ro13-9904 and Morphine-Dependence

Morphine withdrawal is associated with a hyperactivity of locus coeruleus (LC) neurons by an elevated glutamate neurotransmission in this nucleus. We postulate that reductions in the amount of glutamate in the LC by enhancing its reuptake or inhibiting its release could attenuate the behavioral and cellular consequences of morphine withdrawal.. We investigated the effect of chronic treatment with ceftriaxone (CFT), an excitatory amino acid transporter (EAAT2) enhancer, and acute administration of topiramate (TPM), a glutamate release inhibitor, on morphine withdrawal syndrome and withdrawal-induced glutamate receptor (GluR) desensitization in LC neurons from morphine-dependent rats.. Morphine withdrawal behavior was measured after naltrexone administration in rats implanted with a morphine (200 mg kg(-1)) emulsion for 3 days. GluR desensitization in the LC was assessed by performing concentration-effect curves for glutamate by extracellular electrophysiological recordings in vitro.. Treatments with CFT or TPM reduced, in a dose-related manner, the total behavioral score of naltrexone-precipitated morphine withdrawal. CFT and TPM, at doses that were effective in behavioral tests, also reduced the induction of GluR desensitization normally occurring in LC neurons from morphine-dependent rats. Acute treatment with the specific EAAT2 inhibitor dihydrokainic acid (DHK) prevented the effect of CFT on withdrawal syndrome and GluR desensitization. Perfusion with TPM inhibited KCl-evoked but not glutamate-induced activation of LC neurons in vitro.. Our results suggest that a reduction of synaptic concentrations of glutamate by enhancing EAAT2-mediated uptake or inhibiting glutamate release alleviates the behavioral response and the cellular changes in the LC during opiate withdrawal.

Topics: Analgesics, Opioid; Animals; Ceftriaxone; Fructose; Glutamic Acid; Locus Coeruleus; Male; Morphine Dependence; Neurons; Rats; Rats, Sprague-Dawley; Receptors, Glutamate; Substance Withdrawal Syndrome; Topiramate

Tolerance to and dependence on the analgesic effect of opioids is a pharmacological phenomenon that occurs after their prolonged administration.. The aim of this study was to evaluate the protective effects of ceftriaxone and amitriptyline on the development of morphine-induced tolerance and dependence.. In this study, 18 groups (9 groups each for tolerance and dependency tests) of mice (n = 8) received saline [10 mL/kg, intraperitoneally (i.p.)], morphine (50 mg/kg, i.p.), ceftriaxone (50 mg/kg, i.p., 100 mg/kg, i.p., and 200 mg/kg, i.p.), amitriptyline (5 mg/kg, i.p., 10 mg/kg, i.p., and 15 mg/kg, i.p.), or a combination of ceftriaxone (50 mg/kg, i.p.) and amitriptyline (5 mg/kg, i.p.) once per day for 4 days for investigation and comparison of the effects of ceftriaxone and amitriptyline on the prevention of dependency and tolerance to morphine. Tolerance was assessed with administration of morphine (9 mg/kg, i.p.) and using the hot plate test on the 5(th) day. In dependency tests, withdrawal symptoms were assessed on the 4(th) day for each animal 30 minutes after the administration of naloxone (4 mg/kg, i.p.; 2 hours after the last dose of morphine).. It was found that treatment with ceftriaxone or amitriptyline attenuated the development of tolerance to the antinociceptive effect of morphine and also reduced naloxone-precipitated withdrawal jumping and standing on feet. Furthermore, coadministration of ceftriaxone and amitriptyline at low doses (50 mg/kg, i.p. and 5 mg/kg, i.p., respectively) prior to morphine injection also decreased both morphine-induced tolerance and dependence.. Results indicate that the treatment with ceftriaxone and amitriptyline, alone or in combination, could attenuate the development of morphine-induced tolerance and dependence.

Topics: Amitriptyline; Animals; Ceftriaxone; Drug Tolerance; Male; Mice; Morphine; Morphine Dependence

beta-Lactam antibiotics enhance cellular glutamate uptake. As increased glutamatergic transmission is a primary mediator of opiate dependence, we tested the hypothesis that a beta-lactam antibiotic (ceftriaxone) prevents development of morphine physical dependence in rats. Morphine (20 mg/kg) was injected twice daily for 10 days to induce physical dependence. Naloxone (10 mg/kg) administration 1, 48, and 96 h after the last morphine injection induced a withdrawal syndrome characterized by the appearance of wet-dog shakes, teeth chattering, eye blinking, jumping, and paw tremor. Ceftriaxone (150, 200 mg/kg) injected once daily during chronic morphine exposure inhibited each naloxone-precipitated withdrawal sign. Ceftriaxone efficacy persisted even after the 96 h-naloxone (10 mg/kg) injection. These results suggest that beta-lactam antibiotics inhibit processes leading to development of morphine physical dependence.

Topics: Animals; Anti-Bacterial Agents; Ceftriaxone; Dose-Response Relationship, Drug; Male; Morphine; Morphine Dependence; Naloxone; Narcotic Antagonists; Narcotics; Rats; Rats, Sprague-Dawley; Substance Withdrawal Syndrome; Time Factors

In order to identify ceftriaxone and its analogs whether has the function of anti-tolerance of morphine and study the dose-effect relation of ceftriaxone in mice, hot plate method to measure pain threshold of mouse and naloxone withdrawal models were carried out and compared with normal saline group. Ceftriaxone and cefotaxime had the effect of anti-tolerance and anti-dependence of morphine notably. And ceftriaxone has the effect of anti-tolerance of morphine in a dose dependent manner.

Topics: Animals; Anti-Bacterial Agents; Cefotaxime; Ceftriaxone; Dose-Response Relationship, Drug; Drug Tolerance; Female; Mice; Morphine; Morphine Dependence; Pain Threshold; Random Allocation; Substance Withdrawal Syndrome