Inhibition of fatty acid binding proteins elevates brain anandamide levels and produces analgesia.
The endocannabinoid anandamide (AEA) is an antinociceptive lipid that is inactivated through cellular uptake and subsequent catabolism by fatty acid amide hydrolase (FAAH). Fatty acid binding proteins (FABPs) are intracellular carriers that deliver AEA and related N-acylethanolamines (NAEs) to FAAH...
| Main Authors: | , , , , , , , , , , , |
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| Formato: | Artigo |
| Idioma: | English |
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Public Library of Science (PLoS)
2014-01-01
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| Series: | PLoS ONE |
| Acceso en liña: | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0094200&type=printable |
| _version_ | 1826799252302462976 |
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| author | Martin Kaczocha Mario J Rebecchi Brian P Ralph Yu-Han Gary Teng William T Berger William Galbavy Matthew W Elmes Sherrye T Glaser Liqun Wang Robert C Rizzo Dale G Deutsch Iwao Ojima |
| author_facet | Martin Kaczocha Mario J Rebecchi Brian P Ralph Yu-Han Gary Teng William T Berger William Galbavy Matthew W Elmes Sherrye T Glaser Liqun Wang Robert C Rizzo Dale G Deutsch Iwao Ojima |
| author_sort | Martin Kaczocha |
| collection | DOAJ |
| description | The endocannabinoid anandamide (AEA) is an antinociceptive lipid that is inactivated through cellular uptake and subsequent catabolism by fatty acid amide hydrolase (FAAH). Fatty acid binding proteins (FABPs) are intracellular carriers that deliver AEA and related N-acylethanolamines (NAEs) to FAAH for hydrolysis. The mammalian brain expresses three FABP subtypes: FABP3, FABP5, and FABP7. Recent work from our group has revealed that pharmacological inhibition of FABPs reduces inflammatory pain in mice. The goal of the current work was to explore the effects of FABP inhibition upon nociception in diverse models of pain. We developed inhibitors with differential affinities for FABPs to elucidate the subtype(s) that contributes to the antinociceptive effects of FABP inhibitors. Inhibition of FABPs reduced nociception associated with inflammatory, visceral, and neuropathic pain. The antinociceptive effects of FABP inhibitors mirrored their affinities for FABP5, while binding to FABP3 and FABP7 was not a predictor of in vivo efficacy. The antinociceptive effects of FABP inhibitors were mediated by cannabinoid receptor 1 (CB1) and peroxisome proliferator-activated receptor alpha (PPARα) and FABP inhibition elevated brain levels of AEA, providing the first direct evidence that FABPs regulate brain endocannabinoid tone. These results highlight FABPs as novel targets for the development of analgesic and anti-inflammatory therapeutics. |
| first_indexed | 2024-12-20T20:30:52Z |
| format | Article |
| id | doaj.art-10794bacf1f74e80bc4ed21b0f3987e1 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2025-03-17T00:32:08Z |
| publishDate | 2014-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-10794bacf1f74e80bc4ed21b0f3987e12025-02-21T05:34:53ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-0194e9420010.1371/journal.pone.0094200Inhibition of fatty acid binding proteins elevates brain anandamide levels and produces analgesia.Martin KaczochaMario J RebecchiBrian P RalphYu-Han Gary TengWilliam T BergerWilliam GalbavyMatthew W ElmesSherrye T GlaserLiqun WangRobert C RizzoDale G DeutschIwao OjimaThe endocannabinoid anandamide (AEA) is an antinociceptive lipid that is inactivated through cellular uptake and subsequent catabolism by fatty acid amide hydrolase (FAAH). Fatty acid binding proteins (FABPs) are intracellular carriers that deliver AEA and related N-acylethanolamines (NAEs) to FAAH for hydrolysis. The mammalian brain expresses three FABP subtypes: FABP3, FABP5, and FABP7. Recent work from our group has revealed that pharmacological inhibition of FABPs reduces inflammatory pain in mice. The goal of the current work was to explore the effects of FABP inhibition upon nociception in diverse models of pain. We developed inhibitors with differential affinities for FABPs to elucidate the subtype(s) that contributes to the antinociceptive effects of FABP inhibitors. Inhibition of FABPs reduced nociception associated with inflammatory, visceral, and neuropathic pain. The antinociceptive effects of FABP inhibitors mirrored their affinities for FABP5, while binding to FABP3 and FABP7 was not a predictor of in vivo efficacy. The antinociceptive effects of FABP inhibitors were mediated by cannabinoid receptor 1 (CB1) and peroxisome proliferator-activated receptor alpha (PPARα) and FABP inhibition elevated brain levels of AEA, providing the first direct evidence that FABPs regulate brain endocannabinoid tone. These results highlight FABPs as novel targets for the development of analgesic and anti-inflammatory therapeutics.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0094200&type=printable |
| spellingShingle | Martin Kaczocha Mario J Rebecchi Brian P Ralph Yu-Han Gary Teng William T Berger William Galbavy Matthew W Elmes Sherrye T Glaser Liqun Wang Robert C Rizzo Dale G Deutsch Iwao Ojima Inhibition of fatty acid binding proteins elevates brain anandamide levels and produces analgesia. PLoS ONE |
| title | Inhibition of fatty acid binding proteins elevates brain anandamide levels and produces analgesia. |
| title_full | Inhibition of fatty acid binding proteins elevates brain anandamide levels and produces analgesia. |
| title_fullStr | Inhibition of fatty acid binding proteins elevates brain anandamide levels and produces analgesia. |
| title_full_unstemmed | Inhibition of fatty acid binding proteins elevates brain anandamide levels and produces analgesia. |
| title_short | Inhibition of fatty acid binding proteins elevates brain anandamide levels and produces analgesia. |
| title_sort | inhibition of fatty acid binding proteins elevates brain anandamide levels and produces analgesia |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0094200&type=printable |
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