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dc.contributor.authorWalsh, David A
dc.date.accessioned2021-11-15T14:34:25Z
dc.date.available2021-11-15T14:34:25Z
dc.date.issued2016-11
dc.identifier.citationBurston, J. J. et al. (2016) ‘Robust anti-nociceptive effects of monoacylglycerol lipase inhibition in a model of osteoarthritis pain’, British journal of pharmacology, 173(21), pp. 3134–3144en_US
dc.identifier.urihttp://hdl.handle.net/20.500.12904/14981
dc.description.abstractBackground 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.
dc.description.urihttps://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bph.13574en_US
dc.publisherBJP British Journal of Pharmacologyen_US
dc.subjectOsteoarthritisen_US
dc.subjectPainen_US
dc.subjectAnalgesicsen_US
dc.subjectEnzyme inhibitorsen_US
dc.titleRobust inhibitory effects of MAG lipase inhibition in a model of osteoarthritis pain.en_US
dc.typeArticleen_US
rioxxterms.funderDefault funderen_US
rioxxterms.identifier.projectDefault projecten_US
rioxxterms.versionNAen_US
rioxxterms.versionofrecord10.1111/bph.13574en_US
rioxxterms.typeJournal Article/Reviewen_US
refterms.dateFOA2021-11-15T14:34:25Z
refterms.panelUnspecifieden_US
refterms.dateFirstOnline2016-09
html.description.abstractBackground 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.en_US
rioxxterms.funder.project94a427429a5bcfef7dd04c33360d80cden_US


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