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CYP1B1-derived epoxides modulate the TRPA1 channel in chronic pain
Lili Sun1, Jie Zhang2, Changshan Niu3
1Department of Pharmacology and Toxicology, Center for Human Toxicology, University of Utah, Salt Lake City, UT 84112, USA.
Acta Pharmaceutica Sinica. B
|February 23, 2023
Summary
Researchers identified a new pathway involving CYP1B1, oxylipins like 8,9-EET, and TRPA1 channels that contributes to chronic pain. Targeting this axis may offer novel pain relief strategies.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Chronic pain is a significant health issue with limited effective treatments.
- Transient receptor potential (TRP) ion channels are potential targets for pain management.
- Endogenous ligands regulating TRP channels in pain and inflammation are not well understood.
Purpose of the Study:
- To investigate the role of CYP1B1 and its lipid products in chronic pain.
- To identify endogenous ligands that activate TRP channels involved in pain signaling.
- To explore the therapeutic potential of targeting the CYP1B1-oxylipin-TRPA1 axis.
Main Methods:
- Transcriptomic and lipidomic analysis of a mouse spinal nerve ligation (SNL) pain model.
- In vitro confirmation of 8,9-epoxyeicosatrienoic acid (EET) and 19,20-EpDPA production by CYP1B1.
- Functional assays using HEK-293 cells and cultured mouse neurons to assess TRPA1 channel activity.
- Pharmacological inhibition of TRPA1 and genetic knockout of Cyp1b1 in mice.
Main Results:
- SNL injury increased Cyp1b1 mRNA and led to accumulation of 8,9-EET and 19,20-EpDPA.
- These oxylipins activated and sensitized the TRPA1 channel in a dose-dependent manner.
- Cyp1b1-knockout mice showed reduced chronic pain, and 19,20-EpDPA induced mechanical hypersensitivity blocked by TRPA1 inhibition.
Conclusions:
- The CYP1B1-oxylipin-TRPA1 pathway is implicated in the development of chronic pain.
- 8,9-EET and 19,20-EpDPA are endogenous TRPA1 agonists relevant to pain.
- Targeting the CYP1B1-oxylipin-TRPA1 axis presents a promising therapeutic strategy for pain management.
Keywords:
CYP1B1Calcium imagingChronic painEpoxidesHyperalgesiaInflammationSpinal nerve ligationTRPA1More Related Videos
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