title: Antinociceptive tolerance to NSAIDs microinjected into dorsal hippocampus.
abstract: BACKGROUND
  Pain is characterized as a complex experience, dependent not only on the regulation of nociceptive sensory systems, but also on the activation of mechanisms that control emotional processes in limbic brain areas such as the amygdala and the hippocampus. Several lines of investigations have shown that in some brain areas, particularly the midbrain periaqueductal gray matter, rostral ventro-medial medulla, central nucleus of amygdala and nucleus raphe magnus, microinjections of non-steroidal anti-inflammatory drugs (NSAIDs) induce antinociception with distinct development of tolerance. The present study was designed to examine whether microinjection of NSAIDs, clodifen, ketorolac and xefocam into the dorsal hippocampus (DH) leads to the development of antinociceptive tolerance in male rats.
  
  
  METHODS
  The experiments were carried out on experimental and control (with saline) white male rats. Animals were implanted with a guide cannula in the DH and tested for antinociception following microinjection of NSAIDs into the DH in the tail-flick (TF) and hot plate (HP) tests. Repeated measures of analysis of variance with post-hoc Tukey-Kramer multiple comparison tests were used for statistical evaluations.
  
  
  RESULTS
  We found that microinjection of these NSAIDs into the DH induces antinociception as revealed by a latency increase in the TF and HP tests compared to controls treated with saline into the DH. Subsequent tests on days 2 and 3, however, showed that the antinociceptive effect of NSAIDs progressively decreased, suggesting tolerance developed to this effect of NSAIDs. Both pretreatment and post-treatment with the opioid antagonist naloxone into the DH significantly reduced the antinociceptive effect of NSAIDs in both pain models.
  
  
  CONCLUSIONS
  Our results indicate that microinjection of NSAIDs into the DH induces antinociception which is mediated via the opioid system and exhibits tolerance.
authors.forename: Gulnazi
authors.initials: G
authors.lastname: Gurtskaia
authors.forename: Nana
authors.initials: N
authors.lastname: Tsiklauri
authors.forename: Ivliane
authors.initials: I
authors.lastname: Nozadze
authors.forename: Marina
authors.initials: M
authors.lastname: Nebieridze
authors.affiliation: Dept of Neurophysiology, Ivane Beritashvili Center for Experimental Biomedicine, Gotua Street 14, Tbilisi 0160, Georgia. tsagareli@biphysiol.ge.
authors.forename: Merab G
authors.initials: MG
authors.lastname: Tsagareli
mesh_terms: D000701:Analgesics, Opioid / Q000008:administration & dosage* / Q000627:therapeutic use; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage* / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects; D004008:Diclofenac / Q000008:administration & dosage / Q000627:therapeutic use; D004351:Drug Resistance; D006624:Hippocampus; D020910:Ketorolac / Q000008:administration & dosage / Q000627:therapeutic use; D008297:Male; D008845:Microinjections; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D010146:Pain / Q000188:drug therapy*; D010894:Piroxicam / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000701:Analgesics, Opioid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D009292:Narcotic Antagonists; D010894:Piroxicam; D004008:Diclofenac; D009270:Naloxone; C059451:lornoxicam; D020910:Ketorolac