title: Pioglitazone prevents morphine antinociceptive tolerance via ameliorating neuroinflammation in rat cerebral cortex.
abstract: BACKGROUND
  Opioid induced neuroinflammation is shown to be implicated in opioid analgesic tolerance development. In the present study the effect of pioglitazone on morphine-induced tolerance and neuroinflammation in the cerebral cortex of the rat was investigated.
  
  
  METHODS
  Various groups of rats received morphine (10mg/kg; ip) and vehicle (po), or morphine (10mg/kg) and pioglitazone (20 or 40 mg/kg; po) once a day for 17 days. In order to determine the possible involvement of PPAR-γ in the pioglitazone effect, one group of rats received PPAR-γ antagonist, GW-9662 (2mg/kg; sc), and pioglitazone (40 mg/kg) and morphine once daily for 17 days. Nociception was assessed using a tail flick apparatus and the percentage of the maximal possible effect was calculated as well. On 18th day, 2h after the last morphine injection, the cerebral cortex of the animals were harvested and the tissue levels of tumour necrosis factor alpha, interleukin-1beta, interleukin-6, interleukin-10 and nuclear factor-kappa B activity were determined.
  
  
  RESULTS
  Co-administration of pioglitazone (40 mg/kg) with morphine not only attenuated morphine-induced tolerance, but also prevented the up-regulation of pro-inflammatory cytokines (tumour necrosis factor alpha, interleukin-1beta, interleukin-6) and nuclear factor-kappa B activity in the rat cerebral cortex. Moreover, GW-9662 (2mg/kg) administration 30 min before pioglitazone, antagonized the above mentioned pioglitazone-induced effects.
  
  
  CONCLUSIONS
  It is concluded that oral administration of pioglitazone attenuates morphine-induced tolerance. This effect of pioglitazone may be, at least in part, due to its anti-inflammatory property which suppressed the cortical pro-inflammatory cytokine and inhibited of nuclear factor-kappa B activity.
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran; Biotechnology Research Center and Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.
authors.forename: Hamed
authors.initials: H
authors.lastname: Ghavimi
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Charkhpour
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy, Rasht University of Medical Sciences, Gilan, Iran.
authors.forename: Saeed
authors.initials: S
authors.lastname: Ghasemi
authors.affiliation: Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
authors.forename: Mehran
authors.initials: M
authors.lastname: Mesgari
authors.affiliation: Department of Clinical Pharmacy, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.
authors.forename: Hadi
authors.initials: H
authors.lastname: Hamishehkar
authors.affiliation: Department of Physiology and Pharmacology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran.
authors.forename: Katayoun
authors.initials: K
authors.lastname: Hassanzadeh
authors.affiliation: Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.
authors.forename: Sanam
authors.initials: S
authors.lastname: Arami
authors.affiliation: Cellular and Molecular Research Center, Kurdistan University of Medical Sciences, Sanandaj, Iran. Electronic address: kambizhassanzadeh@gmail.com.
authors.forename: Kambiz
authors.initials: K
authors.lastname: Hassanzadeh
mesh_terms: D000284:Administration, Oral; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000473:pathology*; D016207:Cytokines / Q000097:blood; D004361:Drug Tolerance; D004660:Encephalitis / Q000473:pathology / Q000517:prevention & control*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000378:metabolism; D010147:Pain Measurement / Q000187:drug effects; D000077205:Pioglitazone; D051381:Rats; D017208:Rats, Wistar; D045162:Thiazolidinediones / Q000494:pharmacology*
chemical_list: C457499:2-chloro-5-nitrobenzanilide; D000701:Analgesics, Opioid; D000813:Anilides; D016207:Cytokines; D007004:Hypoglycemic Agents; D016328:NF-kappa B; D047495:PPAR gamma; D045162:Thiazolidinediones; D009020:Morphine; D000077205:Pioglitazone
keywords: Cerebral cortex; Morphine tolerance; Neuroinflammation; Pioglitazone