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Pretreatment with midazolam suppresses morphine withdrawal response in mice and rats
Jun-Li Cao1, Hai-Lei Ding, Li-Cai Zhang
1Department of Anesthesiology, Affiliated Hospital of Xuzhou Medical College, Xuzhou 221002, China. xmcfa@public.xz.js.cn
Aim:
To investigate the roles of pretreatment with midazolam on morphine withdrawal in mice and rats.
Methods:
Acute and chronic morphine dependence and naloxone-precipitated withdrawal models were employed in the present study. Cyclic adenosine monophosphate (AMP) content and Fos protein expression were measured by radioimmunoassay and immunocytochemistry, respectively.
Results:
Coadministration of midazolam (2 mg/kg, ip) and morphine prevented the development of both acute and chronic morphine dependence in mice. Compared to saline-morphine group (3.0, 95 % confidence limits: 1.9-4.3 mg/kg), ED50 of naloxone-precipitated withdrawal jumping increased significantly in midazolam-morphine group (10.4, 95 % confidence limits: 8.5-12.3 mg/kg) in acute morphine-dependent mice (P<0.01). Pretreatment with midazolam lowered the number and incidence of naloxone-precipitated withdrawal jumping and prevented loss in body weight in chronic morphine-dependent mice (P<0.01). Midazolam-pretreatment inhibited the increase of Fos protein expression, not cyclic AMP content, in rat spinal cord during morphine withdrawal.
Conclusion:
Midazolam suppresses morphine withdrawal response by inhibiting hypersensitization of the spinal cord neurons, and this effect may not be mediated by cAMP pathway.
Insights
Midazolam pretreatment effectively suppresses morphine withdrawal symptoms in mice and rats by inhibiting spinal cord neuron hypersensitization. This effect on opioid withdrawal appears independent of the cyclic adenosine monophosphate (cAMP) pathway.
Area of Science:
- Neuroscience
- Pharmacology
Background:
- Opioid dependence and withdrawal present significant clinical challenges.
- Understanding the neurobiological mechanisms underlying morphine withdrawal is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the efficacy of midazolam pretreatment in mitigating morphine withdrawal symptoms in rodent models.
- To explore the potential involvement of cyclic adenosine monophosphate (cAMP) and Fos protein expression in midazolam's effects on morphine withdrawal.
Main Methods:
- Utilized acute and chronic morphine dependence models in mice and rats.
- Assessed naloxone-precipitated withdrawal behaviors, including jumping and body weight changes.
- Measured cyclic adenosine monophosphate (cAMP) content and Fos protein expression in the rat spinal cord.
Main Results:
- Midazolam co-administration with morphine prevented the development of both acute and chronic morphine dependence.
- Midazolam significantly increased the ED50 of naloxone-precipitated withdrawal jumping in acute models and reduced withdrawal incidence in chronic models.
- Midazolam pretreatment inhibited Fos protein expression but not cAMP levels in the rat spinal cord during morphine withdrawal.
Conclusions:
- Midazolam effectively suppresses morphine withdrawal responses in rodents.
- The mechanism of action involves inhibiting hypersensitization of spinal cord neurons.
- The observed effects of midazolam on morphine withdrawal are likely not mediated by the cAMP pathway.