title: Analgesic tolerance to morphine is regulated by PPARγ.
abstract: OBJECTIVE
  Opioid drugs are potent analgesics. However, their chronic use leads to the rapid development of tolerance to their analgesic effects and subsequent increase of significant side effects, including drug dependence and addiction. Here, we investigated the role of PPARγ in the development of analgesic tolerance to morphine in mice.
  
  
  METHODS
  We monitored analgesia on alternate days using the tail immersion test.
  
  
  RESULTS
  Daily administration of morphine (30 mg·kg(-1) , bid) resulted in the rapid development of tolerance to thermal analgesia. Co-administration of pioglitazone (10 and 30 mg·kg(-1) , bid) significantly attenuated the development and expression of tolerance. However, pretreatment with GW-9662 (5 mg·kg(-1) , bid), a selective PPARγ antagonist, completely abolished this effect. Injection of GW-9662 and a lower dose of morphine (15 mg·kg(-1) , bid) accelerated the development of tolerance to its antinociceptive effect. Subsequently, we found that conditional neuronal PPARγ knockout (KO) mice develop a more rapid and pronounced tolerance to morphine antinociception compared with wild-type (WT) controls. Moreover, in PPARγ KO mice, pioglitazone was no longer able to prevent the development of morphine tolerance.
  
  
  CONCLUSIONS
  Overall, our results demonstrate that PPARγ plays a tonic role in the modulation of morphine tolerance, and its pharmacological activation may help to reduce its development. These findings provide new information about the role of neuronal PPARγ and suggest that combining PPARγ agonists with opioid analgesics may reduce the development of tolerance and possibly attenuate the potential for opioid abuse.
authors.affiliation: School of Pharmacy, Pharmacology Unit, University of Camerino, Camerino, Italy.
authors.forename: Giordano
authors.initials: G
authors.lastname: de Guglielmo
authors.forename: Marsida
authors.initials: M
authors.lastname: Kallupi
authors.forename: Giulia
authors.initials: G
authors.lastname: Scuppa
authors.forename: Serena
authors.initials: S
authors.lastname: Stopponi
authors.forename: Gregory
authors.initials: G
authors.lastname: Demopulos
authors.forename: George
authors.initials: G
authors.lastname: Gaitanaris
authors.forename: Roberto
authors.initials: R
authors.lastname: Ciccocioppo
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology* / Q000627:therapeutic use; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D004361:Drug Tolerance / Q000502:physiology*; D006358:Hot Temperature; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009020:Morphine / Q000494:pharmacology* / Q000627:therapeutic use; D009043:Motor Activity / Q000187:drug effects; D047495:PPAR gamma / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D010146:Pain / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D000077205:Pioglitazone; D045162:Thiazolidinediones / Q000494:pharmacology
chemical_list: C457499:2-chloro-5-nitrobenzanilide; D000701:Analgesics, Opioid; D000813:Anilides; D047495:PPAR gamma; D045162:Thiazolidinediones; D009020:Morphine; D000077205:Pioglitazone