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 Naloxone induced contraction in morphine withdrawn isolated rat ileum was employed as an in vitro model of opioid withdrawal syndrome.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.