Transient Receptor Potential Vanilloid Type 1 Expression Research Articles

Racial Differences in Hemodynamic Responses to Lower Body Negative Pressure: The Effects of Capsaicin

Previous work in vitro suggests that capsaicin, the spicy ingredient in peppers, attenuates the vascular response to sympathetic activity (“sympatholysis”), likely mediated through vascular transient receptor potential vanilloid type 1 (TRPV1), and was associated with improved vascular function, though translational studies are needed. Further, given racial disparities in vascular function, and reported racial differences in sensory TRPV1 activity, exploring the potential TRPV1-related mechanisms underpinning these vascular differences is warranted. Purpose To determine if racial differences existed in the central hemodynamic responses to sympathetic stimuli, via lower body negative pressure (LBNP) at rest and during exercise. Second, using an acute dose of oral capsaicin, we sought to determine the potential role of TRPV1 receptors in mediating any racial differences in sympatholysis or vascular function. Methods In a blinded placebo-controlled crossover design, 23 young healthy black (BM, n=13, 23±5 yrs) and white males (WM, n=10, 19±1 yrs) were given capsules containing either placebo (800mg fiber) or capsaicin (780 mg Chile pepper extract, 2.4±0.04 mg capsaicin, 0.5±0.04 mg dihydrocapsaicin). To assess microvascular responses, frequency-domain, multi-distance, near infrared spectroscopy (NIRS) was placed over the muscular medial forearm (i.e. flexor digitorum profundus) providing measure of oxyhemoglobin (HbO, in μM). Central hemodynamics, namely stroke volume (SV), cardiac output (CO), mean arterial pressure (MAP), and heart rate (HR), were measured continuously using a Finometer. To assess hemodynamic responses and potential differences in sympatholysis, these measures performed at rest, during LBNP (-20 mmHg), handgrip (HG) exercise (30% MVC), and HG+LBNP. Results Under placebo conditions, at rest HR, SV, CO, and MAP were not different between BM and WM (p>0.05), and groups were unaffected by capsaicin (p>0.05). The LBNP-induced changes at rest appeared larger for black males (SV -18±4ml vs. -8±11ml and MAP 4.6±6 vs. 1.3± 5mmHg, BM vs. WM), which were seemingly reversed with acute capsaicin (SV -11±13 vs. -9±16ml and MAP -2±9 vs. 1.2± 8mmHg, BM vs. WM). At rest, with placebo, the LBNP-induced ΔHbO, was similar between groups (-2±6 vs. -2±2μM, BM vs WM), and relatively unaffected by capsaicin (-3±6 vs. -1±2 μM, BM vs WM). During HG exercise, the LBNP-induced ΔHbO was disparate between groups (-5±7 vs. 1±3 μM, BM vs WM), and this difference was ablated by the capsaicin (1±6 vs. 2±2 μM, BM vs WM). Conclusion There were racial differences in the central and peripheral hemodynamic response to LBNP at rest and during exercise, suggesting impaired sympatholysis or altered autonomic regulation. Capsaicin, and assumed activation of TRPV1 receptors, seems to affect the hemodynamic response to LBNP, in a relatively race-specific manner at rest and during exercise, potentially mitigating race-related differences. Further work is needed to determine whether such differences may be due to altered TRPV1 expression between groups.

Stem Cells from Human Exfoliated Deciduous Teeth Attenuate Trigeminal Neuralgia in Rats.

Trigeminal neuralgia is an incurable progressive nervous system disease that can last for several months or years. Stem cells from human exfoliated deciduous teeth (SHED) are a candidate source for cell-based therapy. Owing to their neuroprotective and immunomodulatory effects, these neural crest cells have potential roles in mediating chronic pain. In this study, we established a rat model of chronic constriction injury of the infraorbital nerve (CCI-ION) to evaluate the analgesic effect of SHED in neuropathic pain. The effects of local SHED transplantation on inflammatory cell infiltration in the trigeminal nerve were investigated based on hematoxylin and eosin staining. The levels of proinflammatory factors in the injured nerve and transient receptor potential vanilloid type 1 (TRPV1) expression in the trigeminal nerve and ganglion were quantified. The data showed that systemic or local injection of SHED attenuated the sensitivity of rats to mechanical stimuli after nerve injury, and this effect lasted throughout the observation period of 8 weeks. PKH26-labeled SHED were distributed to the ipsilateral trigeminal ganglions 24 and 72 hours after local injection. SHED transplantation at the lesion site led to reduced inflammatory cell infiltration and proinflammatory cytokine levels in the injured nerve and inhibited CCI-ION-induced upregulation of TRPV1 expression in the trigeminal nerve and ganglion in the early phase. Therefore, these results provide preclinical evidence that supports the use of SHED in the treatment of trigeminal neuralgia and potentially other chronic pain conditions.

Repeated Administration of Baclofen Modulates TRPV-1 Channel Expression by PKC Pathway in Dorsal Root Ganglia of Spinal Cord in Morphine Tolerance Model of Rats

Background:Tolerance and dependence to anti-nociceptive effect of morphine restricted its use. Nowadays co-administration of morphine and other drugs suggests diminishing this tolerance. Baclofen is one of the drugs that may be beneficial in the attenuation of tolerance to morphine. Studies have shown that changes in TRPV-1 expression during administration of morphine have a pivotal role in developing morphine tolerance. Therefore, the effect of baclofen on TRPV-1 expression during chronic administration of morphine was investigated in this study. Methods:A total of 48 rats were divided into four groups of control, morphine single injection, morphine tolerance, and morphine tolerance + baclofen. To induce morphine tolerance in rats, animals received 10 mg/kg of i.p. morphine sulfate once a day for 10 days. In the treatment group, baclofen (0.5 mg/kg) was injected for 10 days, before morphine injection. Finally, to evaluate baclofen treatment on morphine analgesia and hyperalgesia, thermal hyperalgesia and formalin test were used. TRPV-1 and PKC expression and protein production in DRG of spinal cord were then evaluated by real-time PCR and Western blot. Results:In baclofen treatment group, thermal hyperalgesia and formalin test improved in comparison with morphine tolerance group. In morphine tolerance group, both TRPV-1/PKC gene expression and protein levels increased in comparison with the control group. However, following the baclofen treatment, the TRPV-1 and PKC levels decreased. Conclusion:Baclofen can enhance anti-nociceptive effect of morphine by modulating TRPV-1 channel and PKC activity.

Identification of Cardiac Expression Pattern of Transient Receptor Potential Vanilloid Type 1 (TRPV1) Receptor using a Transgenic Reporter Mouse Model

Transient receptor potential vanilloid type 1 (TRPV1) channels are structurally related, non-selective cation channels that exhibit a high permeability to calcium. Sensory nerve endings expressing TRPV1 channels play a prominent role in regulating the cardiac sympathetic afferent reflex and contribute to cardiac remodeling and dysfunction in chronic heart failure. However, the precise expression of TRPV1 channels in cardiomyocytes vs. non-cardiomyocytes remains debated. Here we utilized a tdTomato-GFP reporter mouse crossed with a mouse line expressing Cre recombinase under the control of the TRPV1 promoter to map the TRPV1 expression pattern in heart. In this model, TRPV1-negative cells express tdTomato protein (red), whereas TRPV1-positive cells express GFP protein (green). As we expected, substantial GFP expression was found in many small and medium diameter dorsal root ganglia neurons in heterozygous TRPV1-Cre +/-, tdTomato flox/flox +/- male mice, suggesting that this heterozygous model is sufficient for labeling TRPV1-positive cells. Furthermore, these results showed that GFP green staining was not detectable in cardiomyocytes. Instead, we found strong GFP green staining in cardiac blood vessels—thought to be arterioles—in the heart. We also observed strong GFP signals on PGP9.5-positive cardiac nerve endings in the epicardium. In summary, this study does not support the concept that TRPV1 channels are strongly expressed in mouse cardiomyocytes. We conclude that TRPV1 channels in mouse heart are mostly expressed on non-cardiomyocyte cells including cardiac nerve endings and vessels. These data have important implications for the modulations of cardiogenic reflexes.

Transient receptor potential vanilloid type 1 is expressed in the horizontal pathway of the vervet monkey retina

The ubiquitous distribution of the classic endocannabinoid system (cannabinoid receptors CB1 and CB2) has been demonstrated within the monkey nervous system, including the retina. Transient receptor potential vanilloid type 1 (TRPV1) is a cannabinoid-like non-selective cation channel receptor that is present in the retina and binds to endovannilloids and endocannabinoids, like anandamide, 2-arachidonoylglycerol and N-arachidonoyl dopamine. Retinal expression patterns of TRPV1 are available for rodents and data in higher mammals like humans and monkeys are scarce. We therefore thoroughly examined the expression and localization of TRPV1 in the retina, at various eccentricities, of the vervet (Chlorocebus sabeus) monkey, using Western blots and immunohistochemistry. Our results demonstrate that TRPV1 is found mainly in the outer and inner plexiform layers, and in the retinal ganglion cell (RGC) layer with a higher density in the periphery. Co-immunolabeling of TRPV1 with parvalbumin, a primate horizontal cell marker, revealed a clear overlap of expression throughout the entire cell structure with most prominent staining in the cell body membrane and synaptic terminals. Furthermore, double labeling of TRPV1 and syntaxin was found throughout amacrine cells in the inner plexiform layer. Finally, double staining of TRPV1 and Brn3a allowed us to confirm its previously reported expression in the cell bodies and dendrites of RGCs. The presence of TRPV1 in the horizontal pathway suggests a function of this receptor in lateral inhibition between photoreceptors through the horizontal cells, and between bipolar cells through amacrine cells.

The Combination of Transient Receptor Potential Vanilloid Type 1 (TRPV1) and Phosphatase and Tension Homolog (PTEN) is an Effective Prognostic Biomarker in Cervical Cancer.

Transient receptor potential vanilloid type 1 (TRPV1) has been reported to play an important role in human cancers. However, the knowledge about TRPV1 in cervical cancer is sparse. Therefore, we evaluated the expression and clinical significance of TRPV1 in cervical cancer. Immunohistochemical analyses were performed for TRPV1 and phosphatase and tension homolog (PTEN) to delineate clinical significance using 150 cervical cancers, 230 cervical intraepithelial neoplasias, and 312 normal cervical epithelial tissues in a tissue microarray. Furthermore, the role of TRPV1 in cell growth was assessed in a cervical cancer cell line. The TRPV1 expression was significantly higher in cervical cancer tissues than in cervical intraepithelial neoplasias, and normal epithelial tissues (P<0.001). In cervical cancer tissues, TRPV1 expression negatively correlated with PTEN expression (Spearman ρ=-0.121, P=0.009). Multivariate survival analysis revealed high TRPV1 expression (hazard ratio=3.41, 95% confidence interval: 1.25-9.27, P=0.016) as an independent prognostic factor for overall survival. Notably. the high TRPV1/low PTEN expression showed the highest hazard ratio (5.87; 95% confidence interval: 2.18-15.82, P<0.001) for overall survival. In vitro results demonstrated that the overexpression of TRPV1 was associated with increased cell viability and colony formation. Overexpression of TRPV1 could be a good biomarker for the prediction of chemoradiation response. Our result suggested promising potential of high TRPV1/low PTEN as prognostic and survival makers. The possible link between the biologic function of TRPV1 and PTEN in cervical cancer warrants further studies.

Lipid Nanoparticle Inclusion Prevents Capsaicin-Induced TRPV1 Defunctionalization.

Background: Capsaicin (CPS) is a highly selective agonist of the transient receptor potential vanilloid type 1 (TRPV1) with a nanomolar affinity. High doses or prolonged exposure to CPS induces TRPV1 defunctionalization and, although this effect is currently used for the treatment of thermal hyperalgesia in chronic pain conditions, it is responsible of detrimental effects, such as denervation of sensory fibers. The aim of the present study was to formulate CPS loaded lipid nanocarriers (CPS-LN) in order to optimize CPS release, thus preventing TRPV1 internalization and degradation. Methods: CPS-LNs were formulated and characterized by in vitro studies. The activation of TRPV1 receptors after CPS-LN administration was evaluated by measuring spontaneous pain that was induced by local injection into the plantar surface of the mouse hind-paw. Moreover, the expression of TRPV1 in the skin was evaluated by western blot analysis in CPS-LN injected mice and then compared to a standard CPS solution (CPS-STD). Results: CPS inclusion in LN induced a lower pain response when compared to CPS-STD; further, it prevented TRPV1 down-regulation in the skin, while CPS-STD induced a significant reduction of TRPV1 expression. Conclusions: Drug encapsulation in lipid nanoparticles produced an optimization of CPS release, thus reducing mice pain behavior and avoiding the effects that are caused by TRPV1 defunctionalization related to a prolonged activation of this receptor.

Zerumbone Modulates α2A-Adrenergic, TRPV1, and NMDA NR2B Receptors Plasticity in CCI-Induced Neuropathic Pain In Vivo and LPS-Induced SH-SY5Y Neuroblastoma In Vitro Models.

Zerumbone has shown great potential in various pathophysiological models of diseases, particularly in neuropathic pain conditions. Further understanding the mechanisms of action is important to develop zerumbone as a potential anti-nociceptive agent. Numerous receptors and pathways function to inhibit and modulate transmission of pain signals. Previously, we demonstrated involvement of the serotonergic system in zerumbone’s anti-neuropathic effects. The present study was conducted to determine zerumbone’s modulatory potential involving noradrenergic, transient receptor potential vanilloid type 1 (TRPV1) and N-methyl-D-aspartate (NMDA) receptors in chronic constriction injury (CCI)-induced in vitro and lipopolysaccharide (LPS)-induced SH-SY5Y in vitro neuroinflammatory models. von Frey filament and Hargreaves plantar tests were used to assess allodynia and hyperalgesia in the chronic constriction injury-induced neuropathic pain mouse model. Involvement of specific adrenoceptors were investigated using antagonists— prazosin (α1-adrenoceptor antagonist), idazoxan (α2-adrenoceptor antagonist), metoprolol (β1-adrenoceptor antagonist), ICI 118,551 (β2-adrenoceptor antagonist), and SR 59230 A (β3-adrenoceptor antagonist), co-administered with zerumbone (10 mg/kg). Involvement of excitatory receptors; TRPV and NMDA were conducted using antagonists capsazepine (TRPV1 antagonist) and memantine (NMDA antagonist). Western blot was conducted to investigate the effect of zerumbone on the expression of α2A-adrenoceptor, TRPV1 and NMDA NR2B receptors in CCI-induced whole brain samples of mice as well as in LPS-induced SH-SY5Y neuroblastoma cells. Pre-treatment with α1- and α2-adrenoceptor antagonists significantly attenuated both anti-allodynic and anti-hyperalgesic effects of zerumbone. For β-adrenoceptors, only β2-adrenoceptor antagonist significantly reversed the anti-allodynic and anti-hyperalgesic effects of zerumbone. β1-adrenoceptor antagonist only reversed the anti-allodynic effect of zerumbone. The anti-allodynic and anti-hyperalgesic effects of zerumbone were both absent when TRPV1 and NMDA receptors were antagonized in both nociceptive assays. Zerumbone treatment markedly decreased the expression of α2A-adrenoceptor, while an up-regulation was observed of NMDA NR2B receptors. Expression of TRPV1 receptors however did not significantly change. The in vitro study, representing a peripheral model, demonstrated the reduction of both NMDA NR2B and TRPV1 receptors while significantly increasing α2A-adrenoceptor expression in contrast to the brain samples. Our current findings suggest that the α1-, α2-, β1- and β2-adrenoceptors, TRPV1 and NMDA NR2B are essential for the anti-allodynic and antihyperalgesic effects of zerumbone. Alternatively, we demonstrated the plasticity of these receptors through their response to zerumbone’s administration.

Prognostic Significance of Transient Receptor Potential Vanilloid Type 1 (TRPV1) and Phosphatase and Tension Homolog (PTEN) in Epithelial Ovarian Cancer.

Transient receptor potential vanilloid type 1 (TRPV1) has been studied in human malignancies, but has not been studied in epithelial ovarian cancer (EOC). We, therefore, investigated the significance of TRPV1 and correlation with phosphatase and tension homolog (PTEN) in EOC. Immunohistochemical analyses for TRPV1 and PTEN were performed using a tissue microarray. Moreover, the role of TRPV1 in cell growth was assessed in a EOC cell line. High TRPV1 expression and the combination of high TRPV1 and low PTEN expression were an independent prognostic factor for overall survival and disease-free survival. In vitro results demonstrated that knockdown of TRPV1 was associated with decreased cell viability and colony formation. There is a strong association between TRPV1 and PTEN and the combination of TRPV1 and PTEN is a strong indicator of prognostic predictor in EOC.

Knockout of TRPV1 Exacerbates Ischemia-reperfusion-induced Renal Inflammation and Injury in Obese Mice.

Transient receptor potential vanilloid type 1 (TRPV1) has anti-inflammatory properties. The present study aimed to investigate the role of TRPV1 in renal inflammatory responses and tissue injury following renal ischemia-reperfusion (I/R) in diet-induced obese mice. TRPV1 knockout and wild type mice were fed a normal or western diet (WD) for 23 weeks and were then subjected to renal I/R injury. TRPV1 knockout mice showed enhanced WD-induced renal macrophage infiltration and collagen deposition. Knocking out TRPV1 exacerbated renal I/R-induced increase of malondialdehyde, interleukin-6, monocyte chemoattractant protein-1, and NF-ĸB in obese mice. Similar results were observed in the expression of phosphorylated Smad1 and Smad2/3. Blockade of calcitonin gene-related peptide (CGRP) receptors with CGRP8-37 worsened the I/R-induced renal inflammation and injury. Our data indicate that preserving TRPV1 expression and function may prevent renal I/R injury in obesity likely through alleviating inflammatory responses.

Activation of TRPV1 Contributes to Recurrent Febrile Seizures via Inhibiting the Microglial M2 Phenotype in the Immature Brain.

Transient receptor potential vanilloid type 1 (TRPV1) is a nonselective cation channel implicated in the nervous system as a key component of several inflammatory diseases. A massive amount of evidence has demonstrated that TRPV1 is extensively expressed in the central nervous system (CNS) and there might be a close relationship between TRPV1 and neuroinflammation, which is a crucial pathogenic factor in seizure generation, although it’s signaling mechanism has been less well characterized. Herein, we identified that TRPV1 is functionally expressed in the primary cultured mouse microglia and the membrane expression of TRPV1 is upregulated in rFS mice brain and specifically in activated microglia. Stimulation of TRPV1 promoted microglia activation and indirectly enhanced seizure susceptibility by inhibiting the neuroprotective effects of microglial transforming growth factor-beta1 (TGF-β1) via interaction with Toll-like receptor 4 (TLR4) in mice. Conversely, genetic deletion of TRPV1 alleviated hyperthermia or LPS-induced abnormal microglial activation and restored a balanced inflammatory microenvironment in the brain. Taken together, these findings show that microglial TRPV1, as a potential pro-inflammatory mediator, and participate in neuroinflammatory response, which will provide a novel therapeutic strategy for controlling the neuroinflammation-induced seizure.

Role of transient receptor potential vanilloid type 1 in the trigeminal ganglion and brain stem following dental pulp inflammation.

To verify whether experimentally induced pulpitis activates the expression of transient receptor potential vanilloid type 1 (TRPV1) and c-Fos, both peripherally and centrally. Acute pulpitis was induced in Sprague-Dawley rats via pulp exposure and application of complete Freund's adjuvant (CFA; n=13). Saline-treated (n=13) rats and rats that did not undergo tooth preparation (n=13) served as control groups. Three days post-CFA or post-saline application, face grooming activity was recorded, and the rats were then euthanized to allow for immunohistochemical analysis of the trigeminal ganglion (TG) and spinal trigeminal nucleus. anova with Student's t-test for post-hoc analysis was used to quantify the differences in behavioural tests and immunohistochemical labelling (c-Fos and TRPV1) in TG amongst groups. Kruskal-Wallis test with Dunnett's test for post-hoc analysis was used to compare immunohistochemical labelling (c-Fos and TRPV1) in the brainstem amongst groups. Histological evidence of severe pulp inflammation was found, and there was a significant increase in pain-like behaviour (P<0.05) in CFA-treated animals. C-Fos labelling and TRPV1 immunoreactivity in the TG were significantly higher (both P<0.05) in the CFA group than in the control groups. In the spinal trigeminal nucleus, the immunoreactivity for c-Fos was absent in the intermediate region (trigeminal subnucleus interpolaris) in all animals, with comparable expression of TRPV1 amongst all groups. In contrast, neurons in the trigeminal subnucleus caudalis (TSC) exhibited significant c-Fos immunoreactivity in the CFA group (P=0.0063). The expression of TRPV1 did not differ amongst the three groups, but the superficial laminae of the TSC exhibited significantly greater expression of TRPV1 than did the deep layers (P=0.0014). Following acute pulp inflammation, the TRPV1 channel was significantly involved in nociceptive signal processing in the peripheral nervous system, but not in the CNS. Because pulpitis induced some neuronal activation at the brainstem levels, further studies are needed to identify additional transducers that mediate signal transmission from pulpal afferents to their central targets.

High expression of TRPV-1 is associated with poor prognosis in cervical cancer

Objective: The Transient Receptor Potential Vanilloid type 1 (TRPV-1) is one of the well-investigated transient receptor potential (TRP) channels, nonselective membranous ion channels associated with calcium and sodium ion exchange. Its role has been pronounced in malignancies. However, the role of TRPV-1 in cervical cancer has not yet been elucidated. Here, we investigated the expression and clinical significance of TRPV-1 in cervical cancer.

Long-Term Diabetic Microenvironment Augments the Decay Rate of Capsaicin-Induced Currents in Mouse Dorsal Root Ganglion Neurons.

Individuals with end-stage diabetic peripheral neuropathy present with decreased pain sensation. Transient receptor potential vanilloid type 1 (TRPV1) is implicated in pain signaling and resides on sensory dorsal root ganglion (DRG) neurons. We investigated the expression and functional activity of TRPV1 in DRG neurons of the Ins2+/Akita mouse at 9 months of diabetes using immunohistochemistry, live single cell calcium imaging, and whole-cell patch-clamp electrophysiology. 2′,7′-Dichlorodihydrofluorescein diacetate (DCFH-DA) fluorescence assay was used to determine the level of Reactive Oxygen Species (ROS) in DRGs. Although TRPV1 expressing neuron percentage was increased in Ins2+/Akita DRGs at 9 months of diabetes compared to control, capsaicin-induced Ca2+ influx was smaller in isolated Ins2+/Akita DRG neurons, indicating impaired TRPV1 function. Consistently, capsaicin-induced Ca2+ influx was decreased in control DRG neurons cultured in the presence of 25 mM glucose for seven days versus those cultured with 5.5 mM glucose. The high glucose environment increased cytoplasmic ROS accumulation in cultured DRG neurons. Patch-clamp recordings revealed that capsaicin-activated currents decayed faster in isolated Ins2+/Akita DRG neurons as compared to those in control neurons. We propose that in poorly controlled diabetes, the accelerated rate of capsaicin-sensitive TRPV1 current decay in DRG neurons decreases overall TRPV1 activity and contributes to peripheral neuropathy.

Chronic colitis-induced visceral pain is associated with increased anxiety during quiescent phase.

Inflammatory bowel diseases (IBD) are characterized by repetition of flares and remission periods leading to chronic postinflammatory sequelae. Among postinflammatory sequelae, one-third of patients with IBD are suffering from functional symptoms or psychological comorbidities that persist during remission. The aim of our study was to assess functional and behavioral sequelae of chronic colitis in rats with quiescent intestinal inflammation. Chronic colitis was induced by a weekly intrarectal injection of increasing concentrations of trinitrobenzene sulfonic acid (TNBS) for 3 wk (15-45 mg of TNBS) in 30 rats, whereas the control rats (n = 24) received the vehicle. At 50 days post-TNBS, visceral sensitivity was assessed by visceromotor response to colorectal distension, and transient receptor potential vanilloid type 1 (TRPV1) expression was also quantified in the colon and dorsal root ganglia. Barrier function and inflammatory response were assessed by studying intestinal permeability, tight junction protein, myeloperoxidase activity, histological score, and cytokine production (IL-6, IL-10, and TNF-α). Anxiety behavioral tests were performed from 50 to 64 days after the last TNBS injection. Chronic TNBS induced 1) a visceral hypersensitivity (P = 0.03), 2) an increased colon weight-to-length ratio (P = 0.01), 3) higher inflammatory and fibrosis scores (P = 0.0390 and P = 0.0016, respectively), and 4) a higher colonic IL-6 and IL-10 production (P = 0.008 and P = 0.005, respectively) compared with control rats. Intestinal permeability, colonic production of TNF-α, myeloperoxidase activity, and TRPV1 expression did not differ among groups. Chronic TNBS increased anxiety-related behavior in the open-field test and in the acoustic stress test. In conclusion, chronic colitis induced functional sequelae such as visceral hypersensitivity and increased anxiety with a low-grade intestinal inflammation. Development of a representative animal model will allow defining novel therapeutic approaches to achieve a better management of IBD-related sequelae. NEW & NOTEWORTHY Patients with inflammatory bowel diseases have impaired quality of life. Therapeutic progress to control mucosal inflammation provides us an opportunity to develop novel approaches to understand mechanisms behind postinflammatory sequelae. We used a chronic colitis model to study long-term sequelae on visceral pain, gut barrier function, and psychological impact. Chronic colitis induced functional symptoms and increased anxiety in the remission period. It might define novel therapeutic approaches to achieve a better inflammatory bowel disease-related sequelae management.

Interaction between TRPV1-expressing neurons in the hypothalamus

Transient receptor potential vanilloid type 1 (TRPV1) is a ligand-gated ion channel expressed in the peripheral and central nervous systems. TRPV1-dependent mechanisms take part in a wide range of physiological and pathophysiological pathways including the regulation of homeostatic functions. TRPV1 expression in the hypothalamus has been described as well as evidence that TRPV1-dependent excitatory inputs to hypothalamic preautonomic neurons are diminished in diabetic conditions. Here we aimed to determine the functional expression of TRPV1 in two hypothalamic nuclei known to be involved in the central control of metabolism and to test the hypothesis that TRPV1-expressing neurons receive TRPV1-expressing inputs. A mouse model (TRPV1Cre/tdTom) was generated to identify TRPV1-expressing cells and determine the cellular properties of TRPV1-expressing neurons in adult mice. Our study demonstrated the functional expression of TRPV1 in the dorsomedial hypothalamic nucleus and paraventricular nucleus in adult mice. Our findings revealed that a subset of TRPV1Cre/tdTom neurons receive TRPV1-expressing excitatory inputs, indicating direct interaction between TRPV1-expressing neurons. In addition, astrocytes likely play a role in the modulation of TRPV1-expressing neurons. In summary, this study identified specific hypothalamic regions where TRPV1 is expressed and functional in adult mice and the existence of direct connections between TRPV1Cre/tdTom neurons. NEW & NOTEWORTHY Transient receptor potential vanilloid type 1 (TRPV1) is expressed in the hypothalamus, and TRPV1-dependent regulation of preautonomic neurons is decreased in hyperglycemic conditions. Our study demonstrated functional expression of TRPV1 in two hypothalamic nuclei involved in the control of energy homeostasis. Our results also revealed that a subset of TRPV1-expressing neurons receive TRPV1-expressing excitatory inputs. These findings suggest direct interaction between TRPV1-expressing neurons.

Activation of TRPV1 receptors affects memory function and hippocampal TRPV1 and CREB mRNA expression in a rat model of biliary cirrhosis

ABSTRACTObjective: Memory impairment induced by biliary cirrhosis is associated with abnormalities in the function of different neurotransmitter systems. However, the exact molecular mechanisms involved in the learning and memory dysfunctions following biliary cirrhosis is largely unknown. This study set out to determine whether activation of transient receptor potential vanilloid type 1 (TRPV1) in the CA1 area of the hippocampus in rats improve memory impairment induced by biliary cirrhosis.Methods: To assess learning and memory, passive avoidance task was carried out using a shuttle box. The mRNA expression of TRPV1 and cAMP response element binding (CREB) protein in the hippocampus were also evaluated by qT-PCR.Results: Our results indicated that activation of TRPV1 channels by capsaicin significantly decreased memory impairment and increased mRNA expression of the TRPV1 and CREB in the hippocampus of rats with biliary cirrhosis. Our findings also demonstrated that a positive correlation existed between mRNA expression of TRPV1 and CREB, and between memory function and TRPV1 expression.Discussion: Taken together, the results of this study support the view that TRPV1 receptor may play an important role in the regulation of learning and memory functions, and suggest that activation of TRPV1 channels seems to be a promising therapeutic target for learning and memory impairments following biliary cirrhosis.

Inflammation induces Epac-protein kinase C alpha and epsilon signaling in TRPV1-mediated hyperalgesia.

The exchange proteins activated by cAMP (Epacs) have been shown to play important roles in producing inflammation-induced nociception. Transient receptor potential vanilloid type 1 (TRPV1) is a major receptor processing thermal and chemosensitive nociceptive information. The role of Epacs in modulating the activity of TRPV1 has yet to be determined. Studying the effect of complete Freund adjuvant (CFA)-induced inflammation on capsaicin-activated TRPV1 nociceptive responses in dorsal root ganglia (DRG), we found that CFA produced a large increase in capsaicin-induced responses. The increase was inhibited by Epac1 and Epac2 antagonists. Thus, activation of Epacs is critical in producing enhancement in TRPV1-mediated responses under inflammatory conditions. In addition, the inflammation-induced enhancement of TRPV1 responses was blocked by PKCα and PKCε inhibitors, suggesting the essential roles of these PKCs in enhancing TRPV1 responses. To determine the mechanism underlying the Epac actions on TRPV1, we studied the effects of the Epac activator, 8-(4-chlorophenylthio)-2-O-methyl-cAMP (CPT), on capsaicin-induced nociceptive behavioral responses, capsaicin-activated currents, expression and membrane trafficking of PKC and TRPV1 in DRG. CPT was found to enhance capsaicin-induced nociception and ionic currents. The enhancement was inhibited by PKCα and PKCε inhibitors. In addition, CPT increased the expression of phosphorylated PKCα (pPKCα) and membrane TRPV1 expression in DRG. Studying the colocalization of TRPV1 and pPKCα or pPKCε in DRG slices prepared from CFA-treated rats, we found that pPKCα or pPKCε expressed with TRPV1 in different-sized neurons to exert differential influences on TRPV1 activity. Thus, Epac-PKC signaling is critically important in producing inflammation-induced potentiation of TRPV1 functions.

Decreased expression of TRPV1 in renal cell carcinoma: association with tumor Fuhrman grades and histopathological subtypes.

PurposeThe aim of this study was to investigate whether the expression of the ligand-gated Ca2+ channel transient receptor potential vanilloid type-1 (TRPV1) in primary human renal cell carcinoma (RCC) is associated with clinicopathological features.Patients and methodsFresh and frozen primary tumor and normal peritumoral kidney tissues from 127 patients diagnosed with RCC were analyzed for TRPV1 expression by quantitative reverse transcription polymerase chain reaction (RT-PCR), Western blotting and immunohistochemistry.ResultsQuantitative RT-PCR revealed that TRPV1 was decreased 3.20-fold in RCC tissue vs normal peritumoral kidney tissue (p=0.012). Significantly different TRPV1 mRNA expression was detected in RCC tissues of different Fuhrman grades and histopathological subtypes (F=4.282, p=0.015 and F=5.205, p=0.014, respectively). Decreased TRPV1 expression was correlated with RCC histopathological subtype (R=-0.554, p=0.003) and Fuhrman grade (R=−0.525, p=0.006). Western blot analysis of TRPV1 protein expression showed similar results. Immunohistochemical analysis showed strong expression of TRPV1 in kidney tubules but demonstrated weak or no immunostaining in RCC tissues.ConclusionTRPV1 expression was decreased in RCC, which was significantly associated with tumor Fuhrman grades and histopathological subtypes. It seems to suggest that TRPV1 expression may be a valuable tool to predict the extent of RCC progression.

Activation of TRPV1 Prevents Salt-Induced Kidney Damage and Hypertension After Renal Ischemia-Reperfusion Injury in Rats

Background/Aims: High-salt intake after recovery from renal ischemia-reperfusion (I/R) injury leads to hypertension with severe renal damage. Transient receptor potential vanilloid type 1 (TRPV1) channels have been involved in the regulation of inflammation and oxidative stress following ischemic organ injury. We tested the hypothesis that activation of TRPV1 conveys preconditioning protection to the kidney subjected to I/R. Methods: TRPV1 was activated or down-regulated by subcutaneous injection of a low (1mg/kg) or high (100mg/kg) dose of capsaicin, respectively, 3 hours before ischemia. Rats were fed a 0.4% NaCl diet for 5 weeks after I/R followed by a 4% NaCl diet for 4 more weeks in 4 groups: sham, I/R, I/R+high-dose capsaicin (HCap), and I/R+low-dose capsaicin (LCap). Results: Renal TRPV1 expression was decreased in I/R rats (P< 0.05) and further reduced in I/R+HCap group (P< 0.05) but unchanged in I/R+LCap rats compared with the sham group. Blood pressure were elevated in I/R rats (P< 0.05) and further increased in I/R+HCap group (P< 0.05) but unchanged in I/R+LCap rats compared with sham. Renal function was impaired in I/R rats (P< 0.05) and further deteriorated in I/R+HCap group (P< 0.05) but unchanged in I/R+LCap group. Renal inflammatory responses, oxidative stress, and renal collagen deposition were augmented in I/R rats (all P< 0.05) and further intensified in I/R+HCap group (all P< 0.05) but unchanged in I/R+LCap group. Conclusion: Activation of TRPV1 plays an anti-inflammatory and anti-oxidative stress role in preventing renal tissue damage and salt-induced hypertension after I/R injury, indicating that TRPV1 conveys preconditioning protection that may have therapeutic implication.