Changes in benzodiazepine-receptor activity modify morphine withdrawal syndrome in mice

doi:10.1016/0376-8716(92)90064-J

Drug and Alcohol Dependence

Volume 30, Issue 3, August 1992, Pages 293-300

https://doi.org/10.1016/0376-8716(92)90064-J Get rights and content

Abstract

The effects of different benzodiazepine-receptor ligands on morphine withdrawal were studied: a benzodiazepine agonist, flunitrazepam; a benzodiazepine antagonist, flumazenil; a partial inverse benzodiazepine agonist, Ro 15-4513; and a partial benzodiazepine agonist, Ro 16-6028. Benzodiazepine-ligands were administered i.p. 30 min before naloxone-induced morphine withdrawal syndrome. Jumping behaviour was significantly increased by Ro 15-4513 at 10 and 20 mg/kg. Flunitrazepam decreased jumps at all the doses used. Wet dog shakes were decreased by flumazenil and Ro 15-4513 and increased by Ro 16-6028 (only at the highest dose) and flunitrazepam. Our results show that the activation of the benzodiazepine receptor by agonists or high doses of partial agonists decreases jumping and increases wet dog shake behaviour, while the antagonists or the partial inverse agonists enhance jumping and decrease wet dog shakes. These modifications could be interpreted as an attenuation in the severity of the morphine withdrawal syndrome by benzodiazepine agonists.

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GABA withdrawal syndrome: GABA<inf>A</inf> receptor, synapse, neurobiological implications and analogies with other abstinences
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Citation Excerpt :
When GABA-produced hyperexcitability is present, neurons of the somatomotor cortex that exhibit an increase in their activity also demonstrate a decrease in the activity of the muscarinic receptors (Silva-Barrat et al., 2001), an increase in the activation of narcotic receptors (Silva-Barrat et al., 2005), and a decrease in the outward current of K+, (Silva-Barrat and Champagnat, 1995), as well as an increase in the expression of the acetyl-cholinesterase enzyme in epileptic discharge foci (Araneda et al., 1994). Withdrawal induced by the interruption of the administration of drugs such as benzodiazepines produces an increase in the expression of opioid receptors and, in addition, pre-treatment with benzodiazepines decreases the symptoms of morphine abstinence (MA) (Valverde et al., 1992; Suzuki et al., 1996). These synaptic changes suggest a functional and neurochemical arrangement in the brain cortex and hippocampus as a consequence of the hyperexcitability produced by the abstinences.
The sudden interruption of the increase of the concentration of the gamma-aminobutyric acid (GABA), determines an increase in neuronal activity. GABA withdrawal (GW) is a heuristic analogy, with withdrawal symptoms developed by other GABA receptor-agonists such as alcohol, benzodiazepines, and neurosteroids. GW comprises a model of neuronal excitability validated by electroencephalogram (EEG) in which high-frequency and high-amplitude spike–wave complexes appear. In brain slices, GW was identified by increased firing synchronization of pyramidal neurons and by changes in the active properties of the neuronal membrane. GW induces pre- and postsynaptic changes: a decrease in GABA synthesis/release, and the decrease in the expression and composition of GABA_A receptors associated with increased calcium entry into the cell.
GW is an excellent bioassay for studying partial epilepsy, epilepsy refractory to drug treatment, and a model to reverse or prevent the generation of abstinences from different drugs.
The effects of diazepam dependence and withdrawal on morphine-induced antinociception and changes in locomotion in male and female rats
2001, Pharmacology Biochemistry and Behavior
Male and female rats were exposed for 3 weeks to diazepam (DZ)-filled or empty capsules (CTR) prior to the daily administration of morphine (MOR, 5 mg/kg, IP) for 5 days. Thereafter, capsules were removed and 48 h later MOR was injected for the next 5 days. The tail-flick latency (TFL) was measured prior to and 15, 30, and 60 min after MOR assessed analgesia. Locomotion (LOC) was determined before and 15 min after injection. Prior to MOR injection (baseline), male rats were more sensitive to the thermal stimulus and were less active than female rats. Daily MOR injections neither affected the baseline TFL nor LOC. Regardless of gender, MOR produced greater analgesia in DZ-dependent and withdrawn rats than in CTR. MOR analgesia was greater in DZ-dependent male than in female rats. Gender differences in MOR analgesia were not of statistical significance in DZ-withdrawn rats. The first dose of MOR produced more depression of LOC in DZ-dependent female than in male rats. Across the time of MOR injections, female DZ-dependent and withdrawn rats were less active than CTR. LOC increased with repeated administration of MOR in all groups of rats. In summary, DZ dependence and withdrawal enhanced MOR analgesia in rats of both sexes. Regardless of chronic treatment, MOR produced more analgesia and less depression of LOC in male than in female rats. It is suggested that a decrease in the function of the GABAergic system plays a role in alteration of MOR analgesia.
Reversal of morphine tolerance and dependence by melatonin: Possible role of central and peripheral benzodiazepine receptors
1999, Brain Research
Possible reversal by melatonin of morphine-induced tolerance and dependence was studied in mice. A 10-day repeated injection regimen was followed to induce morphine tolerance and dependence. Co-administration of melatonin (1–10 mg/kg, i.p.) with morphine (10 mg/kg, s.c.) during the induction phase (day 1 to 9) reversed the development of opioid tolerance and dependence tested on 10th day. On the other hand acute administration of melatonin (1–10 mg/kg) on the 10th day, ie. during the expression phase of morphine dependence, it reduced the incidence of naloxone-induced withdrawal jumps without affecting the tolerance to analgesic effect. Co-administration of flumazenil (2 mg/kg, i.p.), a central benzodiazepine (BZ) receptor antagonist had no effect on melatonin response, whereas peripheral antagonist for BZ receptor PK11195 (2 mg/kg, i.p.) significantly reversed the attenuating effect of melatonin on physical dependence both during induction and expression phase of morphine tolerance and dependence. These observations suggest that melatonin reverses development of tolerance and dependence to morphine, and this action possibly involved peripheral benzodiazepine receptors.
Inhibition of morphine tolerance and dependence by diazepam and its relation to μ-opioid receptors in the rat brain and spinal cord
1998, Brain Research
We have recently observed that concomitant administration of diazepam to morphine pellet implanted rats results in the inhibition of the development of morphine tolerance and dependence. We have now analyzed μ-opioid receptors in rats treated with morphine and diazepam for 5 days by using $[^{3} H]$ -DAMGO for binding studies. Male Sprague–Dawley rats were made tolerant and dependent by subcutaneous (s.c.) implantation of six morphine pellets (two pellets on the first day, and four on the second day). Diazepam (0.25 mg/kg b.wt) was injected once daily intraperitoneally (i.p.) for 5 days. Control rats were implanted with placebo pellets and injected once daily with saline or diazepam (i.p.). Animals were administered s.c. naloxone (10 mg/kg) to induce naloxone-precipitated withdrawal syndrome on the final day of the experiment (day 5). There was an up-regulation of μ-receptor (B_max increased) in the spinal cord of morphine tolerant (+139%) and dependent (+155%) rats compared to saline treated animals. Diazepam treatment abolished the up-regulation of μ-receptors in spinal cord of morphine treated rats. In the cortex, B_max was not affected in morphine tolerant or dependent rats but it decreased by 38% in morphine tolerant and 65% in morphine dependent rats treated with diazepam. The K_d of μ-receptors increased in the cortex, striatum and hypothalamus of morphine dependent rats. Diazepam treatment decreased the K_d of μ-receptors in the cortex of morphine tolerant and hypothalamus of morphine-dependent rats. These results suggest that diazepam treatment antagonizes the up-regulation of CNS μ-receptors observed in morphine tolerant rats. In addition, morphine tolerance and dependence may be associated with conversion of μ-opioid receptors to μ*-constitutive opioid receptors that are less active, and this conversion is prevented in the brain of animals treated with diazepam.
Study of the mechanisms involved in behavioral changes induced by flunitrazepam in morphine withdrawal
1995, Progress in Neuropsychopharmacology and Biological Psychiatry
- 1.
  1. The attenuation of morphine withdrawal syndrome by acute benzodiazepine administration has been well documented. However, the pharmacological mechanisms implicated in this effect remain unclear.
- 2.
  2. In this study, the possible participation of noradrenergic, serotonergic and benzodiazepine receptors on flunitrazepam-modified morphine withdrawal syndrome was investigated in mice. Flunitrazepam was associated to the noradrenergic antagonists prazosin (1 mg/kg) and propranolol (0.5 mg/kg), the serotonergic agents ritanserine (1 mg/kg) and p-chloro phenylalanine (600 mg/kg), the benzodiazepine antagonist flumazenil (10 mg/kg), and the benzodiazepine partial inverse agonist Ro 15-4513 (5 mg/kg).
- 3.
  3. The decrease in jumping behavior-induced by flunitrazepam was potentiated by prazosin, while ritanserine, flumazenil and Ro 15-4513 blocked this effect.
- 4.
  4. Flunitrazepam-induced increase on wet dog shake frequency was partially reduced by flumazenil, and strongly antagonized by ritanserine and Ro 15-4513.
- 5.
  5. Noradrenergic and serotonergic systems seem to be primarily implicated in the changes induced on jumping and wet dog shakes respectively. These modifications are induced through the activation of the benzodiazepine receptors.
Intracisternal administration of interleukin-1β attenuates naloxone-precipitated withdrawal in morphine-dependent mice
1995, European Journal of Pharmacology
The effect of central administration of interleukin-1β on naloxone-precipitated withdrawal in morphine-dependent mice was studied. The degree of physical dependence on morphine was estimated by counting the number of jumps precipitated by naloxone, one of the typical withdrawal signs. Intracisternal (i.c.) administration of interleukin-1β (0.01 – 1 ng/5 μl per mouse) to morphine-dependent mice 30 min prior to the injection of naloxone (10 mg/kg i.p.) decreased the number of jumps in a dose-dependent manner. The effect of interleukin-1β (1 ng) was significantly antagonized when it was co-administered with interleukin-1 receptor antagonist (1 μg/mouse). These results suggest that centrally administered interleukin-1β could attenuate naloxone-precipitated withdrawal in morphine-dependent mice via interleukin-1 receptors in the brain. Co-administration of α-melanocyte-stimulating hormone (300 ng/mouse) or α-helical corticotropin-releasing factor (CRF)-(9–41), a CRF receptor antagonist (300 ng/mouse), with interleukin-1β also antagonized the inhibitory effect of interleukin-1β (1 ng). Moreover, i.c. administration of CRF (200 ng/mouse) significantly decreased the number of jumps.

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^∗: Present address: Unité de Pharmacochimie Moléculaire. INSERM U 266. Faculté de Pharmacie. 4, avenue de l'Observatoire. 75006 Paris, France.

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Changes in benzodiazepine-receptor activity modify morphine withdrawal syndrome in mice

Abstract

Pharmacol. Biochem. Behav.

Neuroscience

Gen. Pharmacol.

Neuropharmacology

Prog. Neuro-Psychopharmacol. Biol. Psychiat.

Neurosci. Lett.

Eur. J. Pharmacol.

Pharmacol. Biochem. Behav.

Pharmacol. Biochem. Behav.

Exp. Neurol.

Brain Res. (Mol. Brain Res.)

Pharmacol. Biochem. Behav.

Life Sci.

Neuropharmacology

Eur. J. Pharmacol.

Neurosci. Lett.

Cortical acetylcholine release is increased and gamma-aminobutyric acid outflow is reduced during morphine withdrawal

Br. J. Pharmacol.

Dopaminergic mechanisms in precipitated withdrawal in morphine dependent rats

J. Pharmacol. Exp. Ther.

Similar effects of a beta-carboline and of flumazenil in negatively and positively reinforced learning tasks in mice

Life Sci.

Effects of antispychotic and antianxiety drugs on morphine abstinence syndrome in rats

J. Pharmacol. Exp. Ther.

Behavioural effects of the benzodiazepine receptor partial agonist Ro. 16-6028 in mice

Psychopharmacology

Development of physical dependence on morphine in respect to time and dosage and quantification of the precipitated withdrawal syndrome in rats

Psychopharmacologia

An azido analogue of the benzodiazepine antagonist Ro. 15-1788 (Ro. 15-4513) behaves as partial inverse agonist

Neurosci. Lett. Suppl.