Robust anti‐nociceptive effects of monoacylglycerol lipase inhibition in a model of osteoarthritis pain
Open accessAbstract
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.
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Weight bearing restoration by MJN110 was only partially blocked by the CB2 receptor antagonist SR144528.
“However, weight bearing was only partially blocked by the CB 2 receptor antagonist, SR144528, but fully blocked by rimonabant, indicating a difference in receptor mechanism (Burston et al, 2016).”
From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Burston et al, 2016
The anti-allodynic effects of MJN110 are mediated by a CB2 receptor mechanism of action.
“The anti-allodynic effects of MJN110 were mediated by a CB 2 receptor mechanism of action, while CB 1 receptors did not play a necessary role in this effect.”
From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Burston et al, 2016
CB1 receptors did not play a necessary role in the anti-allodynic effects of MJN110.
“while CB 1 receptors did not play a necessary role in this effect.”
From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Burston et al, 2016
Weight bearing restoration by MJN110 was fully blocked by rimonabant.
“but fully blocked by rimonabant, indicating a difference in receptor mechanism (Burston et al, 2016).”
From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Burston et al, 2016
The differential blockade of MJN110 effects by SR144528 and rimonabant indicates a difference in receptor mechanism.
“indicating a difference in receptor mechanism (Burston et al, 2016).”
From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Burston et al, 2016
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- Authors
- Burston, J. J., Mapp, P. I., Sarmad, S., Barrett, D. A., Niphakis, M. J., Cravatt, B. F., Walsh, D. A., & Chapman, V.
- Affiliations
- University of Nottingham (GB)
- Scripps Research Institute (US)
- Corresponding author
- Burston, James J
- Chapman, Victoria
- ORCID
- Venue
- British Journal of Pharmacology
- Publisher
- Wiley
- Published
- 2016-09-23
- Volume
- 173
- Issue
- 21
- Pages
- 3134-3144
- ISSN
- 0007-1188 (ISSN-L)
- 1476-5381
- PMC
- PMC5056226
- OpenAlex
- W2528493014
- Cited by
- 30
- References
- 45
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 3 · 2023: 4 · 2022: 2 · 2021: 4 · 2020: 5 · 2019: 1 · 2018: 4 · 2017: 5
- FWCI
- 2.69
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- British Journal of Pharmacology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Repository@Nottingham (University of Nottingham) (publishedVersion, other-oa)
- Lincoln Repository (University of Lincoln) (acceptedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
- Repository@Nottingham (University of Nottingham) (submittedVersion, cc-by)
- Nottingham ePrints (University of Nottingham) (submittedVersion, cc-by)
- Figshare (submittedVersion, cc-by)
- Funders
- Versus Arthritis (18769)
- Topics
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Health Sciences › Medicine › Rheumatology › Osteoarthritis Treatment and Mechanisms
- Keywords
- monoacylglycerol lipase inhibition, monosodium iodoacetate, endocannabinoid system, CB1 receptor, CB2 receptor, antinociception, analgesic tolerance, prostaglandin E synthase-1, dorsal horn, 2-arachidonoylglycerol, weight-bearing asymmetry, paw withdrawal threshold
- MeSH terms
- Analgesics, Animals, Disease Models, Animal, Enzyme Inhibitors, Injections, Intra-Articular, Male, Monoacylglycerol Lipases, Osteoarthritis, Pain, Pain Measurement, Rats, Sprague-Dawley, Iodoacetic Acid, Rats
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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