PMID- 31937359
OWN - NLM
STAT- MEDLINE
DCOM- 20201124
LR  - 20201124
IS  - 1478-6362 (Electronic)
IS  - 1478-6354 (Print)
IS  - 1478-6354 (Linking)
VI  - 22
IP  - 1
DP  - 2020 Jan 14
TI  - Combatting joint pain and inflammation by dual inhibition of monoacylglycerol 
      lipase and cyclooxygenase-2 in a rat model of osteoarthritis.
PG  - 9
LID - 10.1186/s13075-020-2096-3 [doi]
LID - 9
AB  - BACKGROUND: Endocannabinoids are showing great promise as effective mediators for 
      controlling joint inflammation and pain. One strategy that could be harnessed to 
      promote endogenous cannabinoid function is to inhibit the enzymatic break down of 
      endocannabinoids locally in the joint. KML29 is an inhibitor of monoacylglycerol 
      lipase (MAGL) activity which has been shown to promote increased 
      2-arachodonylglycerol (2-AG) levels in the circulation and in peripheral tissues. 
      It is also known that 2-AG can be metabolised via the cyclo-oxygenase-2 (COX-2) 
      pathway leading to the production of pro-inflammatory prostaglandins, which may 
      counteract the effects of 2-AG. Therefore, this study examined the effect of 
      KML29 alone as well as in combination with low-dose celecoxib (CXB) on joint 
      pain and inflammation in the monoiodoacetate (MIA) model of osteoarthritis (OA) 
      pain. METHODS: Injection of MIA (3 mg) into the knee joints of male Wistar rats 
      was used to model OA pain, inflammation, and nerve damage. Pain behaviour was 
      assessed by von Frey hair algesiometry, and inflammation was evaluated using 
      intravital microscopy to measure leukocyte trafficking in the synovial 
      microvasculature. RESULTS: Intra-articular injection of MIA produced mechanical 
      hypersensitivity as measured by von Frey hair algesiometry. Local injection of 
      KML29 (700 mug) reduced joint pain at day 14 post-MIA induction, and this 
      analgesic effect was blocked by the cannabinoid receptor antagonists AM281 and 
      AM630 (P < 0.0001; n = 6). During the acute inflammatory phase of the MIA model 
      (day 1), a significant reduction in withdrawal threshold (P < 0.0001; n = 6-8) 
      and leukocyte trafficking was seen after treatment with KML29 + CXB (P < 0.0001; 
      n = 6-8). Early treatment of MIA-injected knees (days 1-3) with KML29 + CXB 
      ameliorated the development of mechanical secondary allodynia (P < 0.0001; n = 8) 
      in the later stages of the MIA model. CONCLUSIONS: Combination therapy of KML29 
      plus CXB reduced joint pain and inflammation. Thus, dual inhibition of MAGL and 
      cyclooxygenase-2 pathways could be a useful approach to alleviate joint 
      inflammation and pain in OA joints.
FAU - Philpott, Holly T
AU  - Philpott HT
AD  - Departments of Pharmacology and Anaesthesia, Pain Management & Perioperative 
      Medicine, Dalhousie University, 5850 College Street, Halifax, Nova Scotia, B3H 
      4R2, Canada.
FAU - McDougall, Jason J
AU  - McDougall JJ
AUID- ORCID: 0000-0003-4529-3428
AD  - Departments of Pharmacology and Anaesthesia, Pain Management & Perioperative 
      Medicine, Dalhousie University, 5850 College Street, Halifax, Nova Scotia, B3H 
      4R2, Canada. jason.mcdougall@dal.ca.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200114
PL  - England
TA  - Arthritis Res Ther
JT  - Arthritis research & therapy
JID - 101154438
RN  - 0 (1,1,1,3,3,3-hexafluoropropan-2-yl 
      4-(bis(benzo(d)(1,3)dioxol-5-yl)(hydroxy)methyl)piperidine-1-carboxylate)
RN  - 0 (Anti-Inflammatory Agents)
RN  - 0 (Benzodioxoles)
RN  - 0 (Cyclooxygenase 2 Inhibitors)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Piperidines)
RN  - EC 3.1.1.23 (Monoacylglycerol Lipases)
RN  - JCX84Q7J1L (Celecoxib)
SB  - IM
MH  - Animals
MH  - Anti-Inflammatory Agents/pharmacology
MH  - Arthralgia/etiology
MH  - Benzodioxoles/*pharmacology
MH  - Celecoxib/pharmacology
MH  - Cyclooxygenase 2 Inhibitors/*pharmacology
MH  - Disease Models, Animal
MH  - Drug Therapy, Combination
MH  - Enzyme Inhibitors/pharmacology
MH  - Inflammation/etiology
MH  - Knee Joint/*drug effects
MH  - Male
MH  - Monoacylglycerol Lipases/antagonists & inhibitors
MH  - *Osteoarthritis, Knee/complications
MH  - Piperidines/*pharmacology
MH  - Rats
MH  - Rats, Wistar
PMC - PMC6961325
OTO - NOTNLM
OT  - Cannabinoids
OT  - Coxib
OT  - Inflammation
OT  - Neuropathy
OT  - Osteoarthritis
OT  - Pain
COIS- The authors declare that they have no competing interests.
EDAT- 2020/01/16 06:00
MHDA- 2020/11/25 06:00
PMCR- 2020/01/14
CRDT- 2020/01/16 06:00
PHST- 2019/06/26 00:00 [received]
PHST- 2020/01/05 00:00 [accepted]
PHST- 2020/01/16 06:00 [entrez]
PHST- 2020/01/16 06:00 [pubmed]
PHST- 2020/11/25 06:00 [medline]
PHST- 2020/01/14 00:00 [pmc-release]
AID - 10.1186/s13075-020-2096-3 [pii]
AID - 2096 [pii]
AID - 10.1186/s13075-020-2096-3 [doi]
PST - epublish
SO  - Arthritis Res Ther. 2020 Jan 14;22(1):9. doi: 10.1186/s13075-020-2096-3.