title: Is withdrawal hyperalgesia in morphine-dependent mice a direct effect of a low concentration of the residual drug?
abstract: Withdrawal of opioid drugs leads to a cluster of unpleasant symptoms in dependent subjects. These symptoms are stimulatory in nature and oppose the acute, inhibitory effects of opiates. The conventional theory that explains the opioid withdrawal syndrome assumes that chronic usage of opioid drugs activates compensatory mechanisms whose stimulatory effects are revealed upon elimination of the inhibitory opioid drug from the body. Based on previous studies that show a dose-dependent dual activity of opiates, including pain perception, we present here an alternative explanation to the phenomenon of withdrawal-induced hyperalgesia. According to this explanation, the residual low concentration of the drug that remains after cessation of its administration elicits the stimulatory withdrawal hyperalgesia. The goal of the present study was to test this hypothesis. In the present study we rendered mice dependent on morphine by a daily administration of the drug. Cessation of morphine application elicited withdrawal hyperalgesia that was completely blocked by a high dose of the opiate antagonist naloxone (100 mg/kg). Similarly, naloxone (2 mg/kg)-induced withdrawal hyperalgesia was also blocked by 100 mg/kg of naloxone. The blockage of withdrawal hyperalgesia by naloxone suggested the involvement of opioid receptors in the phenomenon and indicated that withdrawal hyperalgesia is a direct effect of a residual, low concentration of morphine. Acute experiments that show morphine- and naloxone-induced hyperalgesia further verified our hypothesis. Our findings offer a novel, alternative approach to opiate detoxifications that may prevent withdrawal symptoms by a complete blockage of the opioid receptors using a high dose of the opioid antagonist.
authors.affiliation: Department of Physiology and Pharmacology, Tel-Aviv University, Tel-Aviv, Israel. rubovitc@post.tau.ac.il
authors.forename: Vardit
authors.initials: V
authors.lastname: Rubovitch
authors.forename: Chaim G
authors.initials: CG
authors.lastname: Pick
authors.forename: Yosef
authors.initials: Y
authors.lastname: Sarne
mesh_terms: D000818:Animals; D002908:Chronic Disease; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D006930:Hyperalgesia / Q000175:diagnosis / Q000209:etiology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009020:Morphine / Q000009:adverse effects* / Q000097:blood / Q000378:metabolism*; D009270:Naloxone / Q000494:pharmacology / Q000627:therapeutic use; D009292:Narcotic Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D009619:Nociceptors / Q000378:metabolism; D011957:Receptors, Opioid / Q000187:drug effects; D012720:Severity of Illness Index; D013375:Substance Withdrawal Syndrome / Q000150:complications* / Q000209:etiology* / Q000517:prevention & control; D019966:Substance-Related Disorders / Q000378:metabolism
chemical_list: D009292:Narcotic Antagonists; D011957:Receptors, Opioid; D009270:Naloxone; D009020:Morphine