Activation of cannabinoid receptor 1 inhibits increased bladder activity induced by nerve growth factor

Abstract

Nerve growth factor (NGF) is an important mediator of inflammatory pain, in part by sensitizing afferent nerve fibers, and expression of NGF is increased during bladder inflammation. We investigated whether intravesical instillation of the selective cannabinoid receptor 1 (CB1) agonist arachidonyl-2'-chloroethylamide (ACEA) affects NGF-induced increased bladder activity in female C57BL/6J wild-type (WT) mice. We also examined the effects of intravesical NGF in female fatty acid amide hydrolase knock-out (FAAH KO) mice. We found that CB1 and tyrosine kinase A (trkA, the high-affinity NGF receptor) were present in L6 dorsal root ganglion (DRG) afferent neurons and in bladders of both genotypes. Intravesical NGF increased bladder activity that was inhibited by intravesical ACEA in WT mice. The inhibitory effects of ACEA were reversed by the selective CB1 antagonist AM 251. Intravesical NGF failed to affect bladder activity in FAAH KO mice, and treatment with AM251, restored the stimulatory effects of NGF on the bladder in FAAH KO mice. These results indicate that activation of CB1 inhibits increased bladder activity induced by NGF.

Expression of cannabinoid 1 and, 2 receptors and the effects of cannabinoid 1 and, 2 receptor agonists on detrusor overactivity associated with bladder outlet obstruction in rats

“…Systemically administered cannabinoids can act at multiple sites, including the bladder and many sites in the central nerve system. Intravesical activation of CB1 does block Nerve Growth Factor-induced increased bladder activity [ 17 ]. In addition, according to Tyagi et al, CB1 and CB2 receptors have higher expression rates in the bladder urothelium, and bladder strips incubated for 15 min CB agonists show a decreased detrusor muscle contraction amplitude [ 8 ].…”

Potential of Endocannabinoids to Control Bladder Pain

“…Afferent nerve activity was recorded during increasing intravesical pressure in inflamed bladders ex vivo in the presence or absence of intravesical cannabinoid agonists, and it was determined that intravesical cannabinoids suppressed afferent nerve fiber firing in inflamed bladders via CB1 activation (Walczak et al, 2009 ; Walczak and Cervero, 2011 ). We have also observed that intravesical administration of a CB1 agonist inhibited bladder responses to subsequent instillation of NGF (Wang et al, 2015a ). These studies support the concept that intravesical manipulation of the endocannabinoid system may have the capacity to alter nociceptive signaling.…”

“…A majority of somatic and visceral afferent nerve fibers express CB1 (Hohmann and Herkenham, 1999 ; Ahluwalia et al, 2000 ; Agarwal et al, 2007 ), and genetic deletion of CB1 from afferent nerves renders mice sensitive to subthreshold stimuli (allodynia) and enhances response to noxious stimuli (hyperalgesia; Agarwal et al, 2007 ). We demonstrated that CB1 receptors have the capacity to suppress the sensitizing effect of nerve growth factor (NGF) on the response of mouse afferent neurons to capsaicin in vitro (Wang et al, 2015a ). Interestingly, we also showed that intrathecal administration of the CB1 agonist arachidonyl-2’-chloroethylamide (ACEA) blocked referred mechanical hypersensitivity induced by inflammatory cystitis in rats (Jones et al, 2015 ).…”

“…Evaluation of bladder pain in rodent models can be difficult, and the presence of bladder pain is most often inferred by evaluating referred mechanical sensitivity of the hind paws or abdominal wall or activity of bladder afferent nerves (Sadler et al, 2013 ; Stemler et al, 2013 ; Aizawa et al, 2014 , 2016 ; Wang et al, 2014 , 2015a , b ; Girard et al, 2016 ). Inhibition of FAAH to increase AEA by systemic treatment with FAAH inhibitors (Merriam et al, 2011 ; Aizawa et al, 2014 , 2016 ) or genetic disruption of function FAAH (Wang et al, 2015b ) has been shown to suppress surrogates measurements of pain associated with bladder inflammation in rodents.…”

Unmasking roles of the peripheral endocannabinoid system associated with bladder overactivity

“…Supporting this suggestion, a recent report by Wang et al. shows that intravesical application of a CB 1 agonist decreases bladder overactivity induced by intravesical nerve growth factor (NGF) in mice with an intact urothelial layer. Additionally, NGF did not induce bladder overactivity in knockout mice for the FAAH enzyme, reinforcing the suggestion for Aizawa et al.…”