Involvement of the p53 tumor-suppressor protein in the development of antinociceptive tolerance to morphine.
The present study was designed to determine whether the p53 tumor-suppressor protein is involved in the development of antinociceptive tolerance to morphine. When the doses of morphine (mg/kg per injection) were subcutaneously given into mice as pretreatment twice daily for 2 days (first day (30) and second day (60)), intrathecal (i.t.) administration of morphine (0.1nmol) was inactive due to antinociceptive tolerance in the 0.5% formalin test on the third day. Tolerance to i.t. morphine was significantly suppressed by i.t. injection of pifithrin-alpha (1 and 10nmol), an inhibitor of p53 activation, benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone (Z-VAD-fmk) (1 and 10nmol), a non-selective caspase inhibitor, or N(G)-nitro-l-arginine methyl ester (l-NAME) (2 and 20nmol), a non-selective inhibitor of nitric oxide synthase, 5min before each morphine treatment during the induction, with none given on the test day. Moreover, p53 expression in the spinal cord had increased significantly 14h after the last morphine administration. These results indicate that the increased expression and activation of p53, and the nitric oxide and caspase systems related to p53 may contribute to the development of antinociceptive tolerance to morphine in the mouse spinal cord.
Tan-No
Koichi
K
Department of Pharmacology, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan. koichi@tohoku-pharm.ac.jp
Shimoda
Masakazu
M
Watanabe
Kenya
K
Nakagawasai
Osamu
O
Niijima
Fukie
F
Kanno
Syu-Ichi
S
Ishikawa
Masaaki
M
Bakalkin
Georgy
G
Tadano
Takeshi
T
D000818:Animals; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004361:Drug Tolerance / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007278:Injections, Spinal; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D009020:Morphine / Q000494:pharmacology*; D009294:Narcotics / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors / Q000378:metabolism; D010146:Pain / Q000188:drug therapy*; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects* / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D009294:Narcotics; D016159:Tumor Suppressor Protein p53; D009569:Nitric Oxide; D009020:Morphine; D052248:Nitric Oxide Synthase Type I; D020169:Caspases