DOI: 10.5061/dryad.tmpg4f584
title: Acute pain after total knee arthroplasty: 2-arachidonoylglycerol tone and endocannabinoid/eicosanoid crosstalk

description: Background: Total knee arthroplasty (TKA) is a surgical procedure that
 induces intense acute postoperative pain, but the mechanisms that amplify
 post-TKA pain remain incompletely understood. Endocannabinoids, such as
 2-arachidonoylglycerol (2-AG), are endogenous lipids that can produce
 antinociceptive effects. However, hydrolysis of 2-AG by monoacylglycerol
 lipase (MAGL) generates arachidonic acid, the precursor to a host of
 eicosanoids that enhance pain. The presence of this metabolic pathway
 suggests that individuals with elevated 2-AG levels may be primed to
 develop greater postoperative pain. Methods: The primary goal of this
 prospective study was to determine if intraoperative 2-AG levels in the
 synovial fluid (SF) and cerebrospinal fluid (CSF) of TKA patients are
 associated with the magnitude of acute postoperative pain at rest and with
 ambulation. The secondary goal was to determine whether 2-AG metabolism
 contributes to prostaglandin E2 (PGE2) biosynthesis in synovial tissue ex
 vivo. Results: Ninety subjects were enrolled in the study. SF 2-AG was
 positively correlated with pain at rest (r = 0.2644; p = 0.0157) and with
 ambulation (r = 0.3856; p = 0.0005) while CSF 2-AG was associated with
 pain at rest (r = 0.3312; p = 0.0017) but not with ambulation (r = 0.1454;
 p 0.1871). Stratification of the results by gender revealed positive
 correlations between 2-AG and pain in females, which were markedly weaker
 or not observed in males. Ex vivo analysis demonstrated co-expression of
 MAGL and cyclooxygenase-2 in synovial membranes, with MAGL inhibition by
 MJN110 elevating 2-AG levels (median, vehicle: 0.165 nmol/g vs MJN110:
 0.325 nmol/g, p = 0.0269) and concomitantly reducing PGE2 (median,
 vehicle: 5.645 nmol/g vs MJN110: 3.440 nmol/g, p = 0.0425). Conclusions:
 Our findings demonstrate that patients presenting with an elevated 2-AG
 tone develop greater postoperative pain and position MAGL as an enzymatic
 node linking 2-AG metabolism with eicosanoid biosynthesis in perioperative
 human tissue.
description: # Acute pain after total knee arthroplasty: 2-arachidonoylglycerol tone
 and endocannabinoid/eicosanoid crosstalk Dataset DOI:
 [10.5061/dryad.tmpg4f584](10.5061/dryad.tmpg4f584) ## Description of the
 data and file structure Intraoperative 2-AG levels in synovial fluid and
 cerebrospinal fluid of patients undergoing total knee arthroplasty.
 Preoperative and postoperative patient-reported pain. Prostaglandin E2
 (PGE2) levels in the synovial fluid of patients undergoing total knee
 arthroplasty. 2-arachidonoylglycerol (2-AG), arachidonic acid (AA), and
 PGE2 levels in synovial explants treated with vehicle or 10 uM MJN110. ###
 Files and variables #### File: Endocannabinoids_data_repository.xlsx
 **Tab:** Data **Description:** Preoperative pain, postoperative pain, and
 intraoperative 2-AG levels in synovial fluid and cerebrospinal fluid of
 patients undergoing total knee arthroplasty (TKA). ##### Variables * Sex *
 Age * Body mass index (BMI) * Koos Jr interval pain scores * Numeric
 rating scale (NRS) preoperative pain scores * NRS postoperative pain at
 rest 24 hours after TKA * NRS postoperative pain with ambulation 24 hours
 after TKA * Morphine equivalent (MME) postoperative analgesia *
 Cerebrospinal fluid (CSF) 2-AG levels * Synovial fluid (SF) 2-AG levels *
 SF prostaglandin E2 (PGE2) levels **Tab:** Ex vivo
 **Description:** Ex-vivo levels of 2-AG, AA, and PGE2 in synovial tissues
 incubated with vehicle or the monoacylglycerol lipase (MAGL) inhibitor
 MJN110 (10 µM) for 6 hours. **Variables** * PGE2 (nmol/g) * AA (nmol/g) *
 2-AG (nmol/g) * Vehicle * 10 µM MJN110 n/a = data not available ## Human
 subjects data Explicit consent was provided from participants to publish
 the de-identified data in the public domain. Subjects were de-identified
 and were assigned a study number representing their data.