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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
PubMed

Insights

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 ligationTRPA1

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