title: Pharmacological modulation of geranylgeranyltransferase and farnesyltransferase attenuates opioid withdrawal in vivo and in vitro.
abstract: Geranylgeranyltransferase and farnesyltransferase I, are noted to mediate a number of signal transduction cascades which are known to be involved in the causation of opioid withdrawal syndrome. GGTI-2133 and FTI-276 are selective modulators of geranylgeranyltransferase and farnesyltransferase subtype 1 respectively. Therefore, the present study investigated the effect of GGTI-2133 and FTI-276 on propagation of morphine dependence and resultant withdrawal signs in vivo, in sub-chronic morphine mouse model, and in vitro, in isolated rat ileum. 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 & circling. Naloxone induced contraction in morphine withdrawn isolated rat ileum was employed as an in vitro model of opioid withdrawal syndrome. An isobolographic study design was employed to assess a potential synergistic activity between GGTI-2133 and FTI-276. GGTI-2133 and FTI-276 dose dependently attenuated naloxone induced morphine withdrawal syndrome both in vivo and in vitro. GGTI-2133 was also observed to exert a synergistic interaction with FTI-276. It is concluded that GGTI-2133 and FTI-276 attenuate the propagation of morphine dependence and reduce withdrawal signs possibly by a geranylgeranyl transferase; farnesyltransferase activation pathway linked mechanisms potentially in an interdependent manner.
authors: Department of Pharmacology, Chitkara College of Pharmacy, Chitkara University, Chandigarh Patiala National Highway, Rajpura, Patiala 147002 Punjab, India. ashishkrehni@gmail.com
authors: Ashish K
authors: AK
authors: Rehni
authors: Thakur Gurjeet
authors: TG
authors: Singh
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D007082:Ileum; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D066298:In Vitro Techniques; D007930:Leucine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008715:Methionine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D009021:Morphine Dependence / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D009281:Naphthalenes / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D013375:Substance Withdrawal Syndrome / Q000517:prevention & control*
chemical_list: D004791:Enzyme Inhibitors; C404062:FTI 276; C547856:GGTI-2133; D007093:Imidazoles; D009281:Naphthalenes; D008715:Methionine; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; D051231:Farnesyltranstransferase; D007930:Leucine