The effect of <scp>FAAH</scp>,<scp> MAGL</scp>, and Dual <scp>FAAH</scp>/<scp>MAGL</scp> inhibition on inflammatory and colorectal distension‐induced visceral pain models in Rodents

Sakin, Yusuf Serdar; Doğrul, Ahmet; İlkaya, Fatih; Seyrek, Melik; Ulaş, Ümit Hıdır; Gülşen, Mustafa; Bağcı, Sait

doi:10.1111/nmo.12563

Cited by 43 publications

(36 citation statements)

References 53 publications

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“…Supporting the concept that the combined inhibitor increases efficacy, the dual inhibitor of FAAH and MAGL (JZL195) was more effective in reducing allodynia (central pain sensitization following painful, often repetitive, stimulation) than selective FAAH or MAGL inhibitors. The dual inhibitor also had a larger therapeutic window than cannabinoid receptor agonists in a mouse model of neuropathic pain 51 or in animal models of visceral pain 52 .…”

Section: Endocannabinoids Chronic Stress and Painmentioning

confidence: 99%

The Role of the Endocannabinoid System in the Brain–Gut Axis

2016

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The actions of cannabis are mediated by receptors that are part of an endogenous cannabinoid system. The endocannabinoid system (ECS) consists of the naturally occurring ligands N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG), their biosynthetic and degradative enzymes, and the cannabinoid receptors CB1 and CB2. The ECS is a widely distributed transmitter system that controls gut functions peripherally and centrally. It is an important physiologic regulator of gastrointestinal motility. Polymorphisms in the gene encoding CB1 (CNR1) have been associated with some forms of irritable bowel syndrome. The ECS is involved in the control of nausea and vomiting and visceral sensation. The homeostatic role of the ECS also extends to the control of intestinal inflammation. We review the mechanisms by which the ECS links stress and visceral pain. CB1 in sensory ganglia controls visceral sensation, and transcription of CNR1 is modified through epigenetic processes under conditions of chronic stress. These processes might link stress with abdominal pain. The ECS is also involved centrally in the manifestation of stress, and endocannabinoid signaling reduces the activity of hypothalamic–pituitary–adrenal pathways via actions in specific brain regions—notably the prefrontal cortex, amygdala, and hypothalamus. Agents that modulate the ECS are in early stages of development for treatment of gastrointestinal diseases. Increasing our understanding of the ECS will greatly advance our knowledge of interactions between the brain and gut and could lead to new treatments for gastrointestinal disorders.

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Section: Endocannabinoids Chronic Stress and Painmentioning

confidence: 99%

The Role of the Endocannabinoid System in the Brain–Gut Axis

2016

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“…Interestingly, combined inhibition of FAAH and MAGL results in enhanced antinociceptive effects compared with single inhibition of these enzymes. One such dual inhibitor, JZL195 produces augmented antinociceptive effects in mouse models of acute thermal, visceral (Sakin et al, 2015), inflammatory (Long et al, 2009b; Anderson et al, 2014) and neuropathic (Adamson Barnes et al, 2016) pain. Additionally, the combination of a high dose of the FAAH inhibitor PF3845 and a low dose of the MAGL inhibitor JZL184 produces augmented antinociceptive effects in inflammatory and neuropathic pain assays (Ghosh et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

The endocannabinoid hydrolysis inhibitor SA-57: Intrinsic antinociceptive effects, augmented morphine-induced antinociception, and attenuated heroin seeking behavior in mice

et al. 2017

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Although opioids are highly efficacious analgesics, their abuse potential and other untoward side effects diminish their therapeutic utility. The addition of non-opioid analgesics offers a promising strategy to reduce required antinociceptive opioid doses that concomitantly reduce opioid-related side effects. Inhibitors of the primary endocannabinoid catabolic enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) show opioid-sparing effects in preclinical models of pain. As simultaneous inhibition of these enzymes elicits enhanced antinociceptive effects compared with single enzyme inhibition, the present study tested whether the dual FAAH-MAGL inhibitor SA-57 [4-[2-(4-chlorophenyl)ethyl]-1-piperidinecarboxylic acid 2-(methylamino)-2-oxoethyl ester] produces morphine-sparing antinociceptive effects, without major side effects associated with either drug class. SA-57 dose-dependently reversed mechanical allodynia in the constriction injury (CCI) of the sciatic nerve model of neuropathic pain and carrageenan inflammatory pain model. As previously reported, SA-57 was considerably more potent in elevating anandamide (AEA) than 2-arachidonyl glycerol (2-AG) in brain. Its anti-allodynic effects required cannabinoid (CB)1 and CB2 receptors; however, only CB2 receptors were necessary for the anti-edematous effects in the carrageenan assay. Although high doses of SA-57 alone were required to produce antinociception, low doses of this compound, which elevated AEA and did not affect 2-AG brain levels, augmented the antinociceptive effects of morphine, but lacked cannabimimetic side effects. Because of the high abuse liability of opioids and implication of the endocannabinoid system in the reinforcing effects of opioids, the final experiment tested whether SA-57 would alter heroin seeking behavior. Strikingly, SA-57 reduced heroin-reinforced nose poke behavior and the progressive ratio break point for heroin. In conclusion, the results of the present study suggest that inhibition of endocannabinoid degradative enzymes represents a promising therapeutic approach to decrease effective doses of opioids needed for clinical pain control, and may also possess therapeutic potential to reduce opioid abuse.

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“…This leads to the idea that FAAH inhibitors could be valuable therapeutics against PI‐IBS and possibly other forms of IBS. In accordance with this concept, several studies reported that pharmacological inhibition of FAAH and also MGL significantly reduced visceral nociception in rodent models of colorectal distension and acetic acid‐induced abdominal stretching . In this context it is worth to mention the role of mast cells in IBS.…”

Section: Cannabinoids and Functional Bowel Disordersmentioning

confidence: 66%

The gastrointestinal tract – a central organ of cannabinoid signaling in health and disease

Hasenoehrl

Taschler

Storr

et al. 2016

Neurogastroenterology Motil

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The effect of FAAH, MAGL, and Dual FAAH/MAGL inhibition on inflammatory and colorectal distension‐induced visceral pain models in Rodents

Abstract: The selective FAAH inhibitor and dual FAAH/MAGL inhibitors were effective in both inflammatory and mechanically evoked visceral pain, while the MAGL inhibitor elicited an analgesic effect in inflammatory, but not in distension-induced, visceral pain.

Cited by 43 publications

References 53 publications

The Role of the Endocannabinoid System in the Brain–Gut Axis

The Role of the Endocannabinoid System in the Brain–Gut Axis

The endocannabinoid hydrolysis inhibitor SA-57: Intrinsic antinociceptive effects, augmented morphine-induced antinociception, and attenuated heroin seeking behavior in mice

The gastrointestinal tract – a central organ of cannabinoid signaling in health and disease

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