The interactions between TRPV1 and µ-opioid receptors (MOR) have recently attracted much attention because these two receptors play important roles in pain pathways and can apparently modulate each other's functioning. However, the knowledge about signaling interactions and crosstalk between these two receptors is still limited. In this study, we investigated the mutual interactions between MOR and TRPV1 shortly after their activation in HEK293 cells expressing these two receptors. After activation of one receptor we observed significant changes in the other receptor's lateral mobility and vice versa. However, the changes in receptor movement within the plasma membrane were not connected with activation of the other receptor. We also observed that plasma membrane β-arrestin 2 levels were altered after treatment with agonists of both these receptors. Knockdown of β-arrestin 2 blocked all changes in the lateral mobility of both receptors. Furthermore, we found that β-arrestin 2 can play an important role in modulating the effectiveness of ERK1/2 phosphorylation after activation of MOR in the presence of TRPV1. These data suggest that β-arrestin 2 and ERK1/2 are important mediators between these two receptors and their signaling pathways. Collectively, MOR and TRPV1 can mutually affect each other's behavior and β-arrestin 2 apparently plays a key role in the bidirectional crosstalk between these two receptors in the plasma membrane.

• MeSH
• arrestiny metabolismus   MeSH
• beta arrestin 2 metabolismus   fyziologie   MeSH
• beta arrestiny metabolismus   MeSH
• buněčná membrána metabolismus   fyziologie   MeSH
• fosforylace MeSH
• HEK293 buňky MeSH
• kationtové kanály TRPV metabolismus   fyziologie   MeSH
• lidé MeSH
• MAP kinasový signální systém fyziologie   MeSH
• morfin metabolismus   MeSH
• opioidní analgetika metabolismus   MeSH
• receptory opiátové mu metabolismus   fyziologie   MeSH
• receptory opiátové metabolismus   MeSH
• signální transdukce MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Cough is one of the most important defensive reflexes. However, extensive non- productive cough is a harmful mechanism leading to the damage of human airways. Cough is initiated by activation of vagal afferents in the airways. The site of their convergence is particularly the nucleus of the solitary tract (nTS). The second-order neurons terminate in the pons, medulla and spinal cord and there is also the cortical and subcortical control of coughing.Upper airway cough syndrome (UACS) - previously postnasal drip syndrome - is one of the most common causes of chronic cough together with asthma and gastroesophageal reflux. The main mechanisms leading to cough in patients with nasal and sinus diseases are postnasal drip, direct irritation of nasal mucosa, inflammation in the lower airways, upper airway inflammation and the cough reflex sensitization. The cough demonstrated by UACS patients is probably due to hypersensitivity of the upper airways sensory nerve or lower airways sensory nerve, or a combination of both. Further studies are needed to clarify this mechanism.

• MeSH
• chronická nemoc MeSH
• kapsaicin škodlivé účinky   MeSH
• kašel chemicky indukované   patofyziologie   MeSH
• kationtové kanály TRPV agonisté   fyziologie   MeSH
• kationtový kanál TRPA1 agonisté   fyziologie   MeSH
• lidé MeSH
• nervové receptory účinky léků   fyziologie   MeSH
• nervus vagus účinky léků   patofyziologie   MeSH
• nosní sliznice účinky léků   patofyziologie   MeSH
• syndrom MeSH
• trachea účinky léků   patofyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Transient receptor potential vanilloid type 1 (TRPV1) receptors are important in the development of different pathological chronic pain states. Here we examined the role of spinal cord TRPV1 receptors in the mechanisms leading to activation of dorsal horn neurons after paclitaxel (PAC) treatment. PAC is a widely used chemotherapeutic drug that often leads to development of painful neuropathy. Immunohistochemical analysis of c-Fos protein expression in dorsal horn neurons was used as a marker of neuronal activation. Rat spinal cord slices were processed for in vitro incubation with PAC (100 nM) and TRPV1 receptor antagonists (SB366791 and AMG9810; 10 microM). PAC treatment induced significant upregulation of c-Fos nuclear expression in superficial dorsal horn neurons that was diminished by TRPV1 receptor antagonists pre-incubation. These results further substantiated the role of spinal TRPV1 receptors in the development of paclitaxel-induced neuropathic pain and contribute to better understanding of the pathological mechanisms involved.

• MeSH
• antitumorózní látky fytogenní farmakologie   MeSH
• buňky zadních rohů míšních účinky léků   metabolismus   MeSH
• exprese genu MeSH
• kationtové kanály TRPV antagonisté a inhibitory   fyziologie   MeSH
• krysa rodu rattus MeSH
• paclitaxel farmakologie   MeSH
• potkani Wistar MeSH
• protoonkogenní proteiny c-fos agonisté   biosyntéza   genetika   MeSH
• zadní rohy míšní účinky léků   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

• MeSH
• antihistaminika terapeutické užití   MeSH
• chronická nemoc MeSH
• kationtové kanály TRPV fyziologie   MeSH
• lidé MeSH
• pruritus * etiologie   MeSH
• receptor PAR-2 fyziologie   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

Transient receptor potential channels sensitive to vanilloids (TRPVs) are group of ion channels which are sensitive to various tissue damaging signals and their activation is generally perceived as pain. Therefore, they are generally named as nociceptors. Understanding their activation and function as well as their interaction with intracellular pathways is crucial for the development of pharmacological interference in order to reduce pain perception. The current review summarizes basic facts in regard to TRPV and discusses their relevance in the sensing of (pain-) signals and their intracellular processing, focussing on their modulation of the intracellular calcium ([Ca(2+)]i) signal. Furthermore we discuss the basic mechanisms how the modification of [Ca(2+)]i through TRPV might induce long-term-potentiation (LTP) or long-term- depression (LTD) and from "memories" of pain. Understanding of these mechanisms is needed to localize the best point of interference for pharmacological treatment. Therefore, high attention is given to highlight physiological and pathological processes and their interaction with significant modulators and their roles in neuroplasticity and pain modulation.

• MeSH
• kationtové kanály TRPV metabolismus   fyziologie   MeSH
• lidé MeSH
• mozek metabolismus   fyziologie   MeSH
• neurony metabolismus   fyziologie   MeSH
• neuroplasticita * MeSH
• nocicepce fyziologie   MeSH
• signální transdukce MeSH
• vápníková signalizace MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

• MeSH
• bolest * farmakoterapie   patofyziologie   MeSH
• iontové kanály * fyziologie   MeSH
• kapsaicin farmakologie   terapeutické užití   MeSH
• kationtové kanály TRP * fyziologie   MeSH
• kationtové kanály TRPV fyziologie   MeSH
• lidé MeSH
• nociceptory fyziologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH

BACKGROUND: The recent discovery that camphor activates and strongly desensitizes the capsaicin-sensitive and noxious heat-sensitive channel transient receptor potential vanilloid subfamily member 1 (TRPV1) has provided new insights and opened up new research paths toward understanding why this naturally occurring monoterpene is widely used in human medicine for its local counter-irritant, antipruritic, and anesthetic properties. However, the molecular basis for camphor sensitivity remains mostly unknown. The authors attempt to explore the nature of the activation pathways evoked by camphor and narrow down a putative interaction site at TRPV1. METHODS: The authors transiently expressed wild-type or specifically mutated recombinant TRPV1 channels in human embryonic kidney cells HEK293T and recorded cation currents with the whole cell, patch clamp technique. To monitor changes in the spatial distribution of phosphatidylinositol 4,5-bisphosphate, they used fluorescence resonance energy transfer measurements from cells transfected with the fluorescent protein-tagged pleckstrin homology domains of phospholipase C. RESULTS: The results revealed that camphor modulates TRPV1 channel through the outer pore helix domain by affecting its overall gating equilibrium. In addition, camphor, which generally is known to decrease the fluidity of cell plasma membranes, may also regulate the activity of TRPV1 by inducing changes in the spatial distribution of phosphatidylinositol-4,5-bisphosphate on the inner leaflet of the plasma membrane. CONCLUSIONS: The findings of this study provide novel insights into the structural basis for the modulation of TRPV1 channel by camphor and may provide an explanation for the mechanism by which camphor modulates thermal sensation in vivo.

• MeSH
• gating iontového kanálu účinky léků   fyziologie   MeSH
• HEK293 buňky MeSH
• jaderný pór účinky léků   metabolismus   MeSH
• kafr chemie   farmakologie   MeSH
• kationtové kanály TRPV antagonisté a inhibitory   chemie   fyziologie   MeSH
• krysa rodu rattus MeSH
• lidé MeSH
• terciární struktura proteinů účinky léků   fyziologie   MeSH
• vazebná místa účinky léků   fyziologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH

The polymodal transient receptor potential vanilloid 4 (TRPV4) channel, a member of the TRP channel family, is a calcium-permeable cationic channel that is gated by various stimuli such as cell swelling, low pH and high temperature. Therefore, TRPV4-mediated calcium entry may be involved in neuronal and glia pathophysiology associated with various disorders of the central nervous system, such as ischemia. The TRPV4 channel has been recently found in adult rat cortical and hippocampal astrocytes; however, its role in astrocyte pathophysiology is still not defined. In the present study, we examined the impact of cerebral hypoxia/ischemia (H/I) on the functional expression of astrocytic TRPV4 channels in the adult rat hippocampal CA1 region employing immunohistochemical analyses, the patch-clamp technique and microfluorimetric intracellular calcium imaging on astrocytes in slices as well as on those isolated from sham-operated or ischemic hippocampi. Hypoxia/ischemia was induced by a bilateral 15-minute occlusion of the common carotids combined with hypoxic conditions. Our immunohistochemical analyses revealed that 7 days after H/I, the expression of TRPV4 is markedly enhanced in hippocampal astrocytes of the CA1 region and that the increasing TRPV4 expression coincides with the development of astrogliosis. Additionally, adult hippocampal astrocytes in slices or cultured hippocampal astrocytes respond to the TRPV4 activator 4-alpha-phorbol-12,-13-didecanoate (4αPDD) by an increase in intracellular calcium and the activation of a cationic current, both of which are abolished by the removal of extracellular calcium or exposure to TRP antagonists, such as Ruthenium Red or RN1734. Following hypoxic/ischemic injury, the responses of astrocytes to 4αPDD are significantly augmented. Collectively, we show that TRPV4 channels are involved in ischemia-induced calcium entry in reactive astrocytes and thus, might participate in the pathogenic mechanisms of astroglial reactivity following ischemic insult.

• MeSH
• astrocyty fyziologie   MeSH
• DNA primery MeSH
• hipokampus patologie   patofyziologie   MeSH
• imunohistochemie MeSH
• kationtové kanály TRPV fyziologie   MeSH
• krysa rodu rattus MeSH
• metoda terčíkového zámku MeSH
• mozková hypoxie a ischemie patologie   patofyziologie   MeSH
• polymerázová řetězová reakce MeSH
• potkani Wistar MeSH
• sekvence nukleotidů MeSH
• western blotting MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• biomedicínský výzkum metody   trendy   MeSH
• bolest etiologie   farmakoterapie   chirurgie   MeSH
• elektrofyziologie metody   trendy   MeSH
• farmakoterapie metody   trendy   využití   MeSH
• financování organizované MeSH
• kapsaicin farmakokinetika   farmakologie   terapeutické užití   MeSH
• kationtové kanály TRPV farmakologie   fyziologie   terapeutické užití   MeSH
• lidé MeSH
• měření bolesti metody   trendy   využití   MeSH
• molekulární biologie metody   trendy   MeSH
• neurochirurgické výkony metody   trendy   využití   MeSH
• neurofyziologie metody   trendy   MeSH
• neurony aferentní fyziologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

The rationale for the topical application of capsaicin and other vanilloids in the treatment of pain is that such compounds selectively excite and subsequently desensitize nociceptive neurons. This desensitization is triggered by the activation of vanilloid receptors (TRPV1), which leads to an elevation in intracellular free Ca2+ levels. Depending on the vanilloid concentration and duration of exposure, the Ca2+ influx via TRPV1 desensitizes the channels themselves, which may represent not only a feedback mechanism protecting the cell from toxic Ca2+ overload, but also likely contributes to the analgesic effects of capsaicin. This review summarizes the current state of knowledge concerning the mechanisms that underlie the acute capsaicin-induced Ca2+-dependent desensitization of TRPV1 channels and explores to what extent they may contribute to capsaicin-induced analgesia. In view of the polymodal nature of TRPV1, we illustrate how the channels behave in their desensitized state when activated by other stimuli such as noxious heat or depolarizing voltages. We also show that the desensitized channel can be strongly reactivated by capsaicin at concentrations higher than those previously used to desensitize it. We provide a possible explanation for a high incidence of adverse effects of topical capsaicin and point to a need for more accurate clinical criteria for employing it as a reliable remedy.

• MeSH
• analgetika aplikace a dávkování   MeSH
• analgezie * MeSH
• aplikace lokální MeSH
• baryum metabolismus   MeSH
• bolest farmakoterapie   MeSH
• gating iontového kanálu účinky léků   MeSH
• kalmodulin metabolismus   MeSH
• kapsaicin aplikace a dávkování   MeSH
• kationtové kanály TRPV fyziologie   MeSH
• krysa rodu rattus MeSH
• lidé MeSH
• membránové potenciály fyziologie   MeSH
• molekulární modely MeSH
• vápník metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH