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Review
. 2018 May 15:12:17.
doi: 10.3389/fnsys.2018.00017. eCollection 2018.

Potential of Endocannabinoids to Control Bladder Pain

Affiliations
Review

Potential of Endocannabinoids to Control Bladder Pain

Dale E Bjorling et al. Front Syst Neurosci. .

Abstract

Bladder-related pain is one of the most common forms of visceral pain, and visceral pain is among the most common complaints for which patients seek physician consultation. Despite extensive studies of visceral innervation and treatment of visceral pain, opioids remain a mainstay for management of bladder pain. Side effects associated with opioid therapy can profoundly diminish quality of life, and improved options for treatment of bladder pain remain a high priority. Endocannabinoids, primarily anandamide (AEA) and 2-arachidonoylglycerol (2-AG), are endogenously-produced fatty acid ethanolamides with that induce analgesia. Animal experiments have demonstrated that inhibition of enzymes that degrade AEA or 2-AG have the potential to prevent development of visceral and somatic pain. Although experimental results in animal models have been promising, clinical application of this approach has proven difficult. In addition to fatty acid amide hydrolase (FAAH; degrades AEA) and monacylglycerol lipase (MAGL; degrades 2-AG), cyclooxygenase (COX) acts to metabolize endocannabinoids. Another potential limitation of this strategy is that AEA activates pro-nociceptive transient receptor potential vanilloid 1 (TRPV1) channels. Dual inhibitors of FAAH and TRPV1 or FAAH and COX have been synthesized and are currently undergoing preclinical testing for efficacy in providing analgesia. Local inhibition of FAAH or MAGL within the bladder may be viable options to reduce pain associated with cystitis with fewer systemic side effects, but this has not been explored. Further investigation is required before manipulation of the endocannabinoid system can be proven as an efficacious alternative for management of bladder pain.

Keywords: 2-arachidonoylglycerol; anandamide; bladder pain; endocannabinoids; fatty acid amide hydrolase; visceral pain.

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Figures

Figure 1
Figure 1
Bladder content of anandamide (AEA) (A) were consistently greater in fatty acid amide hydrolase (FAAH) knock out (KO) mice than wild-type (WT) mice treated with saline (controls) or cyclophosphamide (CYP; 150 mg/kg) given intraperitoneally 3 h prior to sacrifice. Bladder content of 2-arachidonoylglycerol (2-AG; B) was similar in both KO and WT and was unaffected by treatment. Mean ± SEM. **p < 0.01 KO vs. WT; n = 4 for each group. Reprinted by permission from the publisher of Journal of Molecular Neuroscience, Nature/Springer/Palgrave; (Wang et al., 2015b).
Figure 2
Figure 2
Peripheral mechanical sensitivity determined by application of von Frey monofilaments to hind paws 24 h after treatment with intraperitoneal saline (controls) or CYP (150 mg/kg). Mean ± SEM. **p < 0.01; vs. saline treated; n = 6–8. Reprinted by permission from the publisher of Journal of Molecular Neuroscience, Nature/Springer/Palgrave; (Wang et al., 2015b).
Figure 3
Figure 3
Bladder content of mRNA for inflammatory mediators in male WT and FAAH KO mice treated with saline (controls) or CYP (150 mg/kg) given intraperitoneally 3 h prior to sacrifice. Total bladder RNA was extracted, RT-PCR was performed, and results were normalized to signal for L19, a ribosomal protein. **p < 0.05 CYP vs. saline for each genotype; #p < 0.05 CYP treated KO vs. CYP treated WT; n = 6–8 for each genotype and treatment. Reprinted by permission from the publisher of Journal of Molecular Neuroscience, Nature/Springer/Palgrave; (Wang et al., 2015b).

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