Fatty acid amide hydrolase inhibitor URB597 prevented tolerance and cognitive deficits induced by chronic morphine administration in rats

Hasanein, Parisa; Ghafari-Vahed, Masumeh

doi:10.1097/fbp.0000000000000179

Cited by 13 publications

(9 citation statements)

References 36 publications

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“…Recent experiments indicate that FAAH inhibitors synergize with morphine to attenuate pain‐related responses (Slivicki et al, 2018; Wilkerson et al, 2017). Confirming and extending an earlier report (Hasanein & Ghafari‐Vahed, 2016), the results presented here show that FAAH blockade counters the induction of morphine tolerance. This opioid‐sparing effect appears to be mediated by a central mechanism that requires, unlike CB 1 receptor‐mediated analgesia (Nozaki, Markert, & Zimmer, 2015; Russo et al, 2007), activation of at least three distinct receptor systems—CB 2 , CB 1 , and PPAR‐α.…”

Section: Discussionsupporting

confidence: 92%

Inhibition of fatty acid amide hydrolase in the CNS prevents and reverses morphine tolerance in male and female mice

Fotio

Palese

Tipan

et al. 2020

British J Pharmacology

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Background and Purpose: Fatty acid amide hydrolase (FAAH) is an intracellular serine amidase that terminates the signalling of various lipid messengers involved in pain regulation, including anandamide and palmitoylethanolamide. Here, we investigated the effects of pharmacological or genetic FAAH removal on tolerance to the antinociceptive effects of morphine. Experimental Approach: We induced tolerance in male and female mice by administering twice-daily morphine for 7 days while monitoring nociceptive thresholds by the tail immersion test. The globally active FAAH inhibitor URB597 (1 and 3 mgÁkg −1 , i.p.) or the peripherally restricted FAAH inhibitor URB937 (3 mgÁkg −1 , i.p.) were administered daily 30 min prior to morphine, alone or in combination with the cannabinoid CB 1 receptor antagonist AM251 (3 mgÁkg −1 , i.p.), the CB 2 receptor antagonist AM630 (3 mgÁkg −1 , i.p.), or the PPAR-α antagonist GW6471 (4 mgÁkg −1 , i.p.). Spinal levels of FAAH-regulated lipids were quantified by LC/MS-MS. Gene transcription was assessed by RT-qPCR. Key Results: URB597 prevented and reversed morphine tolerance in both male and female mice. This effect was mimicked by genetic FAAH deletion, but not by URB937. Treatment with AM630 suppressed, whereas treatment with AM251 or GW6471, attenuated the effects of URB597. Anandamide mobilization was enhanced in the spinal cord of morphine-tolerant mice. mRNA levels of the anandamide-producing enzyme N-acyl-phosphatidylethanolamine PLD (NAPE-PLD) and the palmitoylethanolamide receptor PPAR-α, but not those for CB 2 , CB 1 receptors or FAAH, were elevated in spinal cord Conclusion and Implications: FAAH-regulated lipid signalling in the CNS modulated opiate tolerance, suggesting FAAH as a potential target for opiate-sparing medications.

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Section: Discussionsupporting

confidence: 92%

Inhibition of fatty acid amide hydrolase in the CNS prevents and reverses morphine tolerance in male and female mice

Fotio

Palese

Tipan

et al. 2020

British J Pharmacology

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“…Coadministration of D 9 -tetrahydrocannabinol and URB597 attenuates morphine tolerance in the tail-flick assay (Hasanein and Ghafari-Vahed, 2016;Zhang et al, 2016). Similarly, a subthreshold dose of an MGL inhibitor with morphine sustains elevated antinociceptive effects that are greater than those produced by either compound delivered alone (Wilkerson et al, 2016).…”

Section: Discussionmentioning

confidence: 97%

Brain-Permeant and -Impermeant Inhibitors of Fatty Acid Amide Hydrolase Synergize with the Opioid Analgesic Morphine to Suppress Chemotherapy-Induced Neuropathic Nociception Without Enhancing Effects of Morphine on Gastrointestinal Transit

Slivicki

Saberi

Iyer

et al. 2018

J Pharmacol Exp Ther

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Opioid-based therapies remain a mainstay for chronic pain management, but unwanted side effects limit therapeutic use. We compared efficacies of brain-permeant and-impermeant inhibitors of fatty acid amide hydrolase (FAAH) in suppressing neuropathic pain induced by the chemotherapeutic agent paclitaxel. Paclitaxel produced mechanical and cold allodynia without altering nestlet shredding or marble burying behaviors. We compared FAAH inhibitors that differ in their ability to penetrate the central nervous system for antiallodynic efficacy, pharmacological specificity, and synergism with the opioid analgesic morphine. (39-(aminocarbonyl)[1,19-biphenyl]-3-yl)-cyclohexylcarbamate (URB597), a brain-permeant FAAH inhibitor, attenuated paclitaxel-induced allodynia via cannabinoid receptor 1 (CB 1) and cannabinoid receptor 2 (CB 2) mechanisms. URB937, a brainimpermeant FAAH inhibitor, suppressed paclitaxel-induced allodynia through a CB 1 mechanism only. 5-[4-(4-cyano-1butyn-1-yl)phenyl]-1-(2,4-dichlorophenyl)-N-(1,1-dioxido-4thiomorpholinyl)-4-methyl-1H-pyrazole-3-carboxamide (AM6545), a peripherally restricted CB 1 antagonist, fully reversed the antiallodynic efficacy of N-cyclohexyl-carbamic acid, 39-(aminocarbonyl)-6-hydroxy[1,19-biphenyl]-3-yl ester (URB937) but only partially reversed that of URB597. Thus, URB937 suppressed paclitaxel-induced allodynia through a mechanism that was dependent upon peripheral CB 1 receptor activation only. Antiallodynic effects of both FAAH inhibitors were reversed by N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4methyl-1H-pyrazole-3-carboxamide (AM251). Antiallodynic effects of URB597, but not URB937, were reversed by 6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl](4-methoxyphenyl)methanone (AM630). Isobolographic analysis revealed synergistic interactions between morphine and either URB597 or URB937 in reducing paclitaxel-induced allodynia. A leftward shift in the dose-response curve of morphine antinociception was observed when morphine was coadministered with either URB597 or URB937, consistent with morphine sparing. However, neither URB937 nor URB597 enhanced morphine-induced deficits in colonic transit. Thus, our findings suggest that FAAH inhibition may represent a therapeutic avenue to reduce the overall amount of opioid needed for treating neuropathic pain with potential to reduce unwanted side effects that accompany opioid administration.

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“…In addition, several preclinical studies have shown that the inhibitors of catabolic enzymes (FAAH and MAGL) may be useful against opiate abuse. Indeed, URB597 protects against tolerance and memory deficits in chronic morphine treatment and does not interfere with druginduced reinstatement of either conditioned floor preference or avoidance [259]. Moreover, these inhibitors reduce somatic morphine withdrawal signs but not aversive aspects (CPA paradigm) [260].…”

Section: Inhibition Of Endocannabinoid Degradation As a Therapeutic Smentioning

confidence: 99%

Cannabinoids: Drug or Medication?

Giron¹,

Befort²

2016

Cannabinoids in Health and Disease

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This chapter aims at exploring the use and misuse of cannabinoids as it has become a major societal issue. In the first section, we describe the historical use of cannabis as a natural cure in ancient civilizations. We then explore the current use of cannabinoids in medicine, which includes innovative strategies for treating various diseases such as multiple sclerosis or cancer-induced pain. In the second section, we consider how the discovery and characterization of the endocannabinoid system have increased knowledge of this system's mode of action. Consumption of cannabis for recreational use however is a significant public health issue today. Scientific advances are confronted with the adverse health effects that are demonstrated in preclinical and clinical studies based on the psychotic and addictive properties of this compound. In the third section, we therefore provide an overview of the recent findings on the endocannabinoid system using animal models with proposed molecular mechanisms and potential interactions with other neuromodulatory systems like the opioid system. Finally, through alternative strategies to current treatments with both phyto-and synthetic cannabinoids, we try to reconcile the beneficial aspects of the use of cannabinoids for medication and the aspects associated with addictive properties.

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Fatty acid amide hydrolase inhibitor URB597 prevented tolerance and cognitive deficits induced by chronic morphine administration in rats

Cited by 13 publications

References 36 publications

Inhibition of fatty acid amide hydrolase in the CNS prevents and reverses morphine tolerance in male and female mice

Inhibition of fatty acid amide hydrolase in the CNS prevents and reverses morphine tolerance in male and female mice

Brain-Permeant and -Impermeant Inhibitors of Fatty Acid Amide Hydrolase Synergize with the Opioid Analgesic Morphine to Suppress Chemotherapy-Induced Neuropathic Nociception Without Enhancing Effects of Morphine on Gastrointestinal Transit

Cannabinoids: Drug or Medication?

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