Blockade of Endocannabinoid-Degrading Enzymes Attenuates Neuropathic Pain
Open accessAbstract
Direct-acting cannabinoid receptor agonists are well known to reduce hyperalgesic responses and allodynia after nerve injury, although their psychoactive side effects have damped enthusiasm for their therapeutic development. Alternatively, inhibiting fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), the principal enzymes responsible for the degradation of the respective endogenous cannabinoids, anandamide (AEA) and 2-arachydonylglycerol (2-AG), reduce nociception in a variety of nociceptive assays, with no or minimal behavioral effects. In the present study we tested whether inhibition of these enzymes attenuates mechanical allodynia, and acetone-induced cold allodynia in mice subjected to chronic constriction injury of the sciatic nerve. Acute administration of the irreversible FAAH inhibitor, cyclohexylcarbamic acid 3'-carbamoylbiphenyl-3-yl ester (URB597), or the reversible FAAH inhibitor, 1-oxo-1-[5-(2-pyridyl)-2-yl]-7-phenylheptane (OL-135), decreased allodynia in both tests. This attenuation was completely blocked by pretreatment with either CB(1) or CB(2) receptor antagonists, but not by the TRPV1 receptor antagonist, capsazepine, or the opioid receptor antagonist, naltrexone. The novel MAGL inhibitor, 4-nitrophenyl 4-(dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate (JZL184) also attenuated mechanical and cold allodynia via a CB(1), but not a CB(2), receptor mechanism of action. Whereas URB597 did not elicit antiallodynic effects in FAAH(-/-) mice, the effects of JZL184 were FAAH-independent. Finally, URB597 increased brain and spinal cord AEA levels, whereas JZL184 increased 2-AG levels in these tissues, but no differences in either endo-cannabinoid were found between nerve-injured and control mice. These data indicate that inhibition of FAAH and MAGL reduces neuropathic pain through distinct receptor mechanisms of action and present viable targets for the development of analgesic therapeutics.
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Ceiling effects and other methodological differences between studies may have precluded the detection of enhanced nociceptive behavior in neuropathic pain models.
“though ceiling effects and other methodological differences between studies may have precluded the detection of enhanced nociceptive behavior.”
From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Kinsey et al, 2009
Other studies using knockout mice or selective inhibitors of CB1 or CB2 receptors show no alterations of nociceptive behavior in neuropathic pain models.
“However, other studies using knockout mice or selective inhibitors of CB 1 or CB 2 receptors show no alterations of nociceptive behavior in neuropathic pain models (Kinsey et al, 2009(Kinsey et al, , 2010) ) though ceiling effects and other methodological differences between studies may have precluded the detection of enhanced nociceptive behavior.”
From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Kinsey et al, 2009
OL135 and URB597 are antinociceptive in FAAH+/+ mice but fail to produce an effect in FAAH-/- mice.
“Additionally both OL135 and URB597 are antinociceptive in FAAH+/+ mice, but fail to produce an effect in FAAH-/- mice.59”
From Cannabinoids as Pharmacotherapies for Neuropathic Pain: From the Bench to the Bedside (2009) · cites this paper as [59]
OL135 and URB597 attenuate cold and mechanical allodynia in a manner that is dependent upon activation of both CB1 and CB2 receptors.
“OL135 and URB597 attenuate cold and mechanical allodynia in a manner that is dependent upon activation of both CB1 and CB2 receptors.59”
From Cannabinoids as Pharmacotherapies for Neuropathic Pain: From the Bench to the Bedside (2009) · cites this paper as [59]
The MGL inhibitor JZL184 attenuates CCI-induced mechanical and cold allodynia through indirect activation of the CB1 receptor and is efficacious in both FAAH+/+ and FAAH-/- mice.
“The novel MGL inhibitor, JZL184, attenuates CCI-induced mechanical and cold allodynia through indirect activation of the CB1 receptor; JZL184 was efficacious in attenuating neuropathic nociception in both FAAH+/+ and FAAH-/- mice.59”
From Cannabinoids as Pharmacotherapies for Neuropathic Pain: From the Bench to the Bedside (2009) · cites this paper as [59]
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Self-citationSelective Monoacylglycerol Lipase Inhibitors: Antinociceptive versus Cannabimimetic Effects in Mice
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- Authors
- Kinsey, S. G., Long, J. Z., O’Neal, S. T., Abdullah, R. A., Poklis, J. L., Boger, D. L., Cravatt, B. F., & Lichtman, A. H.
- Affiliations
- Virginia Commonwealth University (US)
- Scripps Research Institute (US)
- Venue
- The Journal of Pharmacology and Experimental Therapeutics
- Publisher
- Elsevier BV
- Published
- 2009-09
- Volume
- 330
- Issue
- 3
- Pages
- 902-910
- ISSN
- 0022-3565 (ISSN-L)
- PMC
- PMC2729802
- OpenAlex
- W2132380973
- Cited by
- 330
- References
- 43
- Citations by year
- 2026: 9 · 2025: 14 · 2024: 13 · 2023: 8 · 2022: 7 · 2021: 15 · 2020: 9 · 2019: 14 · 2018: 21 · 2017: 24 · 2016: 16 · 2015: 21 · 2014: 35 · 2013: 29 · 2012: 33
- FWCI
- 24.43
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Institute of International Education
- National Institute on Drug Abuse (DA015197, P01DA009789, DA-017259, R01DA015197, DA009789-11, DA007027-32, P01DA017259, DA 009789, DA015648, T32DA007027, DA007027)
- Topics
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
- Keywords
- neuropathic pain, endocannabinoid system, fatty acid amide hydrolase, monoacylglycerol lipase, anandamide, 2-arachidonoylglycerol, CB1 receptor, CB2 receptor, URB597, JZL184, chronic constriction injury, mechanical allodynia, cold allodynia, analgesic drug development
- MeSH terms
- Fatty Acid Amide Hydrolases, Amidohydrolases, Animals, Arachidonic Acids, Benzamides, Carbamates, Cold Temperature, Enzyme Inhibitors, Glycerides, Hyperalgesia, Male, Mice, Inbred C57BL, Monoacylglycerol Lipases, Narcotic Antagonists, Pain, Pain Measurement, Peripheral Nervous System Diseases, Piperidines, Pyridines, Analgesics, Non-Narcotic, Receptor, Cannabinoid, CB1, Receptor, Cannabinoid, CB2, TRPV Cation Channels, Mice, Benzodioxoles, Polyunsaturated Alkamides, Cannabinoid Receptor Modulators, Endocannabinoids
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