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Robust anti-nociceptive effects of MAG lipase inhibition in a model of osteoarthritis pain

Burston, James J.; Mapp, Paul I.; Sarmad, Sarir; Barrett, David A.; Niphakis, Micah J.; Cravatt, Benjamin F.; Walsh, David A.; Chapman, Victoria

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Authors

James J. Burston

Paul I. Mapp

David A. Barrett

Micah J. Niphakis

Benjamin F. Cravatt

David A. Walsh



Abstract

BACKGROUND AND PURPOSE: Chronic pain is often a symptom of knee osteoarthritis (OA) for which current analgesics are either inadequate, or are associated with serious side effects. The endocannabinoid system may offer alternative targets for pain-relief. We evaluated the effects of a potent and selective MAG lipase inhibitor (MJN110) on OA pain behaviour, spinal mechanisms of action and joint histopathology in the rat.
Experimental approach: Intra-articular injection of monosodium iodoacetate (MIA) models OA pain and mimics clinical joint pathology. Effects of MJN110 on MIA-induced weight bearing asymmetry and lowered paw withdrawal thresholds (PWTs), changes in spinal gene expression and brain levels of relevant lipids were determined.
Key results: Acute MJN110 (5 mg·kg−1) significantly reversed MIA induced weight bearing asymmetry (MIA /vehicle: 68 ± 6g; MIA /MJN110: 35 ± 4g, p<0.05) and lowered ipsilateral PWTs (MIA /vehicle: 7 ± 0.8g; MIA /MJN110: 11 ± 0.6g, p<0.05), via both CB1 and CB2 receptors. Repeated treatment with MJN110 (5 mg·kg−1) resulted in anti-nociceptive tolerance. A lower dose of MJN110 (1 mg·kg−1) acutely inhibited pain behaviour, which was maintained for one week of repeated administration, but had no effect on joint histology. MJN110 significantly inhibited expression of MPGES1 (p<0.05) in the ipsilateral dorsal horn of the spinal cord of MIA rats, compared to vehicle treated MIA rats. Both doses of MJN110 significantly elevated brain levels of the endocannabinoid 2-AG.
Conclusions and Implications: Our data support the further investigation of the therapeutic potential of MAG lipase inhibitors for the treatment of OA pain.

Citation

Burston, J. J., Mapp, P. I., Sarmad, S., Barrett, D. A., Niphakis, M. J., Cravatt, B. F., Walsh, D. A., & Chapman, V. (2016). Robust anti-nociceptive effects of MAG lipase inhibition in a model of osteoarthritis pain. British Journal of Pharmacology, 173(21), 3134-3144. https://doi.org/10.1111/bph.13574

Journal Article Type Article
Acceptance Date Jul 22, 2016
Online Publication Date Aug 7, 2016
Publication Date Oct 10, 2016
Deposit Date Sep 20, 2016
Publicly Available Date Sep 20, 2016
Journal British Journal of Pharmacology
Print ISSN 0007-1188
Electronic ISSN 1476-5381
Publisher Wiley
Peer Reviewed Peer Reviewed
Volume 173
Issue 21
Pages 3134-3144
DOI https://doi.org/10.1111/bph.13574
Public URL https://nottingham-repository.worktribe.com/output/824035
Publisher URL http://onlinelibrary.wiley.com/doi/10.1111/bph.13574/abstract
Contract Date Sep 20, 2016

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