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. and Chapman, Victoria (2016) Robust anti-nociceptive effects of MAG lipase inhibition in a model of osteoarthritis pain. British Journal of Pharmacology, 173 (21). pp. 3134-3144. ISSN 1476-5381

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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.

Item Type: Article
Schools/Departments: University of Nottingham, UK > Faculty of Medicine and Health Sciences > School of Medicine
University of Nottingham, UK > Faculty of Medicine and Health Sciences > School of Life Sciences
University of Nottingham, UK > Faculty of Science > School of Pharmacy
Identification Number: https://doi.org/10.1111/bph.13574
Depositing User: Eprints, Support
Date Deposited: 20 Sep 2016 07:37
Last Modified: 08 May 2020 10:15
URI: https://eprints.nottingham.ac.uk/id/eprint/36179

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