Cannabis -vs- Painful Bladder Syndrome
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2878434: These peripherally acting agents could evoke profound pain relief in animal models as well as in a few small clinical studies, but the underlying mechanism and signaling pathways mediating these effects are yet to be completely understood. A major challenge facing the biomedical research community is the identifi cation of compounds that are safe and effective in treating pain, particularly chronic pain such as painful bladder syndrome (PBS) or interstitial cystitis (IC). Various methods, medicines, and devices are available to IC/PBS patients to reduce their pain and symptoms but many of these conventional therapies have significant limitations. Based on the known effects of cannabinoids, in preclinical and clinical studies, it can expected that peripherally acting cannabinoid receptor agonists can modulate bladder sensory pathways by acting on nociceptive pathways originating from bladder.
The diverse effects of CB1 and CB2 receptor system in lower urinary tract may be novel targets for therapies designed to treat diseases afflicting lower urinary tract. The growth-inhibiting action of cannabinoids acting on these receptors expressed on transformed cells might be useful for the management of malignancy in bladder. Recently published pre-clinical studies have demonstrated that cannabinoids appear to act principally as prejunctional modulators of neurotransmission to affect the micturition process indirectly by affecting the nociceptive responses pathways. It is likely that CB1 and CB2 receptors located in periphery such as in bladder participate in the intrinsic control of initiation of afferent stimulus. Emerging studies show that ECBs are mediators of spinal activity-dependent pain sensitization to create a future role for pharmacological antagonists CB1 and CB2 receptors in control of neuropathic pain.
https://www.ncbi.nlm.nih.gov/pubmed/19356696: Pharmacological studies have indirectly shown the possible presence of cannabinoid receptors in the urinary bladder and their potential role in reducing bladder inflammatory pain. However, the localization of cannabinoid receptors in the urinary bladder remains unknown and there are no published data on the effects of cannabinoids on the sensory system of the bladder. The present study was performed to evaluate the expression of the cannabinoid CB(1) receptors in the mouse urinary bladder and to assess their co-localization with the purinergic P2X(3) receptor, a major player in the transduction of sensory events in the bladder. Also, the effect of intravesical administration of a cannabinoid agonist on the electrical activity of bladder afferent fibers was studied. The expression of mRNA coding for CB(1) receptor was assessed by reverse transcriptase-polymerase chain reaction (RT-PCR). Immunofluorescence experiments were performed to study CB(1) and P2X(3) protein expression in the bladder. The electrical activity of bladder afferent fibers was recorded using an ex vivo bladder-nerve preparation. Mechanical stimulation of the bladder was performed by a controlled slow inflation with an external pump. A bolus of a cannabinoid agonist (AZ12646915) was administered intravesically prior to a second inflation. Afferent activity was measured before and after administration of the cannabinoid compound or its vehicle. The effects of CB(1) receptor antagonist (AM251) on the AZ12646915 response were also analyzed. Cannabinoid receptor CB(1) mRNA was detected in the urinary bladder of the mouse. The protein was found in the urothelium, as well as in nerve fibers. CB(1) and P2X(3) receptors were found to be co-expressed in urothelial cells and in some nerve fibers. In addition, intravesical administration of a cannabinoid receptor agonist reduced the mechanically-evoked activity of bladder afferents in the pelvic nerve. This effect was abolished by the previous administration of the CB(1) antagonist AM251. These data demonstrate the presence of cannabinoid CB(1) receptor mRNA and the protein in the mouse urinary bladder. CB(1) and P2X(3) protein co-localization supports the hypothesis of an interaction between the cannabinoid and the purinergic systems in the transduction of sensory information in the urinary bladder. Finally, the reduction of nerve activity induced by cannabinoid-receptor activation implicates CB(1) receptors in the peripheral modulation of bladder afferent information.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2430692: Pain severely impairs quality of life. Currently available treatments, generally opioids and anti-inflammatory drugs, are not always effective for certain painful conditions. The discovery of the cannabinoid receptors in the 1990s led to the characterisation of the endogenous cannabinoid system in terms of its components and numerous basic physiologic functions. CB1 receptors are present in nervous system areas involved in modulating nociception and evidence supports a role of the endocannabinoids in pain modulation. Basic research on how cannabinoid receptors and endocannabinoids intervene in pain mechanisms is progressing rapidly. Clinical progress, however, is advancing slowly. Cannabinoids have antinociceptive mechanisms different from that of other drugs currently in use, which thus opens a new line of promising treatment to mitigate pain that fails to respond to the pharmacologic treatments available, especially for neuropathic and inflammatory pains. The combination of cannabinoids with synergistic analgesic substances is interesting because it may improve the efficacy and safety of treatment. One of the drawbacks of investigating cannabinoids is their typification as substances of abuse. However, compounds blunting severe pain allow patients to perform daily activities more easily, so the potential benefits should be weighed against possible adverse effects. Our current understanding of the physiology and pharmacology of the endogenous cannabinoid system has motivated cannabis-based therapeutic drug design, in which attempts are being made to synthesise compounds with the desired therapeutic actions but without psychoactive adverse effects. Medications prepared with cannabinoid receptor agonists or with drugs that enhance endocannabinoid function (by either increasing release or diminishing reuptake of endocannabinoids) may afford the novel therapeutic approaches demanded by disorders in which pain is a prominent symptom. Clinical trials seem to indicate that either extracts of the Cannabis sativa plant containing known amounts of the active compounds (mainly THC and CBD) or diverse synthetic derivatives of THC are promising treatments for painful conditions that do not respond to available treatments, such as neuropathic, inflammatory and oncologic pain. Specifically, cannabis extracts have shown effectiveness to relief some symptoms of the patients with multiple sclerosis, mainly for pain and spasticity. Pharmacologic manipulation directed to elevate endocannabinoids levels like, for example, with anandamide reuptake inhibitors, or by inhibiting the enzyme fatty acid amide hydrolase (FAAH), which is responsible for intracellular anandamide degradation, may well become a valuable therapeutic tool. CB2 receptor selective agonists with no central effects are other promising pain treatment under investigation. Adequately sized and designed, doubleblind placebo-controlled clinical trials are needed to evaluate the potential applications of cannabis-based medications as novel and effective therapeutic drugs for controlling different types of pain.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2503660: This article reviews recent research on cannabinoid analgesia via the endocannabinoid system and non-receptor mechanisms, as well as randomized clinical trials employing cannabinoids in pain treatment. Tetrahydrocannabinol (THC, Marinol®) and nabilone (Cesamet®) are currently approved in the United States and other countries, but not for pain indications. Other synthetic cannabinoids, such as ajulemic acid, are in development. Crude herbal cannabis remains illegal in most jurisdictions but is also under investigation. Sativex®, a cannabis derived oromucosal spray containing equal proportions of THC (partial CB1 receptor agonist ) and cannabidiol (CBD, a non-euphoriant, anti-inflammatory analgesic with CB1 receptor antagonist and endocannabinoid modulating effects) was approved in Canada in 2005 for treatment of central neuropathic pain in multiple sclerosis, and in 2007 for intractable cancer pain. Numerous randomized clinical trials have demonstrated safety and efficacy for Sativex in central and peripheral neuropathic pain, rheumatoid arthritis and cancer pain. An Investigational New Drug application to conduct advanced clinical trials for cancer pain was approved by the US FDA in January 2006. Cannabinoid analgesics have generally been well tolerated in clinical trials with acceptable adverse event profiles. Their adjunctive addition to the pharmacological armamentarium for treatment of pain shows great promise.
https://www.ncbi.nlm.nih.gov/pubmed/23515618: Cannabinoids have been shown to exert analgesic and anti-inflammatory effects, and the effects of cannabinoids are mediated primarily by cannabinoid receptors 1 and 2 (CB1and CB2). Both CB1 and CB2 are present in bladders of various species, including human, monkey, and rodents, and it appears that CB2 is highly expressed in urothelial cells. We investigated whether treatment with the CB2 agonist GP1a alters severity of experimental cystitis induced by acrolein and referred mechanical hyperalgesia associated with cystitis. We also investigated whether the mitogen-activated protein kinases (MAPK), ERK1/2, p38, and JNK are involved in the functions of CB2. We found that treatment with the selective CB2 agonist GP1a (1-10 mg/kg, ip) inhibited the severity of bladder inflammation 3 h after intravesical instillation of acrolein in a dose-dependent manner, and inhibition reached significance at a dose of 10 mg/kg (P < 0.05). Treatment with GP1a (10 mg/kg) inhibited referred mechanical hyperalgesia associated with cystitis (P < 0.05). The inhibitory effects of the CB2 agonist were prevented by the selective CB2 antagonist AM630 (10 mg/kg, sc). We further demonstrated the inhibitory effects of CB2 appear to be at least partly mediated by reducing bladder inflammation-induced activation of ERK1/2 MAPK pathway. The results of the current study indicate that CB2 is a potential therapeutic target for treatment of bladder inflammation and pain in patients.
https://www.ncbi.nlm.nih.gov/pubmed/24561047: Interstitial cystitis is a debilitating bladder inflammation disorder. To date, the understanding of the causes of interstitial cystitis remains largely fragmentary and there is no effective treatment available. Recent experimental results have shown a functional role of the endocannabinoid system in urinary bladder. In this study, we evaluated the anti-inflammatory effect of selective cannabinoid CB1 and CB2 receptor agonists in a mouse model of interstitial cystitis. Bladder inflammation was induced in mice by lipopolysaccharide (LPS) and whole bladders were removed 24h later. LPS induced a significant increase of the contractile amplitude in spontaneous activity and a hypersensitivity to exogenous acetylcholine-induced contraction of whole-isolated bladder. Next, we evaluated the anti-inflammatory activity of cannabinoidergic compounds by pretreating mice with CB1 or CB2 selective agonist compounds, respectively ACEA and JWH015. Interestingly, JWH015, but not ACEA, antagonized LPS-induced bladder inflammation. Additionally, anti-inflammatory activity was studied by evaluation, leukocytes mucosa infiltration, myeloperoxidase activity, and mRNA expression of pro-inflammatory interleukin (IL-1α and IL-1β), tumor necrosis factor-alpha (TNF-α) and cannabinoid CB1 and CB2 receptors. JWH015 significantly decreased leukocytes infiltration in both submucosa and mucosa, as well as the myeloperoxydase activity, in LPS treated mice. JWH015 reduced mRNA expression of IL-1α, IL-1β, and TNF-α. LPS treatment increased expression of bladder CB2 but not CB1 mRNA. Taken together, these findings strongly suggest that modulation of the cannabinoid CB2 receptors might be a promising therapeutic strategy for the treatment of bladder diseases and conditions characterized by inflammation, such as interstitial cystitis.