FABP5 deletion in nociceptors augments endocannabinoid signaling and suppresses TRPV1 sensitization and inflammatory pain.
FABP5 deletion in nociceptors augments endocannabinoid signaling and suppresses TRPV1 sensitization and inflammatory pain.
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DOI：
10.1038/s41598-022-13284-0
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发表时间：
2022-06-02
影响因子：
4.6
通讯作者：
Kaczocha, Martin
中科院分区：
文献类型：
--
作者：
Bogdan, Diane M.;Studholme, Keith;DiBua, Adriana;Gordon, Chris;Kanjiya, Martha P.;Yu, Mei;Puopolo, Michelino;Kaczocha, Martin
The endocannabinoid anandamide (AEA) produces antinociceptive effects by activating cannabinoid receptor 1 (CB1). However, AEA also serves as an agonist at transient receptor potential vanilloid receptor 1 (TRPV1) in nociceptive sensory neurons, which may exacerbate pain. This potential functional duality is highlighted by the failure of an inhibitor of the AEA catabolic enzyme fatty acid amide hydrolase (FAAH) to afford pain relief in a clinical trial. Consequently, it remains to be determined whether elevating AEA levels in nociceptors leads to antinociceptive or pro-nociceptive effects. Fatty acid binding protein 5 (FABP5) is an intracellular carrier that mediates AEA transport to FAAH for inactivation. Leveraging the abundant expression of FABP5 in TRPV1+ nociceptors, we employed a conditional knockout strategy to demonstrate that FABP5 deletion in nociceptors augments AEA levels, resulting in the emergence of antinociceptive effects mediated by CB1. Mechanistically, FABP5 deletion suppresses inflammation- and nerve growth factor-mediated TRPV1 sensitization via CB1, an effect mediated by calcineurin. Unexpectedly, inhibition of FAAH failed to blunt TRPV1 sensitization, uncovering functionally distinct outputs resulting from FABP5 and FAAH inhibition. Collectively, our results demonstrate that FABP5 serves a key role in governing endocannabinoid signaling in nociceptors to disrupt TRPV1 sensitization and pain, and position FABP5 as a therapeutic target for the development of analgesics.
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影响因子：
16.2
作者：
Cao E;Cordero-Morales JF;Liu B;Qin F;Julius D
通讯作者：
Julius D
影响因子：
2.9
作者：
Engel, Matthias A.;Izydorczyk, Iwona;Reeh, Peter W.
通讯作者：
Reeh, Peter W.
影响因子：
3.3
作者：
Kaczocha M;Glaser ST;Maher T;Clavin B;Hamilton J;O'Rourke J;Rebecchi M;Puopolo M;Owada Y;Thanos PK
通讯作者：
Thanos PK
DOI：
10.1523/jneurosci.4991-12.2013
发表时间：
2013-05-22
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Btesh J;Fischer MJM;Stott K;McNaughton PA
通讯作者：
McNaughton PA
影响因子：
7.4
作者：
Huggins, John P.;Smart, Trevor S.;Young, Tim
通讯作者：
Young, Tim