Robust anti-nociceptive effects of MAG lipase inhibition in a model of osteoarthritis pain
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 sele...
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| Format: | Article |
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Wiley
2016
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| Online Access: | https://eprints.nottingham.ac.uk/36179/ |
| _version_ | 1848795237647908864 |
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| author | Burston, James J. Mapp, Paul I. Sarmad, Sarir Barrett, David A. Niphakis, Micah J. Cravatt, Benjamin F. Walsh, David A. Chapman, Victoria |
| author_facet | Burston, James J. Mapp, Paul I. Sarmad, Sarir Barrett, David A. Niphakis, Micah J. Cravatt, Benjamin F. Walsh, David A. Chapman, Victoria |
| author_sort | Burston, James J. |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | 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. |
| first_indexed | 2025-11-14T19:28:54Z |
| format | Article |
| id | nottingham-36179 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| last_indexed | 2025-11-14T19:28:54Z |
| publishDate | 2016 |
| publisher | Wiley |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-361792024-08-15T15:20:38Z https://eprints.nottingham.ac.uk/36179/ 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 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. Wiley 2016-10-10 Article PeerReviewed 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 http://onlinelibrary.wiley.com/doi/10.1111/bph.13574/abstract doi:10.1111/bph.13574 doi:10.1111/bph.13574 |
| spellingShingle | Burston, James J. Mapp, Paul I. Sarmad, Sarir Barrett, David A. Niphakis, Micah J. Cravatt, Benjamin F. Walsh, David A. Chapman, Victoria Robust anti-nociceptive effects of MAG lipase inhibition in a model of osteoarthritis pain |
| title | Robust anti-nociceptive effects of MAG lipase inhibition in a model of osteoarthritis pain |
| title_full | Robust anti-nociceptive effects of MAG lipase inhibition in a model of osteoarthritis pain |
| title_fullStr | Robust anti-nociceptive effects of MAG lipase inhibition in a model of osteoarthritis pain |
| title_full_unstemmed | Robust anti-nociceptive effects of MAG lipase inhibition in a model of osteoarthritis pain |
| title_short | Robust anti-nociceptive effects of MAG lipase inhibition in a model of osteoarthritis pain |
| title_sort | robust anti-nociceptive effects of mag lipase inhibition in a model of osteoarthritis pain |
| url | https://eprints.nottingham.ac.uk/36179/ https://eprints.nottingham.ac.uk/36179/ https://eprints.nottingham.ac.uk/36179/ |