Interstitial cystitis (IC) is a chronic bladder disorder with unclear etiology. The endocannabinoid system has been identified as a key regulator of immune function, with experimental evidence for the involvement of cannabinoid receptors in bladder inflammation. This study used intravital microscopy (IVM) and behavioral testing in lipopolysaccharide-induced IC, to investigate the anti-inflammatory analgesic effects of a natural dietary sesquiterpenoid, beta-caryophyllene (BCP), which is present in cannabis among other plants, and has reported agonist actions at the cannabinoid 2 receptor (CB2R). BCP’s anti-inflammatory actions were compared to the synthetic CB2R-selective cannabinoid, HU308, and to an FDA-approved clinical treatment (dimethyl sulfoxide: DMSO). IVM data revealed that intravesical instillation of BCP and/or HU308 significantly reduces the number of adhering leukocytes in submucosal bladder venules and improves bladder capillary perfusion. The effects of BCP were found to be comparable to that of the selective CB2R synthetic cannabinoid, HU308, and superior to intravesical DMSO treatment. Oral treatment with BCP was also able to reduce bladder inflammation and significantly reduced mechanical allodynia in experimental IC. Based on our findings, we believe that CB2R activation may represent a viable therapeutic target for IC, and that drugs that activate CB2R, such as the generally regarded as safe (GRAS) dietary sesquiterpenoid, BCP, may serve as an adjunct and/or alternative treatment option for alleviating symptoms of inflammation and pain in the management of IC.

Interstitial cystitis (IC) is a highly prevalent debilitating disease, with its cardinal symptoms being severe pain, urinary urgency and frequency. The associated pain may eventually lead as a last resort to removal of the bladder. Though the initial trigger for IC remains largely unknown, we propose novel iron chelators as a possible new treatment for this disease. Iron is a mandatory component for the generation of reactive oxygen species (ROS). A substantial decrease in ROS production and thus inflammation can be achieved by effectively sequestering host iron, which we believe may improve outcome and quality of life in IC patients. Novel iron chelators could be used via the intravesical route to reduce or attenuate inflammation by effectively sequestering host iron, thus preventing the production of ROS via the Fenton and Haber-Weiss reactions.