title: Robust anti-nociceptive effects of monoacylglycerol lipase inhibition in a model of osteoarthritis pain.
abstract: 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-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 CB1and CB2receptors. 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.
  
  
  
  Our data support further assessment of the therapeutic potential of MAG lipase inhibitors for the treatment of OA pain.
authors: Arthritis Research UK Pain Centre, University of Nottingham, Medical School, Queen's Medical Centre, Nottingham, UK. james.burston@nottingham.ac.uk.|School of Life Sciences, University of Nottingham, Medical School, Queen's Medical Centre, Nottingham, UK. james.burston@nottingham.ac.uk.
authors: James J
authors: JJ
authors: Burston
authors: Arthritis Research UK Pain Centre, University of Nottingham, Medical School, Queen's Medical Centre, Nottingham, UK.
authors: Paul I
authors: PI
authors: Mapp
authors: Centre for Analytical Bioscience, School of Pharmacy, University of Nottingham, Nottingham, UK.
authors: Sarir
authors: S
authors: Sarmad
authors: Centre for Analytical Bioscience, School of Pharmacy, University of Nottingham, Nottingham, UK.
authors: David A
authors: DA
authors: Barrett
authors: The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA, USA.|Committee of Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA, USA.
authors: Micah J
authors: MJ
authors: Niphakis
authors: The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA, USA.|Committee of Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA, USA.
authors: Benjamin F
authors: BF
authors: Cravatt
authors: Arthritis Research UK Pain Centre, University of Nottingham, Medical School, Queen's Medical Centre, Nottingham, UK.
authors: David A
authors: DA
authors: Walsh
authors: Arthritis Research UK Pain Centre, University of Nottingham, Medical School, Queen's Medical Centre, Nottingham, UK. victoria.chapman@nottingham.ac.uk.|School of Life Sciences, University of Nottingham, Medical School, Queen's Medical Centre, Nottingham, UK. victoria.chapman@nottingham.ac.uk.
authors: Victoria
authors: V
authors: Chapman
mesh_terms: D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D007270:Injections, Intra-Articular; D019807:Iodoacetic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010003:Osteoarthritis / Q000188:drug therapy*; D010146:Pain / Q000188:drug therapy*; D010147:Pain Measurement; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000700:Analgesics; D004791:Enzyme Inhibitors; D008994:Monoacylglycerol Lipases; D019807:Iodoacetic Acid