Tags

Type your tag names separated by a space and hit enter

Modulation of the anti-nociceptive effects of 2-arachidonoyl glycerol by peripherally administered FAAH and MGL inhibitors in a neuropathic pain model.
Br J Pharmacol. 2008 Nov; 155(6):913-24.BJ

Abstract

BACKGROUND AND PURPOSE

There are limited options for the treatment of neuropathic pain. Endocannabinoids, such as anandamide and 2-arachidonoyl glycerol (2-AG), are promising pain modulators and there is recent evidence of interactions between anandamide and 2-AG biosynthesis and metabolism. It has been clearly demonstrated that 2-AG degradation is mainly catalysed not only by monoacylglycerol lipase (MGL) but also by a fatty acid amide hydrolase (FAAH). Inhibitors specifically targeting these two enzymes have also been described: URB602 and URB597, respectively. However, the anti-nociceptive effects of the combination of peripherally injected 2-AG, URB602 and URB597 in a neuropathic pain model have not yet been determined. This was performed in the presence or absence of cannabinoid CB(1) (AM251) and CB(2) (AM630) receptor antagonists.

EXPERIMENTAL APPROACH

Mechanical allodynia and thermal hyperalgesia were evaluated in 213 male Wistar rats allocated to 32 different groups. Drugs were injected subcutaneously in the dorsal surface of the hind paw (50 muL) 15 min before pain tests.

KEY RESULTS

2-AG, URB602 and URB597 significantly decreased mechanical allodynia and thermal hyperalgesia with ED50 of 1.6+/-1.5 and 127+/-83 mug for 2-AG and URB602, respectively. These effects were mediated locally and were mostly inhibited by the two cannabinoid antagonists.

CONCLUSIONS AND IMPLICATIONS

The combination of the three compounds did not produce any greater anti-allodynic or anti-hyperalgesic effects, suggesting that FAAH inhibition could reduce or limit the anti-nociceptive effects of 2-AG. Peripheral administration of endocannabinoids or MGL/FAAH inhibitors is a promising analgesic approach requiring further investigation.

Authors+Show Affiliations

Department of Pharmacology, Université de Montréal-CHUM, Montréal, Quebec, Canada.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18695638

Citation

Desroches, J, et al. "Modulation of the Anti-nociceptive Effects of 2-arachidonoyl Glycerol By Peripherally Administered FAAH and MGL Inhibitors in a Neuropathic Pain Model." British Journal of Pharmacology, vol. 155, no. 6, 2008, pp. 913-24.
Desroches J, Guindon J, Lambert C, et al. Modulation of the anti-nociceptive effects of 2-arachidonoyl glycerol by peripherally administered FAAH and MGL inhibitors in a neuropathic pain model. Br J Pharmacol. 2008;155(6):913-24.
Desroches, J., Guindon, J., Lambert, C., & Beaulieu, P. (2008). Modulation of the anti-nociceptive effects of 2-arachidonoyl glycerol by peripherally administered FAAH and MGL inhibitors in a neuropathic pain model. British Journal of Pharmacology, 155(6), 913-24. https://doi.org/10.1038/bjp.2008.322
Desroches J, et al. Modulation of the Anti-nociceptive Effects of 2-arachidonoyl Glycerol By Peripherally Administered FAAH and MGL Inhibitors in a Neuropathic Pain Model. Br J Pharmacol. 2008;155(6):913-24. PubMed PMID: 18695638.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Modulation of the anti-nociceptive effects of 2-arachidonoyl glycerol by peripherally administered FAAH and MGL inhibitors in a neuropathic pain model. AU - Desroches,J, AU - Guindon,J, AU - Lambert,C, AU - Beaulieu,P, Y1 - 2008/08/11/ PY - 2008/8/13/pubmed PY - 2009/2/21/medline PY - 2008/8/13/entrez SP - 913 EP - 24 JF - British journal of pharmacology JO - Br J Pharmacol VL - 155 IS - 6 N2 - BACKGROUND AND PURPOSE: There are limited options for the treatment of neuropathic pain. Endocannabinoids, such as anandamide and 2-arachidonoyl glycerol (2-AG), are promising pain modulators and there is recent evidence of interactions between anandamide and 2-AG biosynthesis and metabolism. It has been clearly demonstrated that 2-AG degradation is mainly catalysed not only by monoacylglycerol lipase (MGL) but also by a fatty acid amide hydrolase (FAAH). Inhibitors specifically targeting these two enzymes have also been described: URB602 and URB597, respectively. However, the anti-nociceptive effects of the combination of peripherally injected 2-AG, URB602 and URB597 in a neuropathic pain model have not yet been determined. This was performed in the presence or absence of cannabinoid CB(1) (AM251) and CB(2) (AM630) receptor antagonists. EXPERIMENTAL APPROACH: Mechanical allodynia and thermal hyperalgesia were evaluated in 213 male Wistar rats allocated to 32 different groups. Drugs were injected subcutaneously in the dorsal surface of the hind paw (50 muL) 15 min before pain tests. KEY RESULTS: 2-AG, URB602 and URB597 significantly decreased mechanical allodynia and thermal hyperalgesia with ED50 of 1.6+/-1.5 and 127+/-83 mug for 2-AG and URB602, respectively. These effects were mediated locally and were mostly inhibited by the two cannabinoid antagonists. CONCLUSIONS AND IMPLICATIONS: The combination of the three compounds did not produce any greater anti-allodynic or anti-hyperalgesic effects, suggesting that FAAH inhibition could reduce or limit the anti-nociceptive effects of 2-AG. Peripheral administration of endocannabinoids or MGL/FAAH inhibitors is a promising analgesic approach requiring further investigation. SN - 1476-5381 UR - https://www.unboundmedicine.com/medline/citation/18695638/Modulation_of_the_anti_nociceptive_effects_of_2_arachidonoyl_glycerol_by_peripherally_administered_FAAH_and_MGL_inhibitors_in_a_neuropathic_pain_model_ L2 - https://doi.org/10.1038/bjp.2008.322 DB - PRIME DP - Unbound Medicine ER -