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Robust anti‐nociceptive effects of monoacylglycerol lipase inhibition in a model of osteoarthritis pain
Author(s) -
Burston James J,
Mapp Paul I,
Sarmad Sarir,
Barrett David A,
Niphakis Micah J,
Cravatt Benjamin F,
Walsh David A,
Chapman Victoria
Publication year - 2016
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13574
Subject(s) - monoacylglycerol lipase , osteoarthritis , endocannabinoid system , medicine , nociception , spinal cord , endocrinology , neuropathic pain , chronic pain , anesthesia , pharmacology , receptor , pathology , physical therapy , alternative medicine , psychiatry
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 CB 1 and CB 2 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.