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

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