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...
| Main Authors: | , , , , |
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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 |
| _version_ | 1811311990956621824 |
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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> |
| first_indexed | 2024-04-13T10:28:30Z |
| format | Article |
| 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 |
| publisher | SAGE Publishing |
| record_format | Article |
| 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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