Experimental Cannabinoid Receptor 2 Activation in Lipopolysaccharide-Induced Interstitial Cystitis in Mice

Abstract

Interstitial cystitis (IC) is a chronic pain disorder of the urinary bladder that causes symptoms of persistent pelvic pain, nocturia, and dysuria with no curative treatment. Medical management is therefore directed toward pain and symptom management. However, many patients remain dissatisfied with the management of their condition. The endocannabinoid system has been identified as a key regulator of immune function, with experimental evidence demonstrating the involvement of cannabinoid receptors in bladder inflammation. Eliciting anti-inflammatory and analgesic effects derived from cannabinoid receptor 2 (CB2R) activation the aim of this study. Evaluating the therapeutic potential of entities that result in local CB2R activation in experimental IC by direct and indirect mechanisms is the objective of this study. Direct activation of the CB2R with β-Caryophyllene (BCP), a dietary sesquiterpenoid and phyto-derived CB2R agonist, or indirect activation through the inhibition of endocannabinoid breakdown with JZL184 exerted anti-inflammatory analgesic effects in experimental IC. Intravital microscopy (IVM) and Luminex immunoassays showed that intravesical treatment with either compound reduced leukocyte adhesion in the bladder microcirculation and inhibited proinflammatory cytokine production, respectively. Von Frey aesthesiometry and behavioral assessment also revealed analgesic effects consistent with activation of the CB2R. However, some results showed confounding effects of JZL184 vehicle treatment, and potential CB2R-independent anti-inflammatory effects of BCP. Our results suggest that pharmacological activation of the CB2R could underscore a novel treatment strategy for reducing IC-induced pain and inflammation.