Molecular mechanisms in dizocilpine-induced attenuation of development of morphine dependence: an association with cortical Ca2+/calmodulin-dependent signal cascade.
We investigated how dizocilpine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, affects the development of morphine dependence in mice. Co-administration of dizocilpine (0.25 mg/kg) and morphine (10 mg/kg) for 5 days attenuated the development of tolerance to the antinociceptive effects of morphine. The withdrawal manifestation induced by the naloxone-challenge (5 mg/kg) was significantly reduced in mice that were treated with a combination of dizocilpine and morphine, compared to the mice treated with morphine and saline. The present study revealed a significant increase in c-Fos protein expression in the cortex and thalamus of mice showing naloxone-precipitated withdrawal syndrome. The combination of dizocilpine and morphine prevented the increase of c-Fos protein expression in the cortex and thalamus. Interestingly, repeated co-administration of dizocilpine and morphine prevented the withdrawal-induced phosphorylation of Ca2+/calmodulin kinase II (p-CaMK II) in the cortex, but not in the thalamus. Acute dizocilpine treatment prior to the naloxone-challenge and repeated treatment with dizocilpine alone had no effect on analgesia, withdrawal manifestations, p-CaMK II levels or c-Fos protein levels. These results showed that co-administration of dizocilpine and morphine prevented the development of morphine tolerance and dependence and suggested that the preventive effect of dizocilpine results from the regulation of c-Fos protein expression, which is possibly involved in the activation of the Ca2+/calmodulin-dependent signal cascade in the cortex.
Hamdy
Moustafa Mahmoud
MM
Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Noda
Yukihiro
Y
Miyazaki
Masayuki
M
Mamiya
Takayoshi
T
Nozaki
Ayumu
A
Nitta
Atsumi
A
Sayed
Merfat
M
Assi
Abdel-Azim
AA
Gomaa
Adel
A
Nabeshima
Toshitaka
T
D000818:Animals; D015153:Blotting, Western / Q000379:methods; D002118:Calcium / Q000378:metabolism*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002452:Cell Count / Q000379:methods; D016291:Dizocilpine Maleate / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D006179:Gyrus Cinguli / Q000187:drug effects / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000009:adverse effects; D009021:Morphine Dependence / Q000188:drug therapy* / Q000378:metabolism; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D010147:Pain Measurement / Q000187:drug effects; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D011930:Reaction Time / Q000187:drug effects; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy / Q000209:etiology; D013788:Thalamus / Q000187:drug effects / Q000378:metabolism
D009292:Narcotic Antagonists; D018696:Neuroprotective Agents; D016760:Proto-Oncogene Proteins c-fos; D009270:Naloxone; D016291:Dizocilpine Maleate; D009020:Morphine; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002118:Calcium