scholarly journals Combined genetic and pharmacological inhibition of TRPV1 and P2X3 attenuates colorectal hypersensitivity and afferent sensitization

2013 ◽  
Vol 305 (9) ◽  
pp. G638-G648 ◽  
Author(s):  
Michael E. Kiyatkin ◽  
Bin Feng ◽  
Erica S. Schwartz ◽  
G. F. Gebhart
Keyword(s):  
Transient Receptor Potential ◽  
Genetic Manipulation ◽  
Afferent Fiber ◽  
Receptor Potential ◽  
Afferent Neuron ◽  
Transient Receptor Potential Vanilloid ◽  
Double Knockout ◽  
Inflammatory Soup ◽  
Trpv1 Antagonist ◽  
Transient Receptor

The ligand-gated channels transient receptor potential vanilloid 1 (TRPV1) and P2X3 have been reported to facilitate colorectal afferent neuron sensitization, thus contributing to organ hypersensitivity and pain. In the present study, we hypothesized that TRPV1 and P2X3 cooperate to modulate colorectal nociception and afferent sensitivity. To test this hypothesis, we employed TRPV1-P2X3 double knockout (TPDKO) mice and channel-selective pharmacological antagonists and evaluated combined channel contributions to behavioral responses to colorectal distension (CRD) and afferent fiber responses to colorectal stretch. Baseline responses to CRD were unexpectedly greater in TPDKO compared with control mice, but zymosan-produced CRD hypersensitivity was absent in TPDKO mice. Relative to control mice, proportions of mechanosensitive and -insensitive pelvic nerve afferent classes were not different in TPDKO mice. Responses of mucosal and serosal class afferents to mechanical probing were unaffected, whereas responses of muscular (but not muscular/mucosal) afferents to stretch were significantly attenuated in TPDKO mice; sensitization of both muscular and muscular/mucosal afferents by inflammatory soup was also significantly attenuated. In pharmacological studies, the TRPV1 antagonist A889425 and P2X3 antagonist TNP-ATP, alone and in combination, applied onto stretch-sensitive afferent endings attenuated responses to stretch; combined antagonism produced greater attenuation. In the aggregate, these observations suggest that 1) genetic manipulation of TRPV1 and P2X3 leads to reduction in colorectal mechanosensation peripherally and compensatory changes and/or disinhibition of other channels centrally, 2) combined pharmacological antagonism produces more robust attenuation of mechanosensation peripherally than does antagonism of either channel alone, and 3) the relative importance of these channels appears to be enhanced in colorectal hypersensitivity.

scholarly journals Activation of TRPV1 channels leads to stimulation of NKCC1 cotransport in the lens

2018 ◽  
Vol 315 (6) ◽  
pp. C793-C802 ◽  
Author(s):  
Mohammad Shahidullah ◽  
Amritlal Mandal ◽  
Nicholas A. Delamere
Keyword(s):  
Ion Transport ◽  
Transient Receptor Potential ◽  
Ion Homeostasis ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Signaling Mechanism ◽  
Trpv1 Channels ◽  
Trpv1 Antagonist ◽  
Transient Receptor ◽  
Stimulation Of

Lens ion homeostasis is crucial in maintaining water content and, in turn, refractive index and transparency of the multicellular syncytium-like structure. New information is emerging on the regulation of ion transport in the lens by mechanisms that rely on transient receptor potential vanilloid (TRPV) ion channels. We found recently that TRPV1 activation leads to Ca2+/PKC-dependent ERK1/2 signaling. Here, we show that the TRPV1 agonist capsaicin (100 nM) and hyperosmotic solution (350 vs. 300 mosM) each caused an increase of bumetanide-inhibitable Rb uptake by intact porcine lenses and Na-K-2Cl cotransporter 1 (NKCC1) phosphorylation in the lens epithelium. The TRPV1 antagonist A889425 (1 µM) abolished the increases of Rb uptake and NKCC1 phosphorylation in response to hyperosmotic solution. Exposing lenses to hyperosmotic solution in the presence of MEK/ERK inhibitor U0126 (10 µM) or the with-no-lysine kinase (WNK) inhibitor WNK463 (1 µM) also prevented NKCC1 phosphorylation and the Rb uptake responses to hyperosmotic solution. WNK463 did not prevent the increase in ERK1/2 phosphorylation that occurs in response to capsaicin or hyperosmotic solution, suggesting that ERK1/2 activation occurs before WNK activation in the sequence of signaling events. Taken together, the evidence indicates that activation of TRPV1 is a critical early step in a signaling mechanism that responds to a hyperosmotic stimulus, possibly lens shrinkage. By activating ERK1/2 and WNK, TRPV1 activation leads to NKCC1 phosphorylation and stimulation of NKCC1-mediated ion transport.

Transient receptor potential vanilloid 1 mediates cocaine reinstatement via the D1 dopamine receptor in the nucleus accumbens

2019 ◽  
Vol 33 (12) ◽  
pp. 1491-1500 ◽  
Author(s):  
In-Jee You ◽  
Sa-Ik Hong ◽  
Shi-Xun Ma ◽  
Thi-Lien Nguyen ◽  
Seung-Hwan Kwon ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Transient Receptor Potential ◽  
Drugs Of Abuse ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Skf 81297 ◽  
Genetic Deletion ◽  
Trpv1 Antagonist ◽  
Transient Receptor ◽  
Cocaine Reinstatement

Purpose: The transient receptor potential vanilloid 1 (TRPV1) is a nonselective cation channel that mediates synaptic modification in the nucleus accumbens (NAc). However, no study has yet examined the mechanism of TRPV1 in the NAc on cocaine reinstatement. We investigated the mechanism of TRPV1 in NAc on cocaine reinstatement using the conditioned place preference (CPP) test in mice. Methods: We examined the effect of capsazepine (5 mg/kg, a TRPV1 antagonist, administered intraperitoneally (i.p.)), capsaicin (0.3 mg/kg, a TRPV1 agonist, administered i.p.), and genetic deletion of TRPV1 on the reinstatement of cocaine-induced CPP (15 mg/kg, administered i.p.). The expression of TRPV1 and Ca2+/calmodulin-mediated kinase II (CaMKII) in the NAc were determined after cocaine reinstatement. Microinjection of SB366791 (0.2 ng, a selective TRPV1 antagonist) in the NAc was assessed on SKF-81297 (1 µg, D1-like dopamine (DA) receptor agonist) primed cocaine reinstatement. Results: Capsazepine suppressed and capsaicin potentiated cocaine CPP in the reinstatement phase. In addition, genetic deletion of TRPV1 inhibited cocaine-priming reinstatement. Cocaine reinstatement was mediated by increased TRPV1 expression in the NAc, which involves CaMKII. Microinjection of SB366791 in the NAc prevented the cocaine reinstatement evoked by microinjection of SKF-81297 in the NAc. Conclusions: These findings suggest that activation of TRPV1 mediates the stimulation of D1-like DA receptors and CaMKII in the NAc, resulting in the facilitation of cocaine reinstatement behaviors. Thus, our findings reveal a previously unknown TRPV1 mechanism in the reinstatement to drugs of abuse.

scholarly journals Hypersensitivity Induced by Intrathecal Bradykinin Administration Is Enhanced by N-oleoyldopamine (OLDA) and Prevented by TRPV1 Antagonist

2021 ◽  
Vol 22 (7) ◽  
pp. 3712
Author(s):  
Eva Uchytilova ◽  
Diana Spicarova ◽  
Jiri Palecek
Keyword(s):  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Mechanical Hypersensitivity ◽  
Peripheral Stimulation ◽  
Trpv1 Channels ◽  
Catheter Implantation ◽  
Trpv1 Antagonist ◽  
Transient Receptor ◽  
Transient Thermal

Transient receptor potential vanilloid 1 (TRPV1) channels contribute to the development of several chronic pain states and represent a possible therapeutic target in many painful disease treatment. Proinflammatory mediator bradykinin (BK) sensitizes TRPV1, whereas noxious peripheral stimulation increases BK level in the spinal cord. Here, we investigated the involvement of spinal TRPV1 in thermal and mechanical hypersensitivity, evoked by intrathecal (i.t.) administration of BK and an endogenous agonist of TRPV1, N-oleoyldopamine (OLDA), using behavioral tests and i.t. catheter implantation, and administration of BK-induced transient thermal and mechanical hyperalgesia and mechanical allodynia. All these hypersensitive states were enhanced by co-administration of a low dose of OLDA (0.42 µg i.t.), which was ineffective only under the control conditions. Intrathecal pretreatment with TRPV1 selective antagonist SB366791 prevented hypersensitivity induced by i.t. co-administration of BK and OLDA. Our results demonstrate that both thermal and mechanical hypersensitivity evoked by co-administration of BK and OLDA is mediated by the activation of spinal TRPV1 channels.

scholarly journals Transient receptor potential vanilloid 1 and 4 double knockout leads to increased bone mass in mice

Bone Reports ◽  
2020 ◽  
Vol 12 ◽  
pp. 100268 ◽  
Author(s):  
Haruki Nishimura ◽  
Makoto Kawasaki ◽  
Manabu Tsukamoto ◽  
Kunitaka Menuki ◽  
Hitoshi Suzuki ◽  
...  
Keyword(s):  
Bone Mass ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Double Knockout ◽  
Transient Receptor

scholarly journals Effect of dural inflammatory soup application on activation and sensitization markers in the caudal trigeminal nucleus of the rat and the modulatory effects of sumatriptan and kynurenic acid

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Eleonóra Spekker ◽  
Klaudia Flóra Laborc ◽  
Zsuzsanna Bohár ◽  
Gábor Nagy-Grócz ◽  
Annamária Fejes-Szabó ◽  
...  
Keyword(s):  
Kynurenic Acid ◽  
Transient Receptor Potential ◽  
Neuronal Nitric Oxide Synthase ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Trigeminal Nucleus ◽  
Inflammatory Soup ◽  
Calcitonin Gene ◽  
Caudal Trigeminal Nucleus ◽  
Transient Receptor

Abstract Background The topical inflammatory soup can model the inflammation of the dura mater causing hypersensitivity and activation of the trigeminal system, a phenomenon present in migraineurs. Calcitonin gene-related peptide, transient receptor potential vanilloid-1 receptor, and neuronal nitric oxide synthase are important in the sensitization process there. 5-HT1B/1D receptor agonists, triptans are used as a treatment of migraine. Kynurenic acid an NMDA antagonist can act on structures involved in trigeminal activation. Aim We investigated the effect of inflammatory soup induced dural inflammation on the calcitonin gene-related peptide, transient receptor potential vanilloid-1 receptor, and neuronal nitric oxide synthase levels in the caudal trigeminal nucleus. We also tested whether pretreatment with a well-known antimigraine drug, such as sumatriptan and kynurenic acid, a compound with a different mechanism of action, can affect these changes and if their modulatory effects are comparable. Material and methods After subcutaneous sumatriptan or intraperitoneal kynurenic acid the dura mater of adult male Sprague-Dawley rats (n = 72) was treated with inflammatory soup or its vehicle (synthetic interstitial fluid). Two and a half or four hours later perfusion was performed and the caudal trigeminal nucleus was removed for immunohistochemistry. Results and conclusion Inflammatory soup increased calcitonin gene-related peptide, transient receptor potential vanilloid-1 receptor, and neuronal nitric oxide synthase in the caudal trigeminal nucleus compared to placebo, which was attenuated by sumatriptan and kynurenic acid. This suggests the involvement of 5-HT1B/1D and NMDA receptors in neurogenic inflammation development of the dura and thus in migraine attacks.

scholarly journals Cardiac-specific knockout of ETA receptor mitigates low ambient temperature-induced cardiac hypertrophy and contractile dysfunction

2012 ◽  
Vol 4 (2) ◽  
pp. 97-107 ◽  
Author(s):  
Yingmei Zhang ◽  
Linlin Li ◽  
Yinan Hua ◽  
Jennifer M. Nunn ◽  
Feng Dong ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Cold Stress ◽  
Cold Exposure ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Maximal Velocity ◽  
Eta Receptor ◽  
Trpv1 Antagonist ◽  
Transient Receptor

Abstract Cold exposure is associated with oxidative stress and cardiac dysfunction. The endothelin (ET) system, which plays a key role in myocardial homeostasis, may participate in cold exposure-induced cardiovascular dysfunction. This study was designed to examine the role of ET-1 in cold stress-induced cardiac geometric and contractile responses. Wild-type (WT) and ETA receptor knockout (ETAKO) mice were assigned to normal or cold exposure (4°C) environment for 2 and 5 weeks prior to evaluation of cardiac geometry, contractile, and intracellular Ca2+ properties. Levels of the temperature sensor transient receptor potential vanilloid (TRPV1), mitochondrial proteins for biogenesis and oxidative phosphorylation, including UCP2, HSP90, and PGC1α were evaluated. Cold stress triggered cardiac hypertrophy, depressed myocardial contractile capacity, including fractional shortening, peak shortening, and maximal velocity of shortening/relengthening, reduced intracellular Ca2+ release, prolonged intracellular Ca2+ decay and relengthening duration, generation of ROS and superoxide, as well as apoptosis, the effects of which were blunted by ETAKO. Western blotting revealed downregulated TRPV1 and PGC1α as well as upregulated UCP2 and activation of GSK3β, GATA4, and CREB in cold-stressed WT mouse hearts, which were obliterated by ETAKO. Levels of HSP90, an essential regulator for thermotolerance, were unchanged. The TRPV1 agonist SA13353 attenuated whereas TRPV1 antagonist capsazepine mimicked cold stress- or ET-1-induced cardiac anomalies. The GSK3β inhibitor SB216763 ablated cold stress-induced cardiac contractile (but not remodeling) changes and ET-1-induced TRPV1 downregulation. These data suggest that ETAKO protects against cold exposure-induced cardiac remodeling and dysfunction mediated through TRPV1 and mitochondrial function.

scholarly journals Simultaneous Deletion of Transient Receptor Potential Vanilloid 3 and Cacna1h Undermines Ca2+ Homeostasis in Oocytes and Fertility in Mice

2018 ◽  
Author(s):  
Aujan Mehregan ◽  
Goli Ardestani ◽  
Ingrid Carvacho ◽  
Rafael Fissore
Keyword(s):  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Functional Expression ◽  
Egg Activation ◽  
Transient Receptor Potential Vanilloid ◽  
Double Knockout ◽  
Knock Out ◽  
Transient Receptor ◽  
Mammalian Eggs ◽  
Channel Currents

In mammals, calcium (Ca2+) influx fills the endoplasmic reticulum, from where Ca2+ is released following fertilization to induce egg activation. However, an incomplete index of the plasma membrane channels and their specific contributions that underlie this influx in oocytes and eggs led us to simultaneously knock out the transient receptor potential vanilloid, member 3 (TRPV3) channel and the T-type channel, CaV3.2. Double knockout (dKO) females displayed subfertility and their oocytes and eggs showed significantly diminished Ca2+ store content and oscillations after fertilization compared to controls. We also found that the cell cycle stage during maturation determines the functional expression of channels whereby they show a distinct permeability to certain ions. In total, we demonstrate that TRPV3 and CaV3.2 are required for initiating physiological oscillations and that Ca2+ influx dictates the periodicity of oscillations during fertilization. dKO gametes will be indispensable to identify the complete native channel currents present in mammalian eggs.

Involvement of TRPV1 channels in the periaqueductal grey on the modulation of innate fear responses

2014 ◽  
Vol 27 (2) ◽  
pp. 97-105 ◽  
Author(s):  
Daniele C. Aguiar ◽  
Ana F. Almeida-Santos ◽  
Fabricio A. Moreira ◽  
Francisco S. Guimarães
Keyword(s):  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Periaqueductal Grey ◽  
Trpv1 Channels ◽  
Conflict Situations ◽  
Natural Predator ◽  
Dorsal Columns ◽  
Trpv1 Antagonist ◽  
Transient Receptor

ObjectivesThe transient receptor potential vanilloid type-1 channel (TRPV1) is expressed in the midbrain periaqueductal grey (PAG), a region of the brain related to aversive responses. TRPV1 antagonism in the dorsolateral PAG (dlPAG) induces anxiolytic-like effects in models based on conflict situations. No study, however, has investigated whether these receptors could contribute to fear responses to proximal threat. Thus, we tested the hypothesis that TRPV1 in the PAG could mediate fear response in rats exposed to a predator.MethodsWe verified whether exposure to a live cat (a natural predator) would activate TRPV1-expressing neurons in the PAG. Double-staining immunohistochemistry was used as a technique to detect c-Fos, a marker of neuronal activation, and TRPV1 expression. We also investigated whether intra-dlPAG injections of the TRPV1 antagonist, capsazepine (CPZ), would attenuate the behavioural consequences of predator exposure.ResultsExposure to a cat increased c-Fos expression in TRPV1-positive neurons, mainly in the dorsal columns of the PAG, suggesting that TRPV1-expressing neurons are activated by threatening stimuli. Accordingly, local injection of CPZ inhibited the fear responses.ConclusionThese data support the hypothesis that TRPV1 channels mediate fear reactions in the dlPAG. This may have an implication for the development of TRPV1-antagonists as potential drugs for the treatment of certain psychiatric disorders.

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