| 1. |
- Alenmyr, Lisa, et al.
(författare)
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Effect of Mucosal TRPV1 Inhibition in Allergic Rhinitis.
- 2012
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Ingår i: Basic & Clinical Pharmacology & Toxicology. - : Wiley. - 1742-7843 .- 1742-7835. ; 110, s. 264-268
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Tidskriftsartikel (refereegranskat)abstract
- Transient receptor potential vanilloid-1 (TRPV1) has been implicated as a mediator of itch in allergic rhinitis. To address this possibility, we synthesized a TRPV1 blocker (SB-705498) for nasal administration in patients with seasonal allergic rhinitis. The pharmacological activity of SB-705498 was confirmed on human TRPV1-expressing HEK293 cells, using fluorometric calcium imaging, and in patients with allergic rhinitis subjected to nasal capsaicin challenges. The effect of SB-705498 was studied in patients with seasonal allergic rhinitis subjected to daily allergen challenges for seven days, using a double-blind, placebo-controlled, randomized and cross-over design. SB-705498 was delivered by nasal lavage 10 min. before each allergen challenge. Primary end-point was total nasal symptom score on days 5 to 7. Nasal peak inspiratory flow and eosinophil cationic protein content in nasal lavages were also monitored. Daily topical applications of SB-705498 at a concentration that inhibited capsaicin-induced nasal symptoms had no effect on total symptom score, nasal peak inspiratory flow and eosinophil cationic protein levels in allergen-challenged patients with seasonal allergic rhinitis. The individual symptom nasal itch or sneezes was also not affected. These findings may indicate that TRPV1 is not a key mediator of the symptoms in allergic rhinitis. However, additional studies, using drug formulations with a prolonged duration of action, should be conducted before TRPV1 is ruled out as a drug target in allergic rhinitis.
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| 2. |
- Alenmyr, Lisa, et al.
(författare)
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TRPV1-mediated itch in seasonal allergic rhinitis.
- 2009
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Ingår i: Allergy. - : Wiley. - 1398-9995 .- 0105-4538. ; 64, s. 807-810
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Tidskriftsartikel (refereegranskat)abstract
- Background: Patients with allergic rhinitis may be abnormally sensitive to stimulation of the ion channel transient receptor potential vanilloid-1 (TRPV1). Aim of the study: To examine effects of various TRP ion channel activators on sensory symptoms in allergic rhinitis prior to and during seasonal allergen exposure. Methods: Nasal challenges were carried out with the TRPV1-activators capsaicin, anandamide and olvanil. Moreover, challenges were performed with mustard oil (allylisothiocyanate) and cinnamaldehyde as well as menthol, activators of TRPA1 and TRPM8, respectively. Nasal symptoms were monitored after each challenge and compared with symptoms reported following corresponding sham challenges. Symptoms recorded after challenge prior to pollen season were also compared with challenge-induced symptoms during pollen season. Results: The TRPV1, TRPA1 and TRPM8-activators produced sensory symptoms dominated by pain and smart. During seasonal allergen exposure, but not prior to season, TRPV1-activators also induced itch. Furthermore, the seasonal challenge to the TRPV1-activator olvanil was associated with rhinorrhoea. Conclusion: Patients with allergic rhinitis feature an increased itch response to TRPV1 stimulation at seasonal allergen exposure. We suggest that this reflects part of the hyperresponsiveness that characterizes on-going allergic rhinitis. Intervention with the TRPV1-signalling pathway may offer potential treatments of this condition.
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| 3. |
- Alenmyr, Lisa, et al.
(författare)
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TRPV4-mediated calcium influx and ciliary activity in human native airway epithelial cells.
- 2014
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Ingår i: Basic & Clinical Pharmacology & Toxicology. - : Wiley. - 1742-7843 .- 1742-7835. ; 114:2, s. 210-216
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Tidskriftsartikel (refereegranskat)abstract
- The transient receptor potential, vanilloid 4 (TRPV4), is a calcium permeable ion channel expressed in airway epithelial cells. Based on studies of cell lines and animals, TRPV4 has been suggested to play a role in the regulation of ciliary beat frequency (CBF). Whether the same is true for human ciliated epithelial cells is not known. Therefore, the aim was to examine the expression and function of TRPV4 in human native nasal epithelial cells. Expression of TRPV4 mRNA in nasal epithelial cells and in the cell lines BEAS2B and 16HBE was confirmed by quantitative real-time PCR. A marked apical TRPV4 immunoreactivity was observed in nasal epithelial cells using immunocytochemistry. Responses to pharmacological modulation of TRPV4 were assessed with calcium imaging and CBF measurements. The TRPV4 agonist GSK1016790A produced concentration-dependent calcium responses in TRPV4-expressing HEK293, BEAS2B and 16HBE cells, and the TRPV4 antagonist HC067047 caused a rightward shift of the GSK1016790A concentration-response curves. Nasal epithelial cells responded to the TRPV4 agonist GSK1016790A with increased intracellular calcium signals and increased CBF, followed by cessation of ciliary beating and cell death. These effects were prevented or inhibited by the TRPV4 antagonist HC067047, the TRP channel blocker ruthenium red or removal of extracellular calcium. We conclude that TRPV4 is expressed in human primary nasal epithelial cells and modulates epithelial calcium levels and CBF. Thus, TRPV4 may participate in mucociliary clearance and airway protection. However, exaggerated activation of TRPV4 may result in epithelial cell death. This article is protected by copyright. All rights reserved.
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| 4. |
- Andersson, David A., et al.
(författare)
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Effects of inhibitors of small- and intermediate-conductance calcium-activated potassium channels, inwardly-rectifying potassium channels and Na+/K+ ATPase on EDHF relaxations in the rat hepatic artery
- 2000
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Ingår i: British Journal of Pharmacology. - : Wiley. - 0007-1188. ; 129:7, s. 1490-1496
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Tidskriftsartikel (refereegranskat)abstract
- 1. In the rat hepatic artery, the SK(Ca) inhibitors UCL 1684 (300 nM) completely blocked, and scyllatoxin (1 μM) and d-tubocurarine (100 μM) partially inhibited EDHF relaxations when each of them was combined with charybdotoxin (300 nM). 2. The IK(Ca) inhibitors clotrimazole (3 μM) and 2-chlorophenyl-bisphenyl-methanol (3 μM) strongly depressed EDHF relaxations when each of them was combined with apamin (300 nM). The cytochrome P450 mono-oxygenase inhibitor ketoconazole (10 μM) had no effect in the presence of apamin. 3. Ciclazindol (10 μM), which abolishes EDHF relaxations in the presence of apamin, almost completely prevented the calcium ionophore (A23187) stimulated 86Rb+ influx via the Gardos channel (IK(Ca)) in human erythrocytes. 4. The Na(+/)K+ ATPase inhibitor ouabain (500 μM) and the K(IR) blocker Ba2+ (30 μM) neither alone nor in combination inhibited EDHF relaxations. Ba2+ was also without effect in the presence of either apamin or charybdotoxin. 5. In contrast to EDHF, an increase in extracellular [K+] from 4.6 mM to 9.6, 14.6 and 19.6 mM inconsistently relaxed arteries. In K+-free physiological salt solution, re-admission of K+ always caused complete and sustained relaxations which were abolished by ouabain but unaffected by Ba2+. 6. The present study provides pharmacological evidence for the involvement of SK(Ca) and IK(Ca) in the action of EDHF in the rat hepatic artery. Our results are not consistent with the idea that EDHF is K+ activating Na+/K+ ATPase and K(IR) in this blood vessel.
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| 5. |
- Andersson, David A., et al.
(författare)
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TRPA1 mediates spinal antinociception induced by acetaminophen and the cannabinoid Delta(9)-tetrahydrocannabiorcol
- 2011
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 2
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Tidskriftsartikel (refereegranskat)abstract
- TRPA1 is a unique sensor of noxious stimuli and, hence, a potential drug target for analgesics. Here we show that the antinociceptive effects of spinal and systemic administration of acetaminophen (paracetamol) are lost in Trpa1(-/-) mice. The electrophilic metabolites N-acetyl-p-benzoquinoneimine and p-benzoquinone, but not acetaminophen itself, activate mouse and human TRPA1. These metabolites also activate native TRPA1 and, as a consequence, reduce voltage-gated calcium and sodium currents in primary sensory neurons. The N-acetyl-p-benzoquinoneimine metabolite l-cysteinyl-S-acetaminophen was detected in the mouse spinal cord after systemic acetaminophen administration. In the hot-plate test, intrathecal administration of N-acetyl-p-benzoquinoneimine, p-benzoquinone and the electrophilic TRPA1 activator cinnamaldehyde produced antinociception that was lost in Trpa1(-/-) mice. Intrathecal injection of a non-electrophilic cannabinoid, Delta(9)-tetrahydrocannabiorcol, also produced TRPA1-dependent antinociception in this test. Our study provides a molecular mechanism for the antinociceptive effect of acetaminophen and discloses spinal TRPA1 activation as a potential pharmacological strategy to alleviate pain.
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| 6. |
- Andersson, David, et al.
(författare)
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Mechanisms underlying tissue selectivity of anandamide and other vanilloid receptor agonists.
- 2002
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Ingår i: Molecular Pharmacology. - 1521-0111. ; 62:3, s. 705-713
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Tidskriftsartikel (refereegranskat)abstract
- Anandamide acts as a full vanilloid receptor agonist in many bioassay systems, but it is a weak activator of primary afferents in the airways. To address this discrepancy, we compared the effect of different vanilloid receptor agonists in isolated airways and mesenteric arteries of guinea pig using preparations containing different phenotypes of the capsaicin-sensitive sensory nerve. We found that anandamide is a powerful vasodilator of mesenteric arteries but a weak constrictor of main bronchi. These effects of anandamide are mediated by vanilloid receptors on primary afferents and do not involve cannabinoid receptors. Anandamide also contracts isolated lung strips, an effect caused by the hydrolysis of anandamide and subsequent formation of cyclooxygenase products. Although capsaicin is equally potent in bronchi and mesenteric arteries, anandamide, resiniferatoxin, and particularly olvanil are significantly less potent in bronchi. Competition experiments with the vanilloid receptor antagonist capsazepine did not provide evidence of vanilloid receptor heterogeneity. Arachidonoyl-5-methoxytryptamine (VDM13), an inhibitor of the anandamide membrane transporter, attenuates responses to olvanil and anandamide, but not capsaicin and resiniferatoxin, in mesenteric arteries. VDM13 did not affect responses to these agonists in bronchi, suggesting that the anandamide membrane transporter is absent in this phenotype of the sensory nerve. Computer simulations using an operational model of agonism were consistent, with differences in intrinsic efficacy and receptor content being responsible for the remaining differences in agonist potency between the tissues. This study describes differences between vanilloid receptor agonists regarding tissue selectivity and provides a conceptual framework for developing tissue-selective vanilloid receptor agonists devoid of bronchoconstrictor activity.
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| 7. |
- Andres Correa, Edwin, et al.
(författare)
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In vitro TRPV1 activity of piperine derived amides
- 2010
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Ingår i: Bioorganic & Medicinal Chemistry. - : Elsevier BV. - 0968-0896. ; 18:9, s. 3299-3306
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Tidskriftsartikel (refereegranskat)abstract
- A series of natural and synthetic piperine amides were evaluated for activity on the human TRPV1 expressed in HEK293 cells. The agonistic effect of piperine amides was mainly dependent on the length of the carbon chain. Structural changes of double bonds and stereochemistry in the aliphatic chain of these compounds did not change their potency or efficacy, indicating that increased rigidity or planarity of the piperine structure does not affect the activity. The opening of the methylenedioxy ring or changes in the heterocyclic ring of the piperine molecule reduced or abolished activity. Furthermore, inactive compounds did not display functional antagonistic activity. (C) 2010 Elsevier Ltd. All rights reserved.
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| 8. |
- Axelsson, H E, et al.
(författare)
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Transient receptor potential vanilloid 1, vanilloid 2 and melastatin 8 immunoreactive nerve fibers in human skin from individuals with and without Norrbottnian congenital insensitivity to pain.
- 2009
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Ingår i: Neuroscience. - : Elsevier BV. - 1873-7544 .- 0306-4522. ; 162, s. 1322-1332
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Tidskriftsartikel (refereegranskat)abstract
- Transient receptor potential vanilloid 1 (TRPV1), vanilloid 2 (TRPV2) and melastatin 8 (TRPM8) are thermosensitive cation channels expressed on primary sensory neurons. In contrast to TRPV1, which is present on nociceptive primary afferents and keratinocytes in human skin, less is known about the distribution of TRPV2 and TRPM8 in this tissue. Immunohistochemistry of human forearm skin identified TRPV2 and TRPM8 immunoreactive nerve fibers in epidermis-papillary dermis and around blood vessels and hair follicles in dermis, although these nerve fibers were less abundant than TRPV1 immunoreactive nerve fibers throughout the skin. The TRPV2 and TRPM8 immunoreactive nerve fibers also showed immunoreactivity for calcitonin gene-related peptide (CGRP) and to a lesser extent substance P (SP). Neither of the TRP ion channels co-localized with neurofilament 200 kDa (NF200), vasoactive intestinal peptide (VIP) or tyrosine hydroxylase (TH). Nerve fibers immunoreactive for TRPV1, TRPV2, TRPM8, CGRP and SP were absent or substantially reduced in number in individuals with Norrbottnian congenital insensitivity to pain, an autosomal disease selectively affecting the development of C-fiber and Adelta-fiber primary afferents. Quantitative real time PCR detected mRNA transcripts encoding TRPV1 and TRPV2, but not TRPM8, in skin from healthy volunteers, suggesting that these ion channels are also expressed extraneuronally. In conclusion, nerve fibers in human skin express TRPV1, TRPV2 and TRPM8 that co-localize with the sensory neuropeptides CGRP and SP, but not with NF200, VIP or TH. A dramatic loss of such nerve fibers was seen in skin from individuals with Norrbottnian congenital insensitivity to pain, further suggesting that these ion channels are expressed primarily on nociceptive primary sensory neurons in human skin.
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| 9. |
- Barriere, David A., et al.
(författare)
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Fatty Acid Amide Hydrolase-Dependent Generation of Antinociceptive Drug Metabolites Acting on TRPV1 in the Brain
- 2013
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:8
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Tidskriftsartikel (refereegranskat)abstract
- The discovery that paracetamol is metabolized to the potent TRPV1 activator N-(4-hydroxyphenyl)-5Z, 8Z, 11Z, 14Z-eicosatetraenamide (AM404) and that this metabolite contributes to paracetamol's antinociceptive effect in rodents via activation of TRPV1 in the central nervous system (CNS) has provided a potential strategy for developing novel analgesics. Here we validated this strategy by examining the metabolism and antinociceptive activity of the de-acetylated paracetamol metabolite 4-aminophenol and 4-hydroxy-3-methoxybenzylamine (HMBA), both of which may undergo a fatty acid amide hydrolase (FAAH)-dependent biotransformation to potent TRPV1 activators in the brain. Systemic administration of 4-aminophenol and HMBA led to a dose-dependent formation of AM404 plus N-(4-hydroxyphenyl)-9Z-octadecenamide (HPODA) and arvanil plus olvanil in the mouse brain, respectively. The order of potency of these lipid metabolites as TRPV1 activators was arvanil = olvanil >> AM404. HPODA. Both 4-aminophenol and HMBA displayed antinociceptive activity in various rodent pain tests. The formation of AM404, arvanil and olvanil, but not HPODA, and the antinociceptive effects of 4-aminophenol and HMBA were substantially reduced or disappeared in FAAH null mice. The activity of 4-aminophenol in the mouse formalin, von Frey and tail immersion tests was also lost in TRPV1 null mice. Intracerebroventricular injection of the TRPV1 blocker capsazepine eliminated the antinociceptive effects of 4-aminophenol and HMBA in the mouse formalin test. In the rat, pharmacological inhibition of FAAH, TRPV1, cannabinoid CB1 receptors and spinal 5-HT3 or 5-HT1A receptors, and chemical deletion of bulbospinal serotonergic pathways prevented the antinociceptive action of 4-aminophenol. Thus, the pharmacological profile of 4-aminophenol was identical to that previously reported for paracetamol, supporting our suggestion that this drug metabolite contributes to paracetamol's analgesic activity via activation of bulbospinal pathways. Our findings demonstrate that it is possible to construct novel antinociceptive drugs based on fatty acid conjugation as a metabolic pathway for the generation of TRPV1 modulators in the CNS.
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| 10. |
- Bautista, D M, et al.
(författare)
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Pungent products from garlic activate the sensory ion channel TRPA1
- 2005
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Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 102:34, s. 12248-12252
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Tidskriftsartikel (refereegranskat)abstract
- Garlic belongs to the Allium family of plants that produce organosulfur compounds, such as allicin and diallyl disulfide (DADS), which account for their pungency and spicy aroma. Many health benefits have been ascribed to Allium extracts, including hypotensive and vasorelaxant activities. However, the molecular mechanisms underlying these effects remain unknown. Intriguingly, allicin and DADS share structural similarities with allyl isothiocyanate, the pungent ingredient in wasabi and other mustard plants that induces pain and inflammation by activating TRPA1, an excitatory ion channel on primary sensory neurons of the pain pathway. Here we show that allicin and DADS excite an allyl isothiocyanate-sensitive subpopulation of sensory neurons and induce vasodilation by activating capsaicin-sensitive perivascular sensory nerve endings. Moreover, allicin and DADS activate the cloned TRPA1 channel when expressed in heterologous systems. These and other results suggest that garlic excites sensory neurons primarily through activation of TRPA1. Thus different plant genera, including Allium and Brassica, have developed evolutionary convergent strategies that target TRPA1 channels on sensory nerve endings to achieve chemical deterrence.
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