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

Burston, James, 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 monoacylglycerol lipase inhibition in a model of osteoarthritis pain. British Journal of Pharmacology 173 (21) , pp. 3134-3144. 10.1111/bph.13574

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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 monoacylglycerol (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 ± 6 g; MIA/MJN110: 35 ± 4 g) and lowered ipsilateral PWTs (MIA/vehicle: 7 ± 0.8 g; MIA/MJN110: 11 ± 0.6 g), 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 1 week of repeated administration but had no effect on joint histology. MJN110 significantly inhibited expression of membrane‐associated PGE synthase‐1 in the ipsilateral dorsal horn of the spinal cord of MIA rats, compared with vehicle‐treated MIA rats. Both doses of MJN110 significantly elevated brain levels of the endocannabinoid 2‐arachidonoylglycerol. Conclusions and Implications Our data support further assessment of the therapeutic potential of MAG lipase inhibitors for the treatment of OA pain.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	Nature Publishing Group
ISSN:	0007-1188
Date of First Compliant Deposit:	7 June 2018
Date of Acceptance:	22 July 2016
Last Modified:	12 May 2023 00:52
URI:	https://orca.cardiff.ac.uk/id/eprint/112056

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