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Blockade of endocannabinoid-degrading enzymes attenuates neuropathic pain.
J Pharmacol Exp Ther. 2009 Sep; 330(3):902-10.JP

Abstract

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.

Authors+Show Affiliations

Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19502530

Citation

Kinsey, S G., et al. "Blockade of Endocannabinoid-degrading Enzymes Attenuates Neuropathic Pain." The Journal of Pharmacology and Experimental Therapeutics, vol. 330, no. 3, 2009, pp. 902-10.
Kinsey SG, Long JZ, O'Neal ST, et al. Blockade of endocannabinoid-degrading enzymes attenuates neuropathic pain. J Pharmacol Exp Ther. 2009;330(3):902-10.
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. (2009). Blockade of endocannabinoid-degrading enzymes attenuates neuropathic pain. The Journal of Pharmacology and Experimental Therapeutics, 330(3), 902-10. https://doi.org/10.1124/jpet.109.155465
Kinsey SG, et al. Blockade of Endocannabinoid-degrading Enzymes Attenuates Neuropathic Pain. J Pharmacol Exp Ther. 2009;330(3):902-10. PubMed PMID: 19502530.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Blockade of endocannabinoid-degrading enzymes attenuates neuropathic pain. AU - Kinsey,S G, AU - Long,J Z, AU - O'Neal,S T, AU - Abdullah,R A, AU - Poklis,J L, AU - Boger,D L, AU - Cravatt,B F, AU - Lichtman,A H, Y1 - 2009/06/05/ PY - 2009/6/9/entrez PY - 2009/6/9/pubmed PY - 2009/9/22/medline SP - 902 EP - 10 JF - The Journal of pharmacology and experimental therapeutics JO - J. Pharmacol. Exp. Ther. VL - 330 IS - 3 N2 - 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. SN - 1521-0103 UR - https://www.unboundmedicine.com/medline/citation/19502530/Blockade_of_endocannabinoid_degrading_enzymes_attenuates_neuropathic_pain_ L2 - http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=19502530 DB - PRIME DP - Unbound Medicine ER -