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Constitutive opioid receptor activation: a prerequisite mechanism involved in acute opioid withdrawal
Author(s) -
Freye E,
Levy JV
Publication year - 2005
Publication title -
addiction biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.445
H-Index - 78
eISSN - 1369-1600
pISSN - 1355-6215
DOI - 10.1080/13556210500123019
Subject(s) - naltrexone , opioid , opioid receptor , opioid antagonist , pharmacology , medicine , agonist , antagonist , anesthesia , receptor antagonist , narcotic antagonist , endocrinology , (+) naloxone , receptor
The opioid receptor antagonist naltrexone, which is used in detoxification and rehabilitation programmes in opioid addicts, can precipitate opioid withdrawal symptoms even in patients who have no opioid present. We tested the hypothesis that in order to precipitate withdrawal, opioids need to convert the inactive opioid receptor site via protein kinase C into a constitutively active form on which the antagonist precipitates withdrawal. Acute abstinence symptoms were induced by the potent opioid receptor agonist sufentanil (21?μg/kg), given for 6 days, which was followed by the antagonist naltrexone (20?μg/kg i.v.) in the awake trained canine (n = 10). Abrupt displacement of opioid binding resulted in acute withdrawal symptoms: increase in blood pressure, heart rate, increase in amplitude height of somatosensory evoked potential, reduced tolerance to colon distention and a significant increase in grading of vegetative variables (restlessness, panting, thrashing of the head, whining, yawning, gnawing, salivation and/or rhinorrhoea, mydriasis, stepping of extremities and vomiting). Following a washout period of 14 days, the same animals were given the highly specific protein kinase C inhibitor H7 (250?μg/kg) prior to the same dosages of sufentanil and naltrexone. Such pretreatment was able to either attenuate or completely abolish the acute withdrawal symptoms. The data suggest that for precipitation of withdrawal, intracellular phosphorylation is a prerequisite in order to activate the opioid μ‐receptor. In such a setting, naltrexone acts like an ‘inverse agonist? relative to the action of the antagonist on a non‐preoccupied receptor site not being exposed previously to a potent opioid agonist.