Very Low Naltrexone Treatment of Opiate Withdrawal
Principal Investigator: Elisabeth J Van Bockstaele
Abstract: It is the intention of this R21 application to gather data regarding the feasibility of a novel opiate detoxification method, with the use of very low-dose naltrexone pretreatment to reduce withdrawal symptoms in morphine dependent rats. Pharmacological withdrawal management is often the first step in the treatment of opiate dependent patients. Although a wide range of detoxification techniques have been employed, there is a continuing search for more effective approaches. Recently, the use of opiate antagonists (i.e. naltrexone, naloxone) in detoxification protocols has been introduced to sharply decrease withdrawal duration, but at the cost of greatly increased symptom intensity requiring heavy sedation and even anesthesia. Resulting serious medical complications has discouraged and limited the use of this approach. On the other hand, experimental evidence on analgesic and dependence-reducing properties of very low doses of opiate antagonists points to an alternative strategy for the use of these antagonist drugs during detoxification. Although the behavioral manifestations of opiate withdrawal have been thoroughly described in animal models, the cellular bases underlying these changes have only recently been characterized. Several brain nuclei exhibit immediate early gene expression (e.g. c-fos), which is used as a marker of neuronal activation, in the course of withdrawal. Furthermore, alterations in intracellular messengers, including cyclic adenosine monophosphate (cAMP)-dependent protein kinases (PKA), and cAMP-response element-binding protein (CREB) have been shown following opiate withdrawal in the central nervous system. Specific purpose of this study is to test the hypothesis that pretreatment of opiate dependent rats with very-low doses of opiate antagonists ameliorates behavioral and biochemical expressions of withdrawal. Experiments in Aim I are proposed to examine whether naltrexone pretreatment reduces the aversive and somatic signs of withdrawal. To this end, behavioral expression of withdrawal will be rated according to a well-described score of behaviors. Aim II will examine the distribution of c-fos protein in brain regions known to be activated following withdrawal to test whether very low-dose naltrexone pretreatment diminishes the expression of c-fos in these brain areas. Finally, Aim Ill will use western blot analysis to examine levels of intracellular messengers known to be increased during withdrawal to determine whether these are altered following pretreatment with low-doses of naltrexone. The information collected will provide the necessary foundation for designing detoxification trials in humans.
Funding Period: 2003-03-15 - 2008-01-31
more information: NIH RePORT
- Elevated mu-opioid receptor expression in the nucleus of the solitary tract accompanies attenuated withdrawal signs after chronic low dose naltrexone in opiate-dependent ratsE J van Bockstaele
Department of Neurosurgery, Farber Institute for Neurosciences, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA
J Neurosci Res 83:508-14. 2006....
- Antagonist treatment of opioid withdrawal translational low dose approachPaolo Mannelli
Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27704, USA
J Addict Dis 25:1-8. 2006....
- Low dose naltrexone administration in morphine dependent rats attenuates withdrawal-induced norepinephrine efflux in forebrainElisabeth J Van Bockstaele
Thomas Jefferson University, Department of Neurosurgery, Farber Institute for Neurosciences, Philadelphia, PA 19107, United States
Prog Neuropsychopharmacol Biol Psychiatry 32:1048-56. 2008....
- Mu-opioid receptor redistribution in the locus coeruleus upon precipitation of withdrawal in opiate-dependent ratsJILLIAN L SCAVONE
Department of Neurosurgery, Farber Institute for Neurosciences, Thomas Jefferson University, Philadelphia, Pennsylania, USA
Anat Rec (Hoboken) 292:401-11. 2009..Mechanisms underlying this effect might include differential MOR regulation in the LC, or downstream effects of withdrawal-induced enkephalin (ENK) release from afferents to the LC...