Cannabinoid receptor GPR18 activation relieved bladder pain and overactivity in rats

What the researchers found

Intrathecal injection of Resolvin D2 (a GPR18 agonist) increased paw withdrawal threshold and micturition interval in rats with cyclophosphamide-induced cystitis. The GPR18 antagonist O-1918 blocked these effects. GPR18 colocalized with TRPV1 in dorsal root ganglia, and RvD2 decreased capsaicin-induced calcium influx.

Why it matters

Interstitial cystitis/bladder pain syndrome affects millions and has limited treatment options. Identifying GPR18 as a therapeutic target through the endocannabinoid system opens a new pathway for pain and bladder dysfunction management.

The numbers in context

GPR18 mRNA and protein expression reduced in bladder and DRG of cystitis rats; RvD2 increased paw withdrawal threshold and micturition interval; O-1918 blocked therapeutic effects

How the study worked

Researchers induced cystitis in rats using cyclophosphamide, then administered intrathecal Resolvin D2 (GPR18 agonist) and O-1918 (GPR18 antagonist). Pain was assessed via paw withdrawal threshold, bladder function via cystometry, and molecular mechanisms via RT-PCR, Western blotting, immunofluorescence, and calcium imaging.

What this study cannot tell us

Animal model only. Intrathecal drug delivery is not a practical clinical approach. Single disease model. Short-term outcomes measured.

How to read the evidence

Well-designed animal study with mechanistic pathway elucidation, but no human data.

When this study was published

Published in 2021.

The bigger picture

GPR18 is a lesser-known member of the cannabinoid receptor family. This study expands understanding of how the endocannabinoid system modulates pain beyond the well-studied CB1 and CB2 receptors.

Questions still open

• Could GPR18 agonists be developed for oral or topical administration? Does GPR18 play a role in other chronic pain conditions? Would combining GPR18 and CB2 activation produce additive pain relief?

Common questions

Read the original research

Activation of GPR18 by Resolvin D2 Relieves Pain and Improves Bladder Function in Cyclophosphamide-Induced Cystitis Through Inhibiting TRPV1.

Drug design, development and therapy, 15, 4687-4699

Citation

Lu, Qudong; Yang, Yang; Zhang, Hengshuai; Chen, Cheng; Zhao, Jiang; Yang, Zhenxing; Fan, Yi; Li, Longkun; Feng, Huan; Zhu, Jingzhen; Yi, Shanhong. (2021). Activation of GPR18 by Resolvin D2 Relieves Pain and Improves Bladder Function in Cyclophosphamide-Induced Cystitis Through Inhibiting TRPV1.. Drug design, development and therapy, 15, 4687-4699. https://doi.org/10.2147/DDDT.S329507

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