Functional characterization and analgesic effects of mixed cannabinoid receptor/T-type channel ligands
<p>Abstract</p> <p>Background</p> <p>Both T-type calcium channels and cannabinoid receptors modulate signalling in the primary afferent pain pathway. Here, we investigate the analgesics activities of a series of novel cannabinoid receptor ligands with T-type calcium cha...
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Format: | Article |
Language: | English |
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SAGE Publishing
2011-11-01
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Series: | Molecular Pain |
Online Access: | http://www.molecularpain.com/content/7/1/89 |
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author | You Haitao Gadotti Vinicius M Petrov Ravil R Zamponi Gerald W Diaz Philippe |
author_facet | You Haitao Gadotti Vinicius M Petrov Ravil R Zamponi Gerald W Diaz Philippe |
author_sort | You Haitao |
collection | DOAJ |
description | <p>Abstract</p> <p>Background</p> <p>Both T-type calcium channels and cannabinoid receptors modulate signalling in the primary afferent pain pathway. Here, we investigate the analgesics activities of a series of novel cannabinoid receptor ligands with T-type calcium channel blocking activity.</p> <p>Results</p> <p>Novel compounds were characterized in radioligand binding assays and <it>in vitro </it>functional assays at human and rat CB1 and CB2 receptors. The inhibitory effects of these compounds on transient expressed human T-type calcium channels were examined in tsA-201 cells using standard whole-cell voltage clamp techniques, and their analgesic effects in response to various administration routes (intrathecally, intraplantarly, intraperitoneally) assessed in the formalin model. A series of compounds were synthesized and evaluated for channel and receptor activity. Compound NMP-7 acted as non-selective CB1/CB2 agonist while NMP4 was found to be a CB1 partial agonist and CB2 inverse agonist. Furthermore, NMP-144 behaved as a selective CB2 inverse agonist. All of these three compounds completely inhibited peak Cav3.2 currents with IC<sub>50 </sub>values in the low micromolar range. All compounds mediated analgesic effects in the formalin model, but depending on the route of administration, could differentially affect phase 1 and phase 2 of the formalin response.</p> <p>Conclusions</p> <p>Our results reveal that a set of novel cannabinioid receptor ligands potently inhibit T-type calcium channels and show analgesic effects <it>in vivo</it>. Our findings suggest possible novel means of mediating pain relief through mixed T-type/cannabinoid receptor ligands.</p> |
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id | doaj.art-921e30c49c934c36bf71025b69c1fe7a |
institution | Directory Open Access Journal |
issn | 1744-8069 |
language | English |
last_indexed | 2024-04-13T10:28:30Z |
publishDate | 2011-11-01 |
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series | Molecular Pain |
spelling | doaj.art-921e30c49c934c36bf71025b69c1fe7a2022-12-22T02:50:14ZengSAGE PublishingMolecular Pain1744-80692011-11-01718910.1186/1744-8069-7-89Functional characterization and analgesic effects of mixed cannabinoid receptor/T-type channel ligandsYou HaitaoGadotti Vinicius MPetrov Ravil RZamponi Gerald WDiaz Philippe<p>Abstract</p> <p>Background</p> <p>Both T-type calcium channels and cannabinoid receptors modulate signalling in the primary afferent pain pathway. Here, we investigate the analgesics activities of a series of novel cannabinoid receptor ligands with T-type calcium channel blocking activity.</p> <p>Results</p> <p>Novel compounds were characterized in radioligand binding assays and <it>in vitro </it>functional assays at human and rat CB1 and CB2 receptors. The inhibitory effects of these compounds on transient expressed human T-type calcium channels were examined in tsA-201 cells using standard whole-cell voltage clamp techniques, and their analgesic effects in response to various administration routes (intrathecally, intraplantarly, intraperitoneally) assessed in the formalin model. A series of compounds were synthesized and evaluated for channel and receptor activity. Compound NMP-7 acted as non-selective CB1/CB2 agonist while NMP4 was found to be a CB1 partial agonist and CB2 inverse agonist. Furthermore, NMP-144 behaved as a selective CB2 inverse agonist. All of these three compounds completely inhibited peak Cav3.2 currents with IC<sub>50 </sub>values in the low micromolar range. All compounds mediated analgesic effects in the formalin model, but depending on the route of administration, could differentially affect phase 1 and phase 2 of the formalin response.</p> <p>Conclusions</p> <p>Our results reveal that a set of novel cannabinioid receptor ligands potently inhibit T-type calcium channels and show analgesic effects <it>in vivo</it>. Our findings suggest possible novel means of mediating pain relief through mixed T-type/cannabinoid receptor ligands.</p>http://www.molecularpain.com/content/7/1/89 |
spellingShingle | You Haitao Gadotti Vinicius M Petrov Ravil R Zamponi Gerald W Diaz Philippe Functional characterization and analgesic effects of mixed cannabinoid receptor/T-type channel ligands Molecular Pain |
title | Functional characterization and analgesic effects of mixed cannabinoid receptor/T-type channel ligands |
title_full | Functional characterization and analgesic effects of mixed cannabinoid receptor/T-type channel ligands |
title_fullStr | Functional characterization and analgesic effects of mixed cannabinoid receptor/T-type channel ligands |
title_full_unstemmed | Functional characterization and analgesic effects of mixed cannabinoid receptor/T-type channel ligands |
title_short | Functional characterization and analgesic effects of mixed cannabinoid receptor/T-type channel ligands |
title_sort | functional characterization and analgesic effects of mixed cannabinoid receptor t type channel ligands |
url | http://www.molecularpain.com/content/7/1/89 |
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