A pharmacological modulation of opiate withdrawal using an up-/down-regulation of the noradrenergic system in opiate-dependent rats.
Chronic opioid exposure induces neuroadaptative changes in several brain systems. Amongst others the alpha adrenergic system appears to be extremely sensitive to opioid exposure and has, therefore, been proposed to play a key role in opiate withdrawal symptoms. In order to better understand the influence of the noradrenergic system in opioid withdrawal and be able to develop new therapeutic strategies, we studied the effect of pre-treatment with the alpha2 agonist (clonidine) and alpha2 antagonist (yohimbine) on naloxone-precipitated withdrawal in opiate-dependent rats. As is already known clonidine pre-treatment significantly enhances autonomic and behavioural signs of opioid withdrawal whereas yohimbine significantly attenuates them with dose-related effect. We also tested the effect of clonidine (0.1 mg/kg) during naloxone-precipitated opiate withdrawal in rats pre-treated with yohimbine (5 mg/kg) and we observed that yohimbine pre-treatment potentiates clonidine efficiency in decreasing opiate withdrawal signs. This study supports the possibility of using a noradrenergic antagonist in order to regulate adrenoreceptors chronically exposed to opioids, therefore interfering with the intensity of naloxone-precipitated opiate withdrawal and potentiating later effectiveness of noradrenergic agonists like clonidine. These results may have various applications in clinical opiate detoxification protocols and are discussed through an up-/down- regulation of adrenoreceptors.
Streel
Emmanuel
E
Université Libre de Bruxelles, CHU Brugmann, Service de Psychiatrie, Clinique d'Alcoologie et Toxicomanies, Laboratoire de recherche sur la biologie des dépendances, Bruxelles, Belgium. manu.streel@chu-brugmann.be
Dan
Bernard
B
Campanella
Salvatore
S
Meyvaert
Alain
A
Hanak
Catherine
C
Pelc
Isy
I
Verbanck
Paul
P
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology / Q000627:therapeutic use; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D003000:Clonidine / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology*; D004347:Drug Interactions; D008297:Male; D009020:Morphine / Q000009:adverse effects; D009021:Morphine Dependence / Q000188:drug therapy / Q000503:physiopathology*; D009294:Narcotics / Q000009:adverse effects; D009638:Norepinephrine / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy / Q000503:physiopathology*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*; D015016:Yohimbine / Q000494:pharmacology / Q000627:therapeutic use
D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D009294:Narcotics; D015016:Yohimbine; D009020:Morphine; D003000:Clonidine; D009638:Norepinephrine