Urology TimesUrology Severity of acute cystitis may be cut with cannabinoid agonist Investigational treatment inhibits inflammation, sensitivity in murine models November 01, 2011 By Penny Allen Madison, WI—Various cannabinoids have been tested in animal models of acute or interstitial cystitis, but how active they are and what they do still needs to be researched. That's what Zun-Yi Wang, PhD, and colleagues at the University of Wisconsin School of Medicine and Public Health, Madison, began to tease out with a recent study. Cannabinoid receptor 2 (CB2) is known to be expressed in bladder tissue, especially in urothelial cells, so Dr. Wang and his team looked at the action of a CB2 receptor stimulator in an experimental cystitis model that used acrolein as the bladder irritant in mice. They looked at whether mitogen-activated protein kinases (MAPKs) are involved in the receptor function and examined the effects on bladder tissue and on the pain behavior of the mice. (MAPKs are involved in a number of cellular processes, including inflammation and pathways related to antiproliferative factor, and these kinases are thought to play a role in bladder lining damage in IC.) The mice were given GP1a, a highly selective CB2 stimulator or agonist, before instillation of acrolein or saline in controls. Some mice also received a CB2 blocker or antagonist before GP1a. Western blot analysis showed CB2 was present in urothelium, and levels of the receptor were not affected by the irritant or treatment with the receptor agonist GP1a. Histologic studies showed the acrolein irritant induced submucosal edema, and the agonist reduced its severity. The antagonist reversed GP1a's anti-inflammatory effects. Bladder weight also increased with the irritant, whereas the increase was inhibited with the agonist, and the inhibition was reversed with the antagonist. With acrolein bladder irritation, the sensitivity of the mice to touch with a Von Frey filament on the hind paw was increased. The agonist inhibited that increased sensitivity, and the inhibition was also reversed by the antagonist. Biochemically, acrolein increased phosphorylation of the MAPK ERK� in the urothelium. Treatment with GP1a inhibited increased phosphorylation of ERK�, and the inhibition was reversed by the antagonist. The MAPKs JNK and p38 did not follow the pattern, however. Although acrolein increased the phosphorylation of JNK in the urothelium, treatment with the agonist did not affect its phosphorylation. Acrolein did not increase phosphorylation of p38 in urothelium, and that remained unaffected by the antagonist. That led the investigators to conclude that treatment with a selective CB2 agonist could reduce the severity of an induced acute cystitis by inhibiting inflammation and by inhibiting increased peripheral sensitivity to manual stimuli associated with cystitis. The effects of CB2 activation, said Dr. Wang, may be partly mediated by MAPK ERK� but not JNK or P38. "Selective CB2 agonists represent a potential therapeutic option for patients with painful bladder disorders," said Dr. Wang, a scientist at the University of Wisconsin who presented the findings at the AUA annual meeting in Washington. Next step: Tests on established cystitis The next research step, he noted, will be to test the effects these chemicals have in mice with an already established cystitis rather than in an acute model, which will be more relevant to IC. This particular agonist hasn't been tried in humans, Dr. Wang noted. The next research step and many more are important, lab leader Dale Bjorling, DVM, emphasized to Urology Times. "I don't think we have a complete understanding, or as complete as we should have, of the effects of these compounds at a local level or potentially at a systemic level as it pertains specifically to the bladder circuitry or the bladder," said Dr. Bjorling, professor of urology and small animal surgery at the University of Wisconsin. He believes it's important not to jump too fast to human trials before the actions and potential side effects of this or any other cannabinoid drug are more thoroughly understood. And that's the aim of this research. An old article that has a bad link, so I am re- posting it here for my List. (Yes, I'm still alive!) -Granny