paxinos and Watson (2005) atlas for the rat brain, small burr holes were drilled in the skull. Recording and stimulating electrodes were positioned in DG [AP: 3.8 mm from bregma; ML: 2.3 mm from midline; DV: 2.7–3.2 mm from the skull surface] and perforant pathway (PP) [AP: 8.1 mm from bregma; ML: 4.3 mm from midline; DV: 3.2 mm from the skull surface] respectively. The electrodes were lowered very slowly (0.2 mm/min) from cortex to hippocampus, in order to minimize trauma to the brain tissue and field potential recording were obtain in the granular cells of the DG following stimulation of the PP. Electrode positions were optimized to record maximal population spike (PS). An input/output (I/O) response curve was constructed by varying the intensity of single pulse stimulation and averaging five responses per intensity. The stimulus intensity that evoked a mean field potential equal to 50% of the maximum response was then used for all subsequent stimulations. Then, substances were injected with hamilton syringe into the DG. A volume of 0.5 ml was microinjected unilaterally over a period of 1 min. The injection syringe was left in position for an additional 60 s before withdrawal to minimize dragging of the injected liquid along the injection tract. After determination of I/O curves, single stimuli were applied for at least 30 min, and responses were monitored. Single stimuli were presented every 10 s. Measurements of the slope of the fEPSP were taken between 20 and 80% of the peak amplitude. Slope of fEPSPs were normalized with respect to the 30 min control period before tetanic stimulation. Once a stable baseline of responses were obtained for at least 20 min, LTP was induced using a HFS protocol of 400 Hz (10 bursts of 20 stimuli, 0.2 ms stimulus duration, 10 s interburst interval) at a stimulus intensity that evoked a PS amplitude and field EPSP slope of approximately 50% of the maximum response. Both EPSP and PS were recorded at 5, 30, and 60 min after HFS in order to determine and changes in the synaptic response of DG neurons. For each
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time-point, 10 consecutive evoked responses were averaged at 10 s stimulus intervals (Karimi et al., 2013, 2015; Komaki et al., 2014; Taube and Schwartzkroin, 1988). For stimulations, the parameters of the stimuli were defined in homemade software and were sent via a data acquisition board linked to a constant current isolator unit (A365 WPI, USA) prior to delivery to the PP through the stimulus electrodes. The induced field potential response from the DG was passed through a preamplifier, then was amplified (1000 ) (Differential amplifier DAM 80 WPI, USA), and filtered (band pass 1–3 kHz). This response was digitized at a sampling rate of 10 kHz, and was observable on a computer. It was saved in a file to facilitate later offline analysis. 2.4. Statistical analysis Data were statistically analyzed by repeated measures ANOVA tests followed by Tukey's test. Values of P o0.05 were considered to be significant.
3. Results 3.1. Measurement of evoked potentials The evoked field potential in the DG has two components: a population spike (PS) and fEPSP (Fig. 1). During electrophysiological recordings, changes in the PS amplitude and fEPSP slope were measured. The amplitude of the PS was measured from the peak of the first positive deflection of the evoked potential to the peak of the following negative potential. The field EPSP slope function was measured as the slope of the line connecting the start of the first positive deflection of the evoked potential with the peak of the second positive deflection of the evoked potential. The slopes for fEPSPs and PS amplitude were calculated using a data analysis program (eTrace, www.sciencebeam.com). 3.2. Effect of HFS on the slope of EPSP and the amplitude of PS The effect of HFS on the slope of EPSP and amplitude of PS in the DG area of the hippocampus in rats were examined. The slopes of fEPSP were strongly enhanced, resulting in a significant amount of LTP at PP-DG synapses in the saline (1457 6.36% of pre-HFS baseline) and DMSO (148 77.3% of pre-HFS baseline) groups. There was no significant difference of fEPSP slope between the saline and DMSO groups [F (4,30) ¼1.57, P 40.05]. Our data demonstrates that the amplitude of PS was 262 712.4% of preHFS baseline in the saline group (n ¼7) and 251 712% of pre-HFS baseline in the DMSO group (n ¼ 7). The data also demonstrates that there was no significant difference of amplitude in PS LTP between the saline and DMSO groups [F (4,30) ¼1.89, P 40.05]. Since there was not difference between DMSO and saline group, these data have been combined and have shown as control group. 3.3. Effect of CB1 agonist on the slope of EPSP and the amplitude of PS The effects of WIN55-212-2 (WIN; a CB1 agonist) on the slope of EPSP and amplitude of PS induced by HFS in the PP to the DG area of the hippocampus in rats were examined. The results showed that HFS directly applied to the PP-DG area can increase synaptic transmission, inducing LTP of EPSP in the WIN group (1317 4.4% of pre-HFS baseline) (Fig. 2). Fig. 3 demonstrates that the amplitude of PS was 161 712.3% of pre-HFS baseline in the WIN group (n ¼7). The CB1 agonist reduced fEPSP slope in compared with control group [F (3,24) ¼3.36, P o0.05]. The
amplitude of PS was also significantly decreased in comparison with the control group [F (3,24)¼ 7.14, P o0.001] 3.4. The effects of capsaicin on the slope of EPSP and amplitude of PS The effects of capsaicin (Cap; TRPV1 agonist) on the slope of EPSP and amplitude of PS induced by HFS in the PP-DG area of the hippocampus in rats were examined. Our data showed that capsaicin (Cap; TRPV1 agonist) (0.03 mg/0.5 ml) application resulted in significantly enhanced slopes of fEPSP (192 712.2%; n ¼7; Fig. 2) [F (3,24)¼5.07; P o0.01] and PS amplitude (352715%; n¼ 7; Fig. 3) [F (3,24) ¼9.26; P o0.001] when compared to the control groups. 3.5. Effect of co-administration of CB1 and TRPV1 agonists on the slope of EPSP and amplitude of PS Considering the involvement of both cannabinoid and vanilloid systems in learning and memory and the overlap of the cannabinoid and vanilloid receptors in the CNS, we investigated the effects of cannabinoid and vanilloid agonist co-administration on LTP. Our results indicated that co-administration of cannabinoid and vanilloid agonists had different effects on the slopes of fEPSP (180712%; n¼7; Fig. 2) and amplitude of PS (290714.5%; n¼7; Fig. 3) when compared to either WIN (amplitude of PS: 161712.3% [F (3,24)¼6.12, Po0.001]; slopes of fEPSP: 13174.4% [F (3,24)¼5.36; Po0.001]) or Cap (amplitude of PS: 352715% [F (3,24)¼4.65, Po0.01; slopes of fEPSP: 192712.2%; [F (3,24)¼2.27, P40.05) groups. These data also demonstrate that there was a significant difference of amplitude in PS LTP between the control and WINþCap groups [F (3,24)¼3.06, Po0.05], also a significant change of slope of EPSP LTP between WINþCap group as compared to the control group [F (3,24)¼4.07, Po0.01] was observed.
4. Discussion The main purpose of the present study was to investigate whether intrahippocampal injection of WIN and Cap can influence synaptic plasticity in PP-DG pathway in vivo. In the present study, we found that the cannabinoid receptor agonist WIN impairs LTP induction in the PP-DG pathway. Previous studies regarding the effects of cannabinoid agonists on learning and memory and cellular mechanism of memory formation have confirmed our observations (Katona et al., 2000; Riedel and Davies, 2005). This is supported by the fact that in hippocampal CA1 neurons of CB1 receptor knockout mice, the LTP induction was enhanced rather than impaired as compared to wild-type controls (Bohme et al., 1999). Impaired spatial memory has also been reported, using the water maze, in male Sprague-Dawley rats with WIN microinjections into the CA1, and impairement of LTP in the Schaffer collateral-CA1 projection has been reported with WIN i.p. administration (Abush and Akirav, 2010). There are some controversies about the involvement of CB1 receptor-mediated signaling in LTP induction. As mentioned earlier, various studies about the effects of CB1 ligands on learning, memory, and LTP have been performed. However, these studies generally investigated hippocampal LTP in the CA1 region. Moreover, several studies have found that a CB1 receptor antagonist inhibited LTP induction in hippocampal CA1 neurons (Carlson et al., 2002; de Oliveira Alvares et al., 2006), while other studies have shown that CB1 receptor antagonists had no effect on HFSinduced LTP induction (Hoffman et al., 2007; Slanina et al., 2005). Furthermore, in some cases it has been reported that cannabinoid agonists stimulate the release of glutamate (Glu), which is necessary for the induction of LTP. This variance may be due to several
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PS Amplitude EPSP Slope
Before HFS
After HFS
4 mV 2 ms
Control
Win
Cap
Win + Cap Fig. 1. (A) EPSP slope and PS amplitude of representative sample traces of field potential recorded in the PP-DG synapses in control group. Arrows indicate population spikes and slope of EPSP. (B) Representative sample traces of evoked field potential in the DG recorded prior to and after high frequency stimulation in all groups.
factors including model systems, different stimulation protocols, different drug doses, and different locations of injection (Abush and Akirav, 2010). For the first time, in rats, we have shown the effects of an intrahippocampal injection of WIN on LTP induction in PP-DG. We found that the intrahippocampal injection of a cannabinoid receptor agonist impairs LTP induction in the PP-DG pathway. According to previous studies, one likely mechanism proposed for this cannabinoid-induced disruption of LTP is that presynaptic CB1 receptors inhibit release of the glutamate necessary to depolarize the postsynaptic cell and release NMDA receptors from the magnesium blockade existing under normal conditions (Sullivan, 2000). While TRPV1 has been previously shown to modulate synaptic plasticity in other regions of the hippocampus (Li et al., 2008), it is currently not known whether TRPV1 modulates LTP and, if so, the location of TRPV1 involved in modulating LTP. In this regard, we investigated the effect of intrahippocampal administration of a TRPV1 receptor agonist, capsaicin, on LTP in the DG of the hippocampus. Our findings confirmed that Cap causes a significant enhancement of granular cell LTP in the hippocampus. Consistent with our results, previous studies have indicated that activation of TRPV1 promotes
excitatory facilitation of synaptic transmission (Marinelli et al., 2002, 2003). Specifically, LTP was reduced in TRPV1 receptor-deficient mice as compared to wild type control mice (Marsch et al., 2007). In addition, behavioral studies have described the effects of TRPV1 activation on learning and spatial memory recall (Li et al., 2008; Marsch et al., 2007). Studies have shown that NMDA receptors (NMDAR) play critical roles in synaptic plasticity (Martin et al., 2000) and TRPV1 activation may stimulate NMDAR-mediated extracellularsignal-regulated kinase (ERK) signaling (Zhuang et al., 2004) that interacts (Thomas and Huganir, 2004) with mitogen activated protein kinases (MAPK) signaling (Zhang et al., 2007), leading to facilitation of LTP. Several mechanisms have been advanced as explanations for the interactions between cannabinoid and vanilloid systems in the CNS. It has been proposed that lipid-based molecules and, in particular, anandamide-related structures, may have activity on TRPV1 (Beltramo and Piomelli, 1999; Di Marzo et al., 1998; Szolcsanyi and Jancso-Gabor, 1975), suggesting an interplay between the cannabinoid and vanilloid systems. Several studies have shown that stimulation of CB1 and TRPV1 often produce opposite effects in various experimental settings, including changes in intracellular Ca2þ concentrations (Szallasi and Di Marzo,
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220
Control
Win **
Cap
Win+Cap
***
***
200
EPSP (%)
180 160 140 120 100 80 Base
LTP 5
LTP 30
LTP 60
Time Fig. 2. Time-dependent changes in hippocampal responses to perforant path stimulation following a HFS. LTP of the EPSP slope in area DG granular cell synapses of the hippocampus are significantly different between groups. Data are expressed as means 7 S.E.M. % of baseline. nn:Po 0.01, nnn:P o0.001 significant difference (Cap in compare with control); #:P o 0.05 significant difference (WIN in compare with control); $:Po 0.05, $$:P o0.01 significant difference (WINþCap in compare with control); &&: P o0.01, &&&: P o 0.001 significant difference (WIN in compare with WIN þCap).
430
Control
Win
Cap
Win+Cap ** *
PS Amplitude (%)
380
** *
**
330 280 230
for effects related to TRPV1 is that activation of TRPV1 results in an increase of intracellular Ca2þ concentrations, which may activate the Ca2þ -dependent N-acyltransferase (NAT) (Reddy et al., 1983). NAT controls the rate-limiting step in anandamide synthesis; consequently, TRPV1 activation may result in increased anandamide formation (Toth et al., 2009). Anandamide may activate TRPV1 either directly or indirectly. In the case of direct activation, anandamide binds to and activates TRPV1. Direct activation apparently occurs when anandamide concentration is high. Low concentrations of anandamide may selectively activate CB1 receptors (Toth et al., 2009). Activating CB1 receptors can lead to potentiation, inhibition, or desensitization of TRPV1 channels in cells co-expressing CB1 receptors and TRPV1 channels (Hermann et al., 2003; Jeske et al., 2006; Evans et al., 2007; Kim et al., 2008; Patwardhan et al., 2006). Furthermore, observations highlight a dual role of the cannabinoid receptors in the regulation of TRPV1 functions: at low levels of endogenous PKA activity, they stimulate TRPV1 responses, while at elevated levels of endogenous PKA activity, they inhibit the PKA-mediated increase in TRPV1 responses (Toth et al., 2009).
5. Conclusion Some aspects of functional interactions between cannabinoid and vanilloid systems have been elicited by synaptic plasticity in hippocampus. Taken together, these two systems show opposing roles in LTP creation. The effects of manipulating the cannabinoid system and modulating vanilloid transmission suggest that these two systems may share certain common signaling pathways. It has been shown that the agonists of vanilloid system modulate cannabinoid output that cause increase in synaptic plasticity, while, in contemporary studies of the consumption of two agonists, a TRPV1 agonist can change the production of endocannabinoids, which in turn results in the enhancement of LTP induction. Future investigations are essential for better understanding the interactive effects and neurobiological mechanisms of action of endocannabinoid and endovanilloid systems on properties of synaptic plasticity.
180
Acknowledgments
130 80
Base
LTP 5
LTP 30
LTP 60
Time Fig. 3. Time-dependent changes in hippocampal responses to perforant path stimulation following a HFS. LTP of the PS amplitude in area DG granular cell synapses of the hippocampus are significantly different between groups. Data are expressed as means 7S.E.M. % of baseline. nn:Po 0.01, nnn:P o 0.001 significant difference (Cap in compare with control); ###:P o 0.001 significant difference (WIN in compare with control); $:Po 0.05 significant difference (WINþ Cap in compare with control); &&: Po 0.01, &&&: Po 0.001 significant difference (WIN in compare with WIN þCap).
2000) and glutamate release in the substantia nigra pars compacta (Marinelli et al., 2003). It has been reported that the synthetic cannabinoid receptor agonist HU210 inhibited the capsaicin-induced influx of Ca2þ . The inhibitory effects of HU210, in general, are consistent with several reports of cannabinoid inhibition of capsaicin-evoked responses (Oshita et al., 2005). Some interplay between TRPV1 channels and CB1 receptors focused on the dualistic nature (activating both CB1 receptors and TRPV1 channels) of cannabinoids and vanilloids (Di Marzo et al., 2002), such as anandamide, the first identified endocannabinoid, which also acts as an endovanilloid (Zygmunt et al., 1999; Smart et al., 2000). Crosstalk between these two receptors has also been addressed. One mechanism
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Contents lists available at ScienceDirect
European Journal of Pharmacology journal homepage: www.elsevier.com/locate/ejphar
Molecular and cellular pharmacology
The interactive role of cannabinoid and vanilloid systems in hippocampal synaptic plasticity in rats Lida Tahmasebi, Alireza Komaki n,1, Ruhollah Karamian, Siamak Shahidi, Abdolrahman Sarihi, Iraj Salehi, Ali Nikkhah Neurophysiology Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
art ic l e i nf o
a b s t r a c t
Article history: Received 30 September 2014 Received in revised form 23 March 2015 Accepted 25 March 2015 Available online 2 April 2015
Long-term potentiation (LTP) has been most thoroughly studied in the hippocampus, which has a key role in learning and memory. Endocannabinoids are one of the endogenous systems that modulate this kind of synaptic plasticity. The activation of the vanillioid system has also been shown to mediate synaptic plasticity in the hippocampus. In addition, immunohistochemical studies have shown that cannabinoid receptor type 1 (CB1) and vanilloid receptor 1 (TRPV1) are closely located in the hippocampus. In this study, we examined the hippocampal effects of co-administrating WIN55-212-2 and capsaicin, which are CB1 and TRPV1 agonists, respectively, on the induction of LTP in the dentate gyrus (DG) of rats. LTP in the hippocampal area was induced by high-frequency stimulation (HFS). Our results indicated that the cannabinoid agonist reduced both field excitatory post-synaptic potential (fEPSP) slope and population spike (PS) amplitude after HFS with respect to the control group, whereas the vanilloid agonist increased these parameters along with the increased induction of LTP as compared to the control group. We also showed that the co-administration of cannabinoid and vanilloid agonists had different effects on fEPSP slope and PS amplitude. It seems that agonists of the vanilloid system modulate cannabinoid outputs that cause an increase in synaptic plastisity, while in contemporary consumption of two agonist, TRPV1 agonist can change production of endocannabinoid, which in turn result to enhancement of LTP induction. These findings suggest that the two systems may interact or share certain common signaling pathways in the hippocampus. & 2015 Elsevier B.V. All rights reserved.
Keywords: Cannabinoid Vanilloid Capsaicin WIN55-212-2 Long-term potentiation Hippocampus Rat
1. Introduction Long-term potentiation (LTP) of synaptic activity is the most popular and widely researched model of synaptic plasticity that occurs during learning and memory (Hölscher, 1999). Neuromodulators are involved in most forms of synaptic plasticity ranging from the short- to long-term (Lovinger, 2010; Pawlak et al., 2010). Neurotransmitters and their receptors play important roles in synaptic plasticity (Swope et al., 1992). Moreover, it has been reported that neuromodulators are involved in most forms of synaptic plasticity ranging from the short- to long-term (Lovinger, 2010; Pawlak et al., 2010).
n Correspondence to: Departement of Physiology, School of Medicine, Hamadan University of Medical Sciences, Shahid Fahmideh Street, Hamadan, Iran. Tel.: þ 98 81 38380267; fax: þ 98 81 38380131. E-mail addresses: [email protected], [email protected] (A. Komaki). 1 URL: umsha.ac.ir
http://dx.doi.org/10.1016/j.ejphar.2015.03.063 0014-2999/& 2015 Elsevier B.V. All rights reserved.
Endocannabinoids and their receptors play a modulatory role in several physiological processes, mainly in the brain (Fernández‐ Ruiz et al., 2010). Cannabinoid receptors are distributed throughout the brain and cannabinoid receptor type 1 (CB1) are particularly well represented in the cortex (entorhinal and cingulate), hippocampus, lateral septum, nucleus accumbens, amygdala, and periaqueductal gray area (PAG) (Millan, 2003). Nevertheless, there are controversies regarding the effects of cannabinoids on synaptic plasticity. For instance, administration of CB1 receptor agonists has been found to exert inhibitory effects on LTP induction (Collins et al., 1994; Nowicky et al., 1987; Terranova et al., 1995). On the other hand, investigations of the induction of LTP in CA1 pyramidal neurons of hippocampal slices has shown that AM281 (a CB1 antagonist) impairs the induction of LTP (de Oliveira Alvares et al., 2006; Lin et al., 2011). Furthermore, CB1 receptor agonists are reported to induce biphasic effects, with lower doses being LTP enhancers and higher doses being LTP suppressers (Abush and Akirav, 2010). Transient receptor potential vanilloid 1 (TRPV1) has been shown to influence different types of synaptic plasticity in the
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hippocampus by altering synaptic calcium levels and neurotransmitter release (Chávez et al., 2010; Gibson et al., 2008; Marsch et al., 2007). The TRPV1 channel can be activated exogenously by various ligand-like agents including capsaicin (the compound responsible for producing the hotness of red chili peppers) (Huang et al., 2002; Montell et al., 2002). Recently reported functions for TRPV1 in the CNS include improved spatial memory retrieval in response to TRPV1 activation under stressful conditions (Li et al., 2008). It has been demonstrated that TRPV1 is required for certain types of synaptic plasticity, although there are controversies regarding the effects of the vanilloid system on synaptic plasticity. For example, research using TRPV1 knockout mice demonstrated reduced CA1 LTP in knockout animals as compared to wild type controls (Marsch et al., 2007). On the other hand, studies indicate that following ether anesthesia, capsaicin (a TRPV1 agonist) has a suppressive effect on lateral amygdala (LA) LTP both in patch clamp and in extracellular recordings (Zschenderlein et al., 2011). Despite these data indicating TRPV1 involvement in hippocampal synaptic plasticity, the mechanism by which it modulates this plasticity has not been identified (Al-Hayani et al., 2001; Huang et al., 2002). Functional interactions between cannabinoid and vanilloid systems have been described. Immunohistochemical studies suggest a similar distribution of TRPV1 and its extensive co-localization with CB1 in areas such as the hippocampus, basal ganglia, hypothalamus, thalamus (Cristino et al., 2006), ventrolateral PAG (Casarotto et al., 2011), dorsolateral PAG (Cristino et al., 2006), and prefrontal cortex (Micale et al., 2008). Although CB1 and TRPV1 receptors are expressed in several overlapping brain regions, they may have opposite roles in the regulation of neural activity (Di Marzo, 2010). It is likely that anandamide may interact with CB1 and TRPV1 receptors to inhibit and promote anxiety-like behaviors, respectively (Hakimizadeh and Oryan, 2012). Unlike established data about the individual effects of cannabinoid system and the vanilloid system on synaptic plasticity and neural function, the simultaneous stimulation effect of these two systems on synaptic plasticity has not been studied in the dentate gyrus (DG) of hippocampus. The DG is part of the hippocampus which is thought to contribute to mechanisms of learning and memory via activity of dentate granule cells (Jedlicka et al., 2011). The DG is one of the few areas of the rat brain which continues to generate new nerve cells well after birth (Blaise and Arnett, 2006; Nakashiba et al., 2012). In the DG, electrical stimuli delivered to perforant pathway (PP) elicit field excitatory postsynaptic potentials (fEPSPs) (Andersen et al., 1971). This area is one of few sites in the adult brain at which synaptic plasticity are induced (Jedlicka et al., 2015). Therefore, in this study, we test the hypothesis that a part of effects of the cannabinoid system on synaptic plasticity are the result of its effects on vanilloid system. The interactions of these two systems in the modulation of synaptic plasticity could have important therapeutic implications in clinical settings. In this study, we examined the effects of co-administration of intrahippocampal injections of cannabinoid and vanilloid agonists on the induction of LTP in the DG of rats.
2. Materials and methods 2.1. Animals Thirty-five experimentally naive, male Wistar rats (weighing 250–300 g) were obtained from the Pasteur Institute, Tehran, Iran. The animals were housed in an air-conditioned room at 22 72 1C under 12 h light/dark cycles (light turned on at 07:00 and turned off at 19:00). The animals were maintained in cages with five rats
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in each cage. Water and food were given ad libitum. After one week of adaptation, subjects were randomly separated into control, DMSO, WIN55-212-2, Capsaicin, and WIN þCapsaicin groups. There were 10 rats in each group. All research and animal care procedures were approved by the Veterinary Ethics Committee of this University and were performed in accordance with the National Institutes of Health Guide for Care and Use of Laboratory Animals (NIH Publication no. 85-23, revised 1985). 2.2. Drugs The synthetic full CB1/2-receptor agonist, WIN55,212-2 [R-(þ)-(2,3dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl)(1-naphthalenyl) methanonemesylate] (Sigma, USA), and the TRPV1 receptor agonist, capsaicin [8-Methyl-N-vanillyl-trans-6nonenamide] (Wako, Japan) were initially dissolved in DMSO [dimethylsulfoxide] (Sigma, USA) and further diluted in saline (0.9% NaCl). DMSO concentration in both drugs waso10%. This DMSO and saline solution was also used as the vehicle. Drug concentrations were based on previous studies: WIN55-212-2: 0.5 mg/0.5 ml (Abush and Akirav, 2010) and capsaicin: 0.03 mg/0.5 ml (Hakimizadeh and Oryan, 2012). Drugs were microinjected into DG approximately 20 min prior to HFS. 2.3. Surgical procedures, electrophysiological recordings, and LTP induction Rats were anesthetized intraperitoneally with urethane [Ethyl carbamate (Sigma, USA)] (1.5 g/kg with supplemental injections as required) (Karimi et al., 2013; Komaki et al., 2014) and fixated in a stereotaxic apparatus for surgery. A heating pad was used to maintain the animals' body temperature. After incision of the skin and obtaining the position of the dentate gyrus (DG) according to the Paxinos and Watson (2005) atlas for the rat brain, small burr holes were drilled in the skull. Recording and stimulating electrodes were positioned in DG [AP: 3.8 mm from bregma; ML: 2.3 mm from midline; DV: 2.7–3.2 mm from the skull surface] and perforant pathway (PP) [AP: 8.1 mm from bregma; ML: 4.3 mm from midline; DV: 3.2 mm from the skull surface] respectively. The electrodes were lowered very slowly (0.2 mm/min) from cortex to hippocampus, in order to minimize trauma to the brain tissue and field potential recording were obtain in the granular cells of the DG following stimulation of the PP. Electrode positions were optimized to record maximal population spike (PS). An input/output (I/O) response curve was constructed by varying the intensity of single pulse stimulation and averaging five responses per intensity. The stimulus intensity that evoked a mean field potential equal to 50% of the maximum response was then used for all subsequent stimulations. Then, substances were injected with hamilton syringe into the DG. A volume of 0.5 ml was microinjected unilaterally over a period of 1 min. The injection syringe was left in position for an additional 60 s before withdrawal to minimize dragging of the injected liquid along the injection tract. After determination of I/O curves, single stimuli were applied for at least 30 min, and responses were monitored. Single stimuli were presented every 10 s. Measurements of the slope of the fEPSP were taken between 20 and 80% of the peak amplitude. Slope of fEPSPs were normalized with respect to the 30 min control period before tetanic stimulation. Once a stable baseline of responses were obtained for at least 20 min, LTP was induced using a HFS protocol of 400 Hz (10 bursts of 20 stimuli, 0.2 ms stimulus duration, 10 s interburst interval) at a stimulus intensity that evoked a PS amplitude and field EPSP slope of approximately 50% of the maximum response. Both EPSP and PS were recorded at 5, 30, and 60 min after HFS in order to determine and changes in the synaptic response of DG neurons. For each
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time-point, 10 consecutive evoked responses were averaged at 10 s stimulus intervals (Karimi et al., 2013, 2015; Komaki et al., 2014; Taube and Schwartzkroin, 1988). For stimulations, the parameters of the stimuli were defined in homemade software and were sent via a data acquisition board linked to a constant current isolator unit (A365 WPI, USA) prior to delivery to the PP through the stimulus electrodes. The induced field potential response from the DG was passed through a preamplifier, then was amplified (1000 ) (Differential amplifier DAM 80 WPI, USA), and filtered (band pass 1–3 kHz). This response was digitized at a sampling rate of 10 kHz, and was observable on a computer. It was saved in a file to facilitate later offline analysis. 2.4. Statistical analysis Data were statistically analyzed by repeated measures ANOVA tests followed by Tukey's test. Values of P o0.05 were considered to be significant.
3. Results 3.1. Measurement of evoked potentials The evoked field potential in the DG has two components: a population spike (PS) and fEPSP (Fig. 1). During electrophysiological recordings, changes in the PS amplitude and fEPSP slope were measured. The amplitude of the PS was measured from the peak of the first positive deflection of the evoked potential to the peak of the following negative potential. The field EPSP slope function was measured as the slope of the line connecting the start of the first positive deflection of the evoked potential with the peak of the second positive deflection of the evoked potential. The slopes for fEPSPs and PS amplitude were calculated using a data analysis program (eTrace, www.sciencebeam.com). 3.2. Effect of HFS on the slope of EPSP and the amplitude of PS The effect of HFS on the slope of EPSP and amplitude of PS in the DG area of the hippocampus in rats were examined. The slopes of fEPSP were strongly enhanced, resulting in a significant amount of LTP at PP-DG synapses in the saline (1457 6.36% of pre-HFS baseline) and DMSO (148 77.3% of pre-HFS baseline) groups. There was no significant difference of fEPSP slope between the saline and DMSO groups [F (4,30) ¼1.57, P 40.05]. Our data demonstrates that the amplitude of PS was 262 712.4% of preHFS baseline in the saline group (n ¼7) and 251 712% of pre-HFS baseline in the DMSO group (n ¼ 7). The data also demonstrates that there was no significant difference of amplitude in PS LTP between the saline and DMSO groups [F (4,30) ¼1.89, P 40.05]. Since there was not difference between DMSO and saline group, these data have been combined and have shown as control group. 3.3. Effect of CB1 agonist on the slope of EPSP and the amplitude of PS The effects of WIN55-212-2 (WIN; a CB1 agonist) on the slope of EPSP and amplitude of PS induced by HFS in the PP to the DG area of the hippocampus in rats were examined. The results showed that HFS directly applied to the PP-DG area can increase synaptic transmission, inducing LTP of EPSP in the WIN group (1317 4.4% of pre-HFS baseline) (Fig. 2). Fig. 3 demonstrates that the amplitude of PS was 161 712.3% of pre-HFS baseline in the WIN group (n ¼7). The CB1 agonist reduced fEPSP slope in compared with control group [F (3,24) ¼3.36, P o0.05]. The
amplitude of PS was also significantly decreased in comparison with the control group [F (3,24)¼ 7.14, P o0.001] 3.4. The effects of capsaicin on the slope of EPSP and amplitude of PS The effects of capsaicin (Cap; TRPV1 agonist) on the slope of EPSP and amplitude of PS induced by HFS in the PP-DG area of the hippocampus in rats were examined. Our data showed that capsaicin (Cap; TRPV1 agonist) (0.03 mg/0.5 ml) application resulted in significantly enhanced slopes of fEPSP (192 712.2%; n ¼7; Fig. 2) [F (3,24)¼5.07; P o0.01] and PS amplitude (352715%; n¼ 7; Fig. 3) [F (3,24) ¼9.26; P o0.001] when compared to the control groups. 3.5. Effect of co-administration of CB1 and TRPV1 agonists on the slope of EPSP and amplitude of PS Considering the involvement of both cannabinoid and vanilloid systems in learning and memory and the overlap of the cannabinoid and vanilloid receptors in the CNS, we investigated the effects of cannabinoid and vanilloid agonist co-administration on LTP. Our results indicated that co-administration of cannabinoid and vanilloid agonists had different effects on the slopes of fEPSP (180712%; n¼7; Fig. 2) and amplitude of PS (290714.5%; n¼7; Fig. 3) when compared to either WIN (amplitude of PS: 161712.3% [F (3,24)¼6.12, Po0.001]; slopes of fEPSP: 13174.4% [F (3,24)¼5.36; Po0.001]) or Cap (amplitude of PS: 352715% [F (3,24)¼4.65, Po0.01; slopes of fEPSP: 192712.2%; [F (3,24)¼2.27, P40.05) groups. These data also demonstrate that there was a significant difference of amplitude in PS LTP between the control and WINþCap groups [F (3,24)¼3.06, Po0.05], also a significant change of slope of EPSP LTP between WINþCap group as compared to the control group [F (3,24)¼4.07, Po0.01] was observed.
4. Discussion The main purpose of the present study was to investigate whether intrahippocampal injection of WIN and Cap can influence synaptic plasticity in PP-DG pathway in vivo. In the present study, we found that the cannabinoid receptor agonist WIN impairs LTP induction in the PP-DG pathway. Previous studies regarding the effects of cannabinoid agonists on learning and memory and cellular mechanism of memory formation have confirmed our observations (Katona et al., 2000; Riedel and Davies, 2005). This is supported by the fact that in hippocampal CA1 neurons of CB1 receptor knockout mice, the LTP induction was enhanced rather than impaired as compared to wild-type controls (Bohme et al., 1999). Impaired spatial memory has also been reported, using the water maze, in male Sprague-Dawley rats with WIN microinjections into the CA1, and impairement of LTP in the Schaffer collateral-CA1 projection has been reported with WIN i.p. administration (Abush and Akirav, 2010). There are some controversies about the involvement of CB1 receptor-mediated signaling in LTP induction. As mentioned earlier, various studies about the effects of CB1 ligands on learning, memory, and LTP have been performed. However, these studies generally investigated hippocampal LTP in the CA1 region. Moreover, several studies have found that a CB1 receptor antagonist inhibited LTP induction in hippocampal CA1 neurons (Carlson et al., 2002; de Oliveira Alvares et al., 2006), while other studies have shown that CB1 receptor antagonists had no effect on HFSinduced LTP induction (Hoffman et al., 2007; Slanina et al., 2005). Furthermore, in some cases it has been reported that cannabinoid agonists stimulate the release of glutamate (Glu), which is necessary for the induction of LTP. This variance may be due to several
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PS Amplitude EPSP Slope
Before HFS
After HFS
4 mV 2 ms
Control
Win
Cap
Win + Cap Fig. 1. (A) EPSP slope and PS amplitude of representative sample traces of field potential recorded in the PP-DG synapses in control group. Arrows indicate population spikes and slope of EPSP. (B) Representative sample traces of evoked field potential in the DG recorded prior to and after high frequency stimulation in all groups.
factors including model systems, different stimulation protocols, different drug doses, and different locations of injection (Abush and Akirav, 2010). For the first time, in rats, we have shown the effects of an intrahippocampal injection of WIN on LTP induction in PP-DG. We found that the intrahippocampal injection of a cannabinoid receptor agonist impairs LTP induction in the PP-DG pathway. According to previous studies, one likely mechanism proposed for this cannabinoid-induced disruption of LTP is that presynaptic CB1 receptors inhibit release of the glutamate necessary to depolarize the postsynaptic cell and release NMDA receptors from the magnesium blockade existing under normal conditions (Sullivan, 2000). While TRPV1 has been previously shown to modulate synaptic plasticity in other regions of the hippocampus (Li et al., 2008), it is currently not known whether TRPV1 modulates LTP and, if so, the location of TRPV1 involved in modulating LTP. In this regard, we investigated the effect of intrahippocampal administration of a TRPV1 receptor agonist, capsaicin, on LTP in the DG of the hippocampus. Our findings confirmed that Cap causes a significant enhancement of granular cell LTP in the hippocampus. Consistent with our results, previous studies have indicated that activation of TRPV1 promotes
excitatory facilitation of synaptic transmission (Marinelli et al., 2002, 2003). Specifically, LTP was reduced in TRPV1 receptor-deficient mice as compared to wild type control mice (Marsch et al., 2007). In addition, behavioral studies have described the effects of TRPV1 activation on learning and spatial memory recall (Li et al., 2008; Marsch et al., 2007). Studies have shown that NMDA receptors (NMDAR) play critical roles in synaptic plasticity (Martin et al., 2000) and TRPV1 activation may stimulate NMDAR-mediated extracellularsignal-regulated kinase (ERK) signaling (Zhuang et al., 2004) that interacts (Thomas and Huganir, 2004) with mitogen activated protein kinases (MAPK) signaling (Zhang et al., 2007), leading to facilitation of LTP. Several mechanisms have been advanced as explanations for the interactions between cannabinoid and vanilloid systems in the CNS. It has been proposed that lipid-based molecules and, in particular, anandamide-related structures, may have activity on TRPV1 (Beltramo and Piomelli, 1999; Di Marzo et al., 1998; Szolcsanyi and Jancso-Gabor, 1975), suggesting an interplay between the cannabinoid and vanilloid systems. Several studies have shown that stimulation of CB1 and TRPV1 often produce opposite effects in various experimental settings, including changes in intracellular Ca2þ concentrations (Szallasi and Di Marzo,
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220
Control
Win **
Cap
Win+Cap
***
***
200
EPSP (%)
180 160 140 120 100 80 Base
LTP 5
LTP 30
LTP 60
Time Fig. 2. Time-dependent changes in hippocampal responses to perforant path stimulation following a HFS. LTP of the EPSP slope in area DG granular cell synapses of the hippocampus are significantly different between groups. Data are expressed as means 7 S.E.M. % of baseline. nn:Po 0.01, nnn:P o0.001 significant difference (Cap in compare with control); #:P o 0.05 significant difference (WIN in compare with control); $:Po 0.05, $$:P o0.01 significant difference (WINþCap in compare with control); &&: P o0.01, &&&: P o 0.001 significant difference (WIN in compare with WIN þCap).
430
Control
Win
Cap
Win+Cap ** *
PS Amplitude (%)
380
** *
**
330 280 230
for effects related to TRPV1 is that activation of TRPV1 results in an increase of intracellular Ca2þ concentrations, which may activate the Ca2þ -dependent N-acyltransferase (NAT) (Reddy et al., 1983). NAT controls the rate-limiting step in anandamide synthesis; consequently, TRPV1 activation may result in increased anandamide formation (Toth et al., 2009). Anandamide may activate TRPV1 either directly or indirectly. In the case of direct activation, anandamide binds to and activates TRPV1. Direct activation apparently occurs when anandamide concentration is high. Low concentrations of anandamide may selectively activate CB1 receptors (Toth et al., 2009). Activating CB1 receptors can lead to potentiation, inhibition, or desensitization of TRPV1 channels in cells co-expressing CB1 receptors and TRPV1 channels (Hermann et al., 2003; Jeske et al., 2006; Evans et al., 2007; Kim et al., 2008; Patwardhan et al., 2006). Furthermore, observations highlight a dual role of the cannabinoid receptors in the regulation of TRPV1 functions: at low levels of endogenous PKA activity, they stimulate TRPV1 responses, while at elevated levels of endogenous PKA activity, they inhibit the PKA-mediated increase in TRPV1 responses (Toth et al., 2009).
5. Conclusion Some aspects of functional interactions between cannabinoid and vanilloid systems have been elicited by synaptic plasticity in hippocampus. Taken together, these two systems show opposing roles in LTP creation. The effects of manipulating the cannabinoid system and modulating vanilloid transmission suggest that these two systems may share certain common signaling pathways. It has been shown that the agonists of vanilloid system modulate cannabinoid output that cause increase in synaptic plasticity, while, in contemporary studies of the consumption of two agonists, a TRPV1 agonist can change the production of endocannabinoids, which in turn results in the enhancement of LTP induction. Future investigations are essential for better understanding the interactive effects and neurobiological mechanisms of action of endocannabinoid and endovanilloid systems on properties of synaptic plasticity.
180
Acknowledgments
130 80
Base
LTP 5
LTP 30
LTP 60
Time Fig. 3. Time-dependent changes in hippocampal responses to perforant path stimulation following a HFS. LTP of the PS amplitude in area DG granular cell synapses of the hippocampus are significantly different between groups. Data are expressed as means 7S.E.M. % of baseline. nn:Po 0.01, nnn:P o 0.001 significant difference (Cap in compare with control); ###:P o 0.001 significant difference (WIN in compare with control); $:Po 0.05 significant difference (WINþ Cap in compare with control); &&: Po 0.01, &&&: Po 0.001 significant difference (WIN in compare with WIN þCap).
2000) and glutamate release in the substantia nigra pars compacta (Marinelli et al., 2003). It has been reported that the synthetic cannabinoid receptor agonist HU210 inhibited the capsaicin-induced influx of Ca2þ . The inhibitory effects of HU210, in general, are consistent with several reports of cannabinoid inhibition of capsaicin-evoked responses (Oshita et al., 2005). Some interplay between TRPV1 channels and CB1 receptors focused on the dualistic nature (activating both CB1 receptors and TRPV1 channels) of cannabinoids and vanilloids (Di Marzo et al., 2002), such as anandamide, the first identified endocannabinoid, which also acts as an endovanilloid (Zygmunt et al., 1999; Smart et al., 2000). Crosstalk between these two receptors has also been addressed. One mechanism
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