Inhibitory effect of anandamide on resiniferatoxin-induced sensory neuropeptide release in vivo and neuropathic hyperalgesia in the rat

Helyes, Zsuzsanna; Németh, József; Thán, Márta; Bölcskei, Kata; Pintér, Erika; Szolcsányi, Janós

doi:10.1016/s0024-3205(03)00651-9

Cited by 81 publications

(47 citation statements)

References 26 publications

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“…Inhibitory effects of peripheral and spinal URB597 in SNL and sham-operated rats were blocked by AM251, demonstrating the contribution of CB 1 receptors. CB 1 receptor-mediated antinociception has been widely described in neuropathic rats (Herzberg et al, 1997;Mao et al, 2000;Bridges et al, 2001;Fox et al, 2001;Monhemius et al, 2001;Helyes et al, 2003;Lim et al, 2003;Scott et al, 2004;Pascual et al, 2005;Sagar et al, 2005). Our data are consistent with reports that CB 1 receptors mediate the inhibitory effects of FAAH inhibitors (Cravatt et al, 2001;Kathuria et al, 2003;Lichtman et al, 2004a,b;Wilson et al, 2004;Hohmann et al, 2005;Jayamanne et al, 2006).…”

Section: Discussionsupporting

confidence: 91%

Analgesic Effects of Fatty Acid Amide Hydrolase Inhibition in a Rat Model of Neuropathic Pain

Jhaveri¹,

Richardson²,

Kendall³

et al. 2006

J. Neurosci.

151

131

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Section: Discussionsupporting

confidence: 91%

Analgesic Effects of Fatty Acid Amide Hydrolase Inhibition in a Rat Model of Neuropathic Pain

Jhaveri¹,

Richardson²,

Kendall³

et al. 2006

J. Neurosci.

151

131

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“…2; dilation, 3 Ϯ 5%). It was also suggested previously that anandamide can desensitize the TRPV1 (Di Marzo et al, 2001a;Smart et al, 2001;Tognetto et al, 2001;Helyes et al, 2003;Toth et al, 2005). We therefore tested the effects of 30 M anandamide (for 20 min followed by a 40-min regeneration period) on the responsiveness of TRPV1 in this system (Fig.…”

Section: Resultsmentioning

confidence: 93%

“…Indeed, it has been published that stimulation of TRPV1 leads to desensitization to subsequent agonist challenge (well known as tachyphylaxis) in the case of anandamide (Di Marzo et al, 2001b;Smart et al, 2001;Tognetto et al, 2001;Helyes et al, 2003). However, in contrast with the others, we used a model of acute desensitization (decrease in the responsiveness in the continuous presence of the agonist) instead of tachyphylaxis.…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation-Dependent Desensitization by Anandamide of Vanilloid Receptor-1 (TRPV1) Function in Rat Skeletal Muscle Arterioles and in Chinese Hamster Ovary Cells Expressing TRPV1

et al. 2005

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It has been proposed that activation of vanilloid receptor-1 (TRPV1) affects the vasotone of resistance arteries. One of the endogenous activators of TRPV1 is anandamide. The effects of anandamide on TRPV1 responsiveness were tested on isolated, pressurized (80 mm Hg) skeletal muscle (m. gracilis) arterioles (179 Ϯ 33 m in diameter). We found that the TRPV1 agonist capsaicin (1 M) elicited a substantial constriction in isolated arterioles (51 Ϯ 12%). In contrast, anandamide (0 -100 M) did not affect arteriolar diameter significantly (3 Ϯ 5%). Isolated vessels were also preincubated with anandamide (30 M for 20 min). This anandamide pretreatment completely blocked capsaicin-induced arteriolar constriction (response decreased to 1 Ϯ 0.6%), and this inhibition was reversed by a protein phosphatase-2B inhibitor (cyclosporin-A; 100 nM, 5 min) treatment (constriction, 31 Ϯ 1%). An exogenous TRPV1-expressing cell line [Chinese hamster ovary (CHO)-TRPV1] was used to specifically evaluate TRPV1-mediated effects of anandamide. The efficacy of anandamide in this system, as determined by 45 Ca 2ϩ uptake, was 65 Ϯ 8% of that of capsaicin. Upon treatment of the cells with cyclosporin-A or the protein kinase C activator phorbol 12-myristate 13-acetate (PMA), anandamide was transformed to a full agonist. Anandamide treatment caused an acute desensitization in these cells as measured by intracellular Ca 2ϩ imaging. Application of cyclosporin-A or PMA reversed this desensitization. Our data suggest that anandamide may cause a complete (albeit phosphorylation-dependent) desensitization of TRPV1 in skeletal muscle arterioles and in CHO-TRPV1 cells, which apparently transforms the ligand-gated TRPV1 into a phosphorylationgated channel. This property of anandamide may provide a new therapeutic strategy to manipulate TRPV1 activity.The vanilloid receptor 1 (TRPV1) is a nonselective cation channel, the structure of which places it in the transient receptor potential family of ion channels. In the periphery, TRPV1 is primarily expressed in sensory C and A-␦ fibers (Caterina et al., 1997) and acts as a ligand-, proton-, and heat-activated molecular integrator of nociceptive stimuli Di Marzo et al., 2002a,b;Ross, 2003). Activation of TRPV1 leads to central (pain) and to local "sensory-efferent" effects (Szolcsanyi, 2000). These include the release of vasoactive agents (such as calcitonin gene-related peptide) and subsequent vasorelaxation (Zygmunt et al., 1999).Compared with the well characterized effects of TRPV1 upon stimulation by exogenous substances , relatively little is known about its endogenous ligands. So far, anandamide (N-arachidonoyl-ethanolamide) (Zygmunt et al., 1999), N-arachidonoyl-dopamine (NADA) (Huang et al., 2002), and different lipoxygenase products (Hwang et al., 2000) have been identified as endogenous agonists of TRPV1. Among them, anandamide was originally identified as an endocannabinoid activating the

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“…Cannabinoids Dephosphorylate Threonine Residues of TRPV1 in TG Neurons-The cannabinoids ACEA, anandamide, and WIN were evaluated in this individual study because all have been shown to result in significant peripheral anti-hyperalgesia and/or antinociception (3,4,33). As TRPV1 has been shown to control peripheral inflammatory thermal hyperalgesia (20,21), it is hypothesized that certain cannabinoids may affect TRPV1 phosphorylation, which is known to regulate channel activity (22, 24, 25, 34 -36).…”

Section: Resultsmentioning

confidence: 99%

Cannabinoid WIN 55,212-2 Regulates TRPV1 Phosphorylation in Sensory Neurons

Jeske

Patwardhan

Gamper

et al. 2006

Journal of Biological Chemistry

133

131

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Cannabinoids are known to have multiple sites of action in the nociceptive system, leading to reduced pain sensation. However, the peripheral mechanism(s) by which this phenomenon occurs remains an issue that has yet to be resolved. Because phosphorylation of TRPV1 (transient receptor potential subtype V1) plays a key role in the induction of thermal hyperalgesia in inflammatory pain models, we evaluated whether the cannabinoid agonist WIN 55,212-2 (WIN) regulates the phosphorylation state of TRPV1. Here, we show that treatment of primary rat trigeminal ganglion cultures with WIN led to dephosphorylation of TRPV1, specifically at threonine residues. Utilizing Chinese hamster ovary cell lines, we demonstrate that Thr 144 and Thr 370 were dephosphorylated, leading to desensitization of the TRPV1 receptor. This post-translational modification occurred through activation of the phosphatase calcineurin (protein phosphatase 2B) following WIN treatment. Furthermore, knockdown of TRPA1 (transient receptor potential subtype A1) expression in sensory neurons by specific small interfering RNA abolished the WIN effect on TRPV1 dephosphorylation, suggesting that WIN acts through TRPA1. We also confirm the importance of TRPA1 in WIN-induced dephosphorylation of TRPV1 in Chinese hamster ovary cells through targeted expression of one or both receptor channels. These results imply that the cannabinoid WIN modulates the sensitivity of sensory neurons to TRPV1 activation by altering receptor phosphorylation. In addition, our data could serve as a useful strategy in determining the potential use of certain cannabinoids as peripheral analgesics.Cannabinoids have been shown to exert anti-inflammatory and anti-hyperalgesic effects via peripheral site(s) of action in several pain models (1-5). These effects are thought to be mediated by cannabinoid type 1 (CB1) 4 and/or 2 (CB2) receptor activation, both peripherally and centrally (4 -7). Cannabinoids could exert their effects by acting on CB1/CB2 receptors located on sensory neurons and/or other peripheral cells influencing sensory neuronal function (8). However, there is a Ͻ5-10% co-localization of metabotropic CB1/CB2 receptors with nociceptive neuronal markers such as TRPV1 (transient receptor potential subtype V1) and calcitonin gene-related peptide in trigeminal and dorsal root ganglion neurons (9 -11), suggesting that cannabinoids could act on nociceptors through non-CB1/CB2 receptor mechanism(s). Certain cannabinoids have been shown to activate channels such as TRPV1, including arachidonyl-2-chloroethylamide (ACEA) (12), N-arachidonoyldopamine (13), and anandamide (14), as well as TRPA1 (transient receptor potential subtype A1), including ⌬ 9 -tetrahydrocannabinol (15). In addition, the synthetic cannabinoid R(ϩ)-WIN 55,212-2 (WIN) has demonstrated non-CB1/CB2 receptor activities in trigeminal ganglia (11). The results from these studies suggest that cannabinoids may activate calcium channel function similar to non-cannabinoid transient receptor potential agonists, including the...

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Inhibitory effect of anandamide on resiniferatoxin-induced sensory neuropeptide release in vivo and neuropathic hyperalgesia in the rat

Cited by 81 publications

References 26 publications

Analgesic Effects of Fatty Acid Amide Hydrolase Inhibition in a Rat Model of Neuropathic Pain

Analgesic Effects of Fatty Acid Amide Hydrolase Inhibition in a Rat Model of Neuropathic Pain

Phosphorylation-Dependent Desensitization by Anandamide of Vanilloid Receptor-1 (TRPV1) Function in Rat Skeletal Muscle Arterioles and in Chinese Hamster Ovary Cells Expressing TRPV1

Cannabinoid WIN 55,212-2 Regulates TRPV1 Phosphorylation in Sensory Neurons

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