title: Cyclooxygenase-2 inhibition potentiates morphine antinociception at the spinal level in a postoperative pain model.
abstract: OBJECTIVE
  After peripheral inflammatory stimuli, spinal cord cyclooyxgenase-2 (COX-2) mRNA and protein levels increase, whereas COX-1 is unchanged. In animal models of inflammatory pain, intrathecal COX-2 selective inhibitors suppress hyperalgesia. However, the role of spinal COX-2 inhibition in postoperative pain is not well elucidated. This study investigates whether a water-soluble COX-2 selective inhibitor, L-745337, can modify allodynic responses in a rat model of postoperative pain.
  
  
  METHODS
  Allodynia was induced in the left plantar hindpaw by surgical incision. Animals then received intrathecal (0-80 micro g) or subcutaneous (0-30 mg/kg) L-745337 coadministered with intrathecal morphine (0-2 nmol). Reduction of mechanical allodynia (increased withdrawal threshold) was quantified with calibrated von Frey hairs.
  
  
  RESULTS
  L-745337 alone, whether intrathecal or systemic, had no effect on withdrawal threshold. When intrathecal L-745337 at doses of 40 to 80 micro g was combined with a subthreshold dose (0.5 nmol) of morphine, withdrawal thresholds were increased in a dose-dependent manner. Adding 80 micro g L-745337 to 1 nmol morphine produced an antiallodynic effect greater than that of morphine at twice the dose. Subcutaneous L-745337, up to 30 mg/kg combined with intrathecal morphine resulted in the same antiallodynic response as morphine alone.
  
  
  CONCLUSIONS
  These results suggest a spinal interaction of COX-2 inhibition with opiate analgesia may allow a reduction of postoperative pain with lower doses of opiate.
authors.affiliation: Department of Anesthesiology, Rush Medical College at Rush-Presbyterian-St. Luke's Medical Center, Chicago IL 60612, USA. jkroin@rush.edu
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Kroin
authors.forename: Asokumar
authors.initials: A
authors.lastname: Buvanendran
authors.forename: Robert J
authors.initials: RJ
authors.lastname: McCarthy
authors.forename: Hila
authors.initials: H
authors.lastname: Hemmati
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Tuman
mesh_terms: D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D007189:Indans / Q000008:administration & dosage / Q000494:pharmacology*; D007278:Injections, Spinal; D007279:Injections, Subcutaneous; D007527:Isoenzymes / Q000378:metabolism*; D008297:Male; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology*; D010147:Pain Measurement / Q000187:drug effects; D017288:Pain Threshold / Q000187:drug effects; D010149:Postoperative Pain / Q000188:drug therapy* / Q000523:psychology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects*
chemical_list: D000701:Analgesics, Opioid; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007189:Indans; D007527:Isoenzymes; C093700:L 745337; D009020:Morphine; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases