Burston James J, Mapp Paul I, Sarmad Sarir, Barrett David A, Niphakis Micah J, Cravatt Benjamin F, Walsh David A, Chapman Victoria
Arthritis Research UK Pain Centre, University of Nottingham, Medical School, Queen's Medical Centre, Nottingham, UK.
School of Life Sciences, University of Nottingham, Medical School, Queen's Medical Centre, Nottingham, UK.
Br J Pharmacol. 2016 Nov;173(21):3134-3144. doi: 10.1111/bph.13574. Epub 2016 Sep 23.
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.
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.
Acute MJN110 (5 mg·kg ) 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 and CB receptors. Repeated treatment with MJN110 (5 mg·kg ) resulted in anti-nociceptive tolerance. A lower dose of MJN110 (1 mg·kg ) 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.
Our data support further assessment of the therapeutic potential of MAG lipase inhibitors for the treatment of OA pain.
慢性疼痛常为膝骨关节炎（OA）的一种症状，而目前的镇痛药对此要么效果不佳，要么伴有严重的副作用。内源性大麻素系统可能为缓解疼痛提供其他靶点。我们评估了一种强效且选择性的单酰甘油（MAG）脂肪酶抑制剂（MJN110）对大鼠OA疼痛行为、脊髓作用机制及关节组织病理学的影响。
关节内注射碘乙酸钠（MIA）可模拟OA疼痛并再现临床关节病理变化。测定了MJN110对MIA诱导的负重不对称及爪部撤离阈值（PWT）降低的影响，以及脊髓基因表达和相关脂质脑水平的变化。
急性给予MJN110（5 mg·kg）可通过CB1和CB2受体显著逆转MIA诱导的负重不对称（MIA/溶剂对照组：68±6 g；MIA/MJN110：35±4 g）并提高同侧PWT（MIA/溶剂对照组：7±0.8 g；MIA/MJN110：11±0.6 g）。重复给予MJN110（5 mg·kg）会导致抗伤害感受耐受性。较低剂量的MJN110（1 mg·kg）急性抑制疼痛行为，这种作用在重复给药1周后仍持续，但对关节组织学无影响。与溶剂对照处理的MIA大鼠相比，MJN110显著抑制MIA大鼠脊髓同侧背角中膜相关前列腺素E合酶-1的表达。两种剂量的MJN110均显著提高脑内内源性大麻素2-花生四烯酸甘油的水平。
我们的数据支持进一步评估MAG脂肪酶抑制剂治疗OA疼痛的治疗潜力。
