title: Antihypersensitivity effects of tramadol hydrochloride in a rat model of postoperative pain.
abstract: BACKGROUND
  Tramadol is used to treat a wide range of acute and chronic pain. This drug induces analgesia by 2 mechanisms of action: opioid receptor activation and enhancement of noradrenaline (NA) and serotonin (5-HT) transmission. The effect of tramadol on NA and 5-HT concentrations in the spinal cord, however, have not been assessed. In the present study, we investigated the antihypersensitivity effect of tramadol using a rat model of postoperative pain. We also evaluated the increase in NA and 5-HT levels in the spinal cord after tramadol injection using in vivo microdialysis.
  
  
  METHODS
  We made a hindpaw incision in male Sprague-Dawley rats (postoperative pain model). Tramadol was administered intraperitoneally and intrathecally 24 hours after paw incision. Mechanical hypersensitivity was measured by determining the withdrawal threshold using von Frey filaments. Microdialysis studies from the dorsal horn of the lumbar spinal cord were performed to measure NA and 5-HT levels after intraperitoneal injection of tramadol. We also measured the NA and 5-HT content in the spinal cord in normal rats and rats with paw incision.
  
  
  RESULTS
  Intraperitoneal (10, 20, and 40 mg/kg) and intrathecal (125, 250, and 500 μg) injection of tramadol produced an antihyperalgesic effect in a dose-dependent manner. The antihypersensitivity effect of tramadol was prevented by intrathecal pretreatment with methysergide (30 μg), a serotonin receptor antagonist; idazoxane (30 μg), a noradrenaline receptor antagonist; and naloxone (30 μg), a nonselective opioid receptor antagonist. Microdialysis study revealed that 5-HT and NA concentrations at the spinal dorsal horn were increased, peaking at 30 minutes after intraperitoneal injection of 20 mg/kg tramadol. Furthermore, the NA and 5-HT content in the ipsilateral dorsal half of the lumbar spinal cord was increased 1 day and 3 days after paw incision, respectively.
  
  
  CONCLUSIONS
  These findings indicate that tramadol inhibits postoperative hypersensitivity by increasing NA and 5-HT levels in the spinal cord and activating opioid receptors. Tramadol might be more effective in the early postoperative period when spinal NA and 5-HT levels are increased.
authors.affiliation: Department of Anesthesiology, Gunma University Graduate School of Medicine, 3-39-22, Showa, Maebashi, Gunma 371-8511, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kimura
authors.forename: Hideaki
authors.initials: H
authors.lastname: Obata
authors.forename: Shigeru
authors.initials: S
authors.lastname: Saito
mesh_terms: D018674:Adrenergic Antagonists / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006930:Hyperalgesia / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D007274:Injections, Intraperitoneal; D007278:Injections, Spinal; D008297:Male; D017551:Microdialysis; D009043:Motor Activity / Q000187:drug effects; D009292:Narcotic Antagonists / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D010149:Postoperative Pain / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D020671:Posterior Horn Cells / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000819:agonists / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D013997:Time Factors; D014147:Tramadol / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D018674:Adrenergic Antagonists; D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D011957:Receptors, Opioid; D012702:Serotonin Antagonists; D012701:Serotonin; D014147:Tramadol; D009638:Norepinephrine