Cannabinoids are the active chemical component of Cannabis sativa (marijuana). The recreational and medical uses of cannabis go back over 5000 years. Cannabinoids produce a wide array of central and peripheral effects, some of which may have beneficial clinical applications. Indeed, cannabis extract-based medicines are used for the treatment of the nausea and vomiting associated with chemotherapy in patients with cancer and have been proposed to be useful in other neurological disorders because of their analgesic, antitumour, anti-inflammatory, and neuroprotective properties .
Cannabinoids are also used in adult patients with moderate to severe spasticity attributable to multiple sclerosis. Those patients present neurogenic detrusor overactivity symptoms. It has been shown that urge incontinence and detrusor overactivity are ameliorated in such patients with the use of cannabis-based extract , and that study sheds light on a putative role of cannabinoid receptors on urological function.
Cannabinoid receptors 1 and 2 (CB1 and CB2) are G-coupled membrane receptors that are linked to adenylcyclase and cAMP intracellular signalling. CB1 is broadly expressed in the CNS and peripheral tissues, while CB2 is mainly expressed in immune cells.
The expression pattern of CB1 and CB2 is still under debate. Some studies have claimed that CB1  is predominantly expressed, whereas others have found a greater expression of CB2 . Although there is no clear consensus, a blurry picture starts to emerge. It seems that both channels are broadly expressed in the bladder in humans and animals. Both CB1 and CB2 are expressed in the urothelium and the detrusor and are also found in the sensory nerve fibres running underneath the epithelial layer. In patients with painful bladder syndrome and idiopathic detrusor overactivity, the density of CB1 expression is enhanced in concert with the afferent sprouting. Interestingly, CB1 colocalizes with P2X3 receptors, suggesting an interaction between the cannabinoid and the purinergic systems . It is worth noting that the ATP-evoked CGRP release (neurotransmitter released by the sensory nerve endings) is inhibited by the activation of both CB1 and CB2 .
The functional involvement of cannabinoid receptors also raises questions. The application of agonists of CB1 or (but not and!) CB2 inhibits the contraction of muscle strips. The activation of CB1 receptors negatively modulates afferent nerve activity. In a preclinical model, the referred hyperalgesia provoked by chemically induced cystitis is reduced after the activation of the CB2 receptor . All the data converge towards the hypothesis that cannabidoid receptors are involved in bladder pathophysiology, even though the relative importance of the two receptors remains unclear.
Deciphering the exact role and localization is a further challenge for scientists. It will indeed be useful in the future to design drugs targeting the cannabinoid receptors. One way to tackle the uncertainty surrounding the role of these receptors lies in the study of knock-out animals. In the accompanying publication by Füllhase et al. , the bladder function of CB1 knock-out mice is investigated. The authors report that the muscarinic agonist-induced contraction of the bladder from null mice was not affected, whereas they were less responsive when electrically stimulated. Moreover, the knock-out mice had an altered urological phenotype characterized by a higher voiding frequency. These results suggest that CB1 is involved in the release of contraction-mediating transmitters (i.e. CGRP). They also clearly suggest a local involvement of CB1 in normal bladder function.
Of course, more evidence needs to be gathered to make CB1 a promising pharmacological target for the treatment of overactive bladder.