title: Spontaneous withdrawal in intermittent morphine administration in rats and mice: effect of clonidine coadministration and sex-related differences.
abstract: OBJECTIVE
  Treating animals repeatedly with intermittent and increasing morphine doses has been suggested to allow some withdrawal during each dosing interval, which causes repeated stress. The present study aimed to test this hypothesis and assess sex-related differences in withdrawal signs and their suppression by clonidine.
  
  
  METHODS
  Male and female rats and mice were administered with increasing doses of morphine twice daily at different dosing intervals. Rats were given clonidine in drinking water (5 μg/mL). Spontaneous and naloxone-precipitated withdrawal signs and novelty-induced grooming were evaluated.
  
  
  RESULTS
  Male rats and male and female rats displayed manifestations of morphine withdrawal at the end of 14-h and 24-h dosing intervals, respectively. Clonidine attenuated the severity of the withdrawal signs. Male but not female mice displayed withdrawal signs at the end of 12-h and 17-h dosing intervals. Female mice exhibited less pronounced naloxone-precipitated withdrawal syndrome. Grooming did not reflect a "stress-like state" in morphine-treated animals.
  
  
  CONCLUSIONS
  These findings indicate intermittent morphine treatment-induced spontaneous withdrawal in rats and mice and sex-related differences in spontaneous and naloxone-precipitated withdrawal signs in mice. Since the treatment protocol closely parallels the drug use pattern in opioid addicts, further experiments are needed to clarify the stress associated with the treatment and the efficacy of sedatives.
authors.forename: Oruc
authors.initials: O
authors.lastname: Allahverdiyev
authors.forename: Asli Zengin
authors.initials: AZ
authors.lastname: Türkmen
authors.forename: Asiye
authors.initials: A
authors.lastname: Nurten
authors.forename: Iclal
authors.initials: I
authors.lastname: Sehirli
authors.forename: Nurhan
authors.initials: N
authors.lastname: Enginar
mesh_terms: D000700:Analgesics / Q000008:administration & dosage*; D000701:Analgesics, Opioid / Q000008:administration & dosage*; D000818:Animals; D003000:Clonidine / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006120:Grooming / Q000187:drug effects; D008297:Male; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D009020:Morphine / Q000008:administration & dosage*; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D017208:Rats, Wistar; D012737:Sex Factors; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy / Q000209:etiology*
chemical_list: D000700:Analgesics; D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D009270:Naloxone; D009020:Morphine; D003000:Clonidine