title: Ammonium pyrrolidine dithiocarbamate and RS 102895 attenuate opioid withdrawal in vivo and in vitro.
abstract: BACKGROUND
  Recently, nuclear factor kappa B is indicated in the precipitation of opioid withdrawal syndrome. NF-κB activation is noted to control the transcription and biochemical activation of chemokines. Opioid receptor activation-linked chemokine stimulation is reported to mediate certain effects produced by prolonged opioid treatment. Ammonium pyrrolidine dithiocarbamate (APD) and RS 102895 are relatively selective inhibitors of NF-κB and C-C chemokine receptor 2, respectively.
  
  
  OBJECTIVE
  The present study investigates the effect of APD and RS 102895 on morphine withdrawal signs in vitro and in vivo.
  
  
  METHODS
  Morphine was administered twice daily for 5 days, following which a single day 6 injection of naloxone (8 mg/kg, i.p.) precipitated opioid withdrawal syndrome in mice. Withdrawal syndrome was quantitatively assessed in terms of withdrawal severity score and the frequency of jumping, rearing, fore paw licking and circling. Naloxone-induced contraction in morphine-withdrawn isolated rat ileum was employed as an in vitro model. An isobolographic study design was employed in the two models to assess potential synergistic activity between APD and RS 102895.
  
  
  RESULTS
  APD and RS 102895 dose-dependently attenuated naloxone-induced morphine withdrawal syndrome both in vivo and in vitro. APD was also observed to exert a synergistic interaction with RS 102895.
  
  
  CONCLUSIONS
  It is concluded that APD and RS 102895 attenuate morphine withdrawal signs possibly by a NF-κB and C-C chemokine receptor 2 activation pathway-linked mechanisms potentially in an interdependent manner.
authors.affiliation: Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, 147002, India.
authors.forename: Ashish K
authors.initials: AK
authors.lastname: Rehni
authors.forename: Nirmal
authors.initials: N
authors.lastname: Singh
mesh_terms: D000818:Animals; D048588:Benzoxazines / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D007082:Ileum / Q000187:drug effects; D008297:Male; D051379:Mice; D009020:Morphine / Q000009:adverse effects*; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D009270:Naloxone / Q000009:adverse effects / Q000037:antagonists & inhibitors; D010880:Piperidines / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy*; D013859:Thiocarbamates / Q000494:pharmacology*
chemical_list: D048588:Benzoxazines; D016328:NF-kappa B; D010880:Piperidines; D011759:Pyrrolidines; C573791:RS 102895; D054390:Receptors, CCR2; D013859:Thiocarbamates; C020972:pyrrolidine dithiocarbamic acid; D009270:Naloxone; D009020:Morphine