title: Brain reward deficits accompany naloxone-precipitated withdrawal from acute opioid dependence.
abstract: Single injections with morphine can induce a state of acute opioid dependence in humans and animals, typically measured as precipitated withdrawal when an antagonist such as naloxone is administered 4-24 h after morphine. Repeated treatment with morphine results in a progressive shift in potency of naloxone to produce such acute withdrawal signs. The current study examined alterations in brain reward thresholds after acute and repeated treatment with morphine (5.6 mg/kg) using a discrete-trial current-intensity brain-stimulation reward procedure. Rats with stimulation electrodes aimed at the medial forebrain bundle at the level of the lateral hypothalamus were tested in twice daily sessions separated by 4 h. Separate groups of rats received treatment with morphine immediately after the first daily test session, and one of several doses of naloxone (0.10, 0.33, 1.0 mg/kg) 4 h later and immediately before the second session; these morphine and naloxone treatments were repeated for four consecutive days (Morphine-Repeat NAL). Additional groups examined the independent contribution of repeated morphine or repeated naloxone. One control group (Morphine-Vehicle) received morphine on all four treatment days, but vehicle before the second test session. A second group (Morphine-Single NAL) also received morphine on all four treatment days, but received 1.0 mg/kg only once after the final morphine pretreatment. A final control group received no morphine at all but received the 1.0-mg/kg dose of naloxone four times (Vehicle-Repeat NAL) before the second daily test session. Repeated naloxone alone (Vehicle-Repeat NAL) produced no changes in brain reward thresholds. Repeated morphine alone (Morphine-Vehicle) failed to alter reward thresholds measured 4 h postmorphine, but produced a slight increase in thresholds in the test sessions that occurred before morphine treatment on Days 3 and 4 (and hence 23.5 h after the previous day's morphine injection). This suggested the development of a modest spontaneous withdrawal-induced reward deficit measurable at 23.5 but not 4 h postmorphine. Naloxone dose-dependently increased brain reward thresholds 4 h after a single morphine pretreatment, with a further shift to the left in the naloxone dose-effect function resulting from repeated morphine and naloxone administration (Morphine-Repeat NAL). However, when the highest dose of naloxone was tested only after the final morphine pretreatment (Morphine-Single NAL), its potency was no different than when administered after the first morphine pretreatment. The results indicate that neuroadaptation within brain reward circuitry results in significant reward deficits after a single morphine pretreatment, and this deficit increases rapidly with repeated morphine and naloxone-induced withdrawal experience.
authors.affiliation: Department of Anesthesiology, UC San Diego School of Medicine, VA San Diego Healthcare System, 3350 La Jolla Village Drive, San Diego, CA 92161-5008, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.forename: Gery
authors.initials: G
authors.lastname: Schulteis
mesh_terms: D000208:Acute Disease; D000818:Animals; D001921:Brain / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D004567:Electrodes, Implanted; D008297:Male; D009020:Morphine / Q000494:pharmacology; D009270:Naloxone / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000494:pharmacology*; D009294:Narcotics / Q000494:pharmacology; D009293:Opioid-Related Disorders / Q000523:psychology*; D051381:Rats; D017208:Rats, Wistar; D012201:Reward; D013375:Substance Withdrawal Syndrome / Q000523:psychology*
chemical_list: D009292:Narcotic Antagonists; D009294:Narcotics; D009270:Naloxone; D009020:Morphine