Pretreatment with midazolam suppresses morphine withdrawal response in mice and rats.
OBJECTIVE
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.


CONCLUSIONS
Midazolam suppresses morphine withdrawal response by inhibiting hypersensitization of the spinal cord neurons, and this effect may not be mediated by cAMP pathway.
Cao
Jun-Li
JL
Department of Anesthesiology, Affiliated Hospital of Xuzhou Medical College, Xuzhou 221002, China. xmcfa@public.xz.js.cn
Ding
Hai-Lei
HL
Zhang
Li-Cai
LC
Duan
Shi-Ming
SM
Zeng
Yin-Ming
YM
D000249:Adenosine Monophosphate / Q000378:metabolism; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D051379:Mice; D008874:Midazolam / Q000494:pharmacology*; D009021:Morphine Dependence; D009270:Naloxone / Q000494:pharmacology; D016761:Oncogene Proteins v-fos / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000378:metabolism; D013375:Substance Withdrawal Syndrome / Q000378:metabolism / Q000517:prevention & control*
D014151:Anti-Anxiety Agents; D016761:Oncogene Proteins v-fos; D009270:Naloxone; D000249:Adenosine Monophosphate; D008874:Midazolam