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

Abstract

BACKGROUND AND PURPOSEChronic 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 APPROACHIntra-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 RESULTSAcute MJN110 (5 mg·kg À1 ) 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 À1 ) resulted in anti-nociceptive tolerance. A lower dose of MJN110 (1 mg·kg À1 ) 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 IMPLICATIONSOur data support further assessment of the therapeutic potential of MAG lipase inhibitors for the treatment of OA pain. Abbreviations

The Endogenous Cannabinoid System: A Budding Source of Targets for Treating Inflammatory and Neuropathic Pain

“…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. 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).…”

Monoacylglycerol Lipase Inhibition in Human and Rodent Systems Supports Clinical Evaluation of Endocannabinoid Modulators

“…The antinociceptive effects observed at the ED 50 were associated with ABD-1970 concentrations less than 10 nM in the brain and blood, 40% inhibition of brain MGLL activity, and 3-fold elevations in brain 2-AG concentrations. Multiple previous studies have demonstrated sustained antinociceptive, antiallodynic, and antihyperalgesic effects after repeated administration of MGLL inhibitors at low doses that partially inhibit MGLL in the brain (Busquets-Garcia et al, 2011;Kinsey et al, 2013;Burston et al, 2016;Curry et al, 2018), whereas tolerance to these effects has been observed after prolonged, complete MGLL inhibition or genetic ablation (Chanda et al, 2010;Schlosburg et al, 2010;Ignatowska-Jankowska et al, 2014). The functional tolerance observed with complete MGLL inactivation and maximal elevation of brain 2-AG concentrations is associated with downregulation and/or desensitization of brain CB1 receptors (Chanda et al, 2010;Schlosburg et al, 2010;Navia-Paldanius et al, 2015).…”

The Endocannabinoid System Alleviates Pain in a Murine Model of Cancer-Induced Bone Pain

“…MJN110, a prototypic MAGL inhibitor, has shown to be effective at alleviating neuropathic pain in animal models (Burston et al, 2016;Wilkerson et al, 2016). Cancer-induced bone pain (CIBP) displays characteristics of neuropathic and inflammatory pain (Lozano-Ondoua et al, 2013b;Slosky et al, 2016); thus targeting pain of inflammatory and neuropathic origin is rational.…”