Opioid Withdrawal for 4 Days Prevents Synaptic Depression Induced by Low Dose of Morphine or Naloxone in Rat Hippocampal CA1 Area In Vivo

The formation of memory is believed to depend on experience- or activity-dependent synaptic plasticity, which is exquisitely sensitive to psychological stress since inescapable stress impairs long-term potentiation (LTP) but facilitates long-term depression (LTD). Our recent studies demonstrated that 4 days of opioid withdrawal enables maximal extents of both hippocampal LTP and drug-reinforced behavior; while elevated-platform stress enables these phenomena at 18 h of opioid withdrawal. Here, we examined the effects of low dose of morphine (0.5 mg kg(-1), i.p.) or the opioid receptor antagonist naloxone (1 mg kg(-1), i.p.) on synaptic efficacy in the hippocampal CA1 region of anesthetized rats. A form of synaptic depression was induced by low dose of morphine or naloxone in rats after 18 h but not 4 days of opioid withdrawal. This synaptic depression was dependent on both N-methyl-D-aspartate receptor and synaptic activity, similar to the hippocampal long-term depression induced by low frequency stimulation. Elevated-platform stress given 2 h before experiment prevented the synaptic depression at 18 h of opioid withdrawal; in contrast, the glucocorticoid receptor (GR) antagonist RU38486 treatment (20 mg kg(-1), s.c., twice per day for first 3 days of withdrawal), or a high dose of morphine reexposure (15 mg kg(-1), s.c., 12 h before experiment), enabled the synaptic depression on 4 days of opioid withdrawal. This temporal shift of synaptic depression by stress or GR blockade supplements our previous findings of potentially correlated temporal shifts of LTP induction and drug-reinforced behavior during opioid withdrawal. Our results therefore support the idea that stress experience during opioid withdrawal may modify hippocampal synaptic plasticity and play important roles in drug-associated memory. (C) 2009 Wiley-Liss, Inc.

Effet de la morphine injectée en épidural associée ou non à la naloxone sur la respiration et la douleur chez des patients souffrant de lombosciatalgie chronique

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal.

Effect of naloxone-precipitated morphine withdrawal on c-fos expression in rat corticotropin-releasing hormone neurons in the paraventricular hypothalamus and extended amygdala

Morphine withdrawal is characterized by physical symptoms and a negative affective state. The 41 amino acid polypeptide corticotropin-releasing hormone (CRH) is hypothesized to mediate, in part, both the negative affective state and the physical withdrawal syndrome. Here, by means of dual-immunohistochemical methodology, we examined the co-expression of the c-Fos protein and CRH following naloxone-precipitated morphine withdrawal. Rats were treated with slow-release morphine 50 mg/kg (subcutaneous, s.c.) or vehicle every 48 h for 5 days, then withdrawn with naloxone 5 mg/kg (s.c.) or saline 48 h after the final morphine injection. Two hours after withdrawal rats were perfused transcardially and their brains were removed and processed for immunohistochemistry. We found that naloxone-precipitated withdrawal of morphine-dependent rats increased c-Fos immunoreactivity (IR) in CRH positive neurons in the paraventricular hypothalamus. Withdrawal of morphine-dependent rats also increased c-Fos-IR in the central amygdala and bed nucleus of the stria terminalis, however these were in CRH negative neurons.

Cardiorespiratory and endocrine effects of endogenous opioid antagonism by naloxone in ponies anaesthetised with halothane

Halothane depresses cardiorespiratory function and activates the pituitary-adrenal axis, increasing beta endorphin. In horses, beta endorphin may enhance the anaesthetic-associated cardiorespiratory depression and mortality risk. The authors studied endogenous opioid effects on cardiorespiratory function and pituitary-adrenal activity in halothane-anaesthetised ponies by investigating opioid antagonism by naloxone. Six ponies were anaesthetised three times (crossover design). Anaesthesia was induced with thiopentone and maintained with 1.2 per cent halothane for 2 hours. Immediately after induction, naloxone was administered either intra venously (0.5 mg kg(-1) bolus then 0.25 mg kg(-1) hour(-1) for 2 hours) or intrathecally (0.5 mg) or was replaced by saline as control. Pulse and respiratory rates, arterial blood gases, cardiac output and plasma cortisol and adrenocorticotrophic hormone (ACTH) concentrations were measured. All groups developed cardiorespiratory depression (40 per cent decrease in cardiac output) and plasma cortisol increased. Plasma ACTH concentration was higher in ponies treated with intrathecal naloxone. Endogenous opioids may inhibit ACTH Secretion, attenuating the stress response to halothane anaesthesia in equidae. (C) 2001 Harcourt Publishers Ltd.

Effect of naloxone-3-glucuronide and N-methylnaloxone on the motility of the isolated rat colon after morphine

The effect of the opioid antagonists naloxone-3-glucuronide and N-methylnaloxone on rat colon motility after morphine stimulation was measured. The rat model consisted of the isolated, vascularly perfused colon. The antagonists (10(-4) M, intraluminally) and morphine (10(-4) M, intra-arterially) were administered from 20 to 30 and from 10 to 50 min, respectively. Colon motility was determined by the luminal outflow. The antagonist concentrations in the luminal and venous outflow were measured by high-performance liquid chromatography. Naloxone-3-glucuronide and N-methylnaloxone reversed the morphine-induced reduction of the luminal outflow to baseline within 10 and 20 min, respectively. These antagonists were then excreted in the luminal outflow and could not be found in the venous samples. Naloxone, produced by hydrolysis or demethylation, was not detectable. In conclusion, highly polar naloxone derivatives peripherally antagonize the motility-lowering effect of morphine in the perfused isolated rat colon, are stable, and are not able to cross the colon-mucosal blood barrier.