Abstract:
BACKGROUND AND PURPOSE:Retinoids, through their activation of retinoic acid receptors (RARs) and retinoid X receptors, regulate diverse cellular processes, and pharmacological intervention in their actions has been successful in the treatment of skin disorders and cancers. Despite the many beneficial effects, administration of retinoids causes irritating side effects with unknown mechanisms. Here, we demonstrate that LE135 [4-(7,8,9,10-tetrahydro-5,7,7,10,10-pentamethyl-5H-benzo[e]naphtho[2,3-b][1,4]diazepin-13-yl)benzoic acid], a selective antagonist of RARβ , is a potent activator of the capsaicin (TRPV1) and wasabi (TRPA1) receptors, two critical pain-initiating cation channels. EXPERIMENTAL APPROACH:We performed to investigate the excitatory effects of LE135 on TRPV1 and TRPA1 channels expressed in HEK293T cells and in dorsal root ganglia neurons with calcium imaging and patch-clamp recordings. We also used site-directed mutagenesis of the channels to determine the structural basis of LE135-induced activation of TRPV1 and TRPA1 channels and behavioural testing to examine if pharmacological inhibition and genetic deletion of the channels affected LE135-evoked pain-related behaviours. KEY RESULTS:LE135 activated both the capsaicin receptor (TRPV1) and the allyl isothiocyanate receptor (TRPA1) heterologously expressed in HEK293T cells and endogenously expressed by sensory nociceptors. Mutations disrupting the capsaicin-binding site attenuated LE135 activation of TRPV1 channels and a single mutation (K170R) eliminated TRPA1 activity evoked by LE135. Intraplantar injection of LE135 evoked pain-related behaviours. Both TRPV1 and TRPA1 channels were involved in LE135-elicited pain-related responses, as shown by pharmacological and genetic ablation studies. CONCLUSIONS AND IMPLICATIONS:This blocker of retinoid acid signalling also exerted non-genomic effects through activating the pain-initiating TRPV1 and TRPA1 channels.
journal_name
Br J Pharmacoljournal_title
British journal of pharmacologyauthors
Yin S,Luo J,Qian A,Yu W,Hu Hdoi
10.1111/bph.12543subject
Has Abstractpub_date
2014-03-01 00:00:00pages
1510-20issue
6eissn
0007-1188issn
1476-5381journal_volume
171pub_type
杂志文章abstract:BACKGROUND AND PURPOSE:Fatty acid amide hydrolase inhibitors show promise as a treatment for anxiety, depression and pain. Here we investigated whether perinatal exposure to URB597, a fatty acid amide hydrolase inhibitor, alters brain development and affects behaviour in adult mice. EXPERIMENTAL APPROACH:Mouse dams we...
journal_title:British journal of pharmacology
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doi:10.1111/bph.12500
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abstract::1. Chronic administration of the benzodiazepine inverse agonist FG 7142 has previously been shown to induce seizure activity in mice. In the present study we have investigated the effects of acute and chronic treatment with FG 7142 in mice on the levels of acetylcholinesterase activity in cortex, hippocampus, midbrain...
journal_title:British journal of pharmacology
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doi:10.1111/j.1476-5381.1990.tb14127.x
更新日期:1990-11-01 00:00:00
abstract::1 The effects of electrical stimulation, changes in external ion concentrations and various drugs on acetylcholine release from the myenteric plexus were measured by bioassay in the presence of physostigmine and by recording the responses of the longitudinal muscle. In preparations from the guinea-pig, the acetylcholi...
journal_title:British journal of pharmacology
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doi:10.1111/j.1476-5381.1978.tb17319.x
更新日期:1978-12-01 00:00:00
abstract:BACKGROUND AND PURPOSE:We recently reported that AAV1-Rheb(S16H) transduction could protect hippocampal neurons through the induction of brain-derived neurotrophic factor (BDNF) in the rat hippocampus in vivo. It is still unclear how neuronal BDNF produced by AAV1-Rheb(S16H) transduction induces neuroprotective effects...
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journal_title:British journal of pharmacology
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doi:10.1111/j.1476-5381.1987.tb08983.x
更新日期:1987-05-01 00:00:00
abstract::The Wnt/β-catenin signalling pathway is pivotal for stem cell function and the control of cellular differentiation, both during embryonic development and tissue homeostasis in adults. Its activity is carefully controlled through the concerted interactions of concentration-limited pathway components and a wide range of...
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journal_title:British journal of pharmacology
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doi:10.1111/j.1476-5381.1988.tb11405.x
更新日期:1988-01-01 00:00:00
abstract:LINKED ARTICLES:This article is part of a themed section on Recent Progress in the Understanding of Relaxin Family Peptides and their Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.10/issuetoc. ...
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pub_type: 社论
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journal_title:British journal of pharmacology
pub_type: 杂志文章
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更新日期:1983-10-01 00:00:00
abstract::1. The effects of an intrathecally administered benzodiazepine receptor (BZR) agonist (midazolam, up to 50 micrograms), antagonist (flumazenil, Ro 15-1788, 5 micrograms) and inverse agonist (Ro 19-4603, 15 micrograms) on nociception and on morphine-induced antinociception were studied in rats. 2. By themselves, none o...
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abstract::1. The present study was undertaken to determine the mechanism of action of endothelin-1 (ET-1)-induced contraction of the guinea-pig isolated trachea. 2. ET-1 (1 nM-0.3 microM) produces a concentration-dependent contraction of guinea-pig trachea with an EC50 of approximately 25 nM. The combination of the peptidoleuko...
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pub_type: 杂志文章
doi:10.1111/j.1476-5381.1993.tb13906.x
更新日期:1993-11-01 00:00:00
abstract:BACKGROUND AND PURPOSE:Oxaliplatin is a platinum-based chemotherapeutic drug used as a first-line therapy for colorectal cancer. However, its use is associated with severe gastrointestinal side-effects resulting in dose limitations and/or cessation of treatment. In this study, we tested whether oxidative stress, caused...
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更新日期:2016-12-01 00:00:00
abstract::1. Measurements were made of the uptake, metabolism and release of [(3)H]-adrenaline by human platelets in citrated plasma or in an artificial medium.2. Radioactive adrenaline was not taken up at 0-2 degrees C. At 37 degrees C there was a slow uptake which continued for at least 5 hours.3. About half of the radioactiv...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1970.tb09903.x
更新日期:1970-08-01 00:00:00
abstract:BACKGROUND AND PURPOSE:An innovative chemical approach, named peptide welding technology (PWT), allows the synthesis of multibranched peptides with extraordinary high yield, purity and reproducibility. With this approach, three different tetrabranched derivatives of nociceptin/orphanin FQ (N/OFQ) have been synthesized ...
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更新日期:2014-09-01 00:00:00
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doi:10.1038/sj.bjp.0702389
更新日期:1999-02-01 00:00:00
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journal_title:British journal of pharmacology
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doi:10.1111/j.1476-5381.2011.01211.x
更新日期:2011-06-01 00:00:00
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journal_title:British journal of pharmacology
pub_type: 杂志文章
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更新日期:2021-01-21 00:00:00
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更新日期:2001-01-01 00:00:00
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更新日期:1978-07-01 00:00:00
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journal_title:British journal of pharmacology
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更新日期:2006-12-01 00:00:00
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更新日期:1995-05-01 00:00:00
abstract::1 Administration of isoprenaline by aerosol inhalation to man results in over 80% being metabolized to the sulphate conjugate.2 The majority of an inhaled dose is probably swallowed since the metabolic pattern resembles that after an oral dose.3 Isoprenaline, administered in aqueous solution directly into the bronchia...
journal_title:British journal of pharmacology
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doi:10.1111/j.1476-5381.1974.tb08593.x
更新日期:1974-04-01 00:00:00
abstract::1. Extracellular recording of the stimulus-evoked population spike in the CA1 region of rat hippocampal slices in vitro was performed in order to investigate whether lappaconitine affects neuronal excitability. Lappaconitine is a diterpene alkaloid of plants of the Aconitum genus and has analgesic properties. 2. The r...
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doi:10.1111/j.1476-5381.1996.tb15440.x
更新日期:1996-06-01 00:00:00
abstract::The effect of adenosine on transepithelial ion transport was investigated in isolated preparations of murine trachea mounted in Ussing chambers. The possible regulation of adenosine receptors in an established model of allergic airway inflammation was also investigated. Mucosally applied adenosine caused increases in ...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0706133
更新日期:2005-04-01 00:00:00
abstract:BACKGROUND AND PURPOSE:We investigated whether or not kinin receptors play a role in diabetic blood-retinal barrier breakdown, which is a leading cause of vision loss. EXPERIMENTAL APPROACH:Blood-retinal barrier breakdown was quantified using Evans blue, and expression of kinin B(1) receptor mRNA was measured using qu...
journal_title:British journal of pharmacology
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doi:10.1038/bjp.2008.48
更新日期:2008-05-01 00:00:00
abstract:LINKED ARTICLES:This article is part of a themed section on Recent Developments in Research of Melatonin and its Potential Therapeutic Applications. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.16/issuetoc. ...
journal_title:British journal of pharmacology
pub_type: 社论
doi:10.1111/bph.14371
更新日期:2018-08-01 00:00:00