Activation of the spinal ERK signaling pathway contributes naloxone-precipitated withdrawal in morphine-dependent rats.
Extracellular signal-regulated kinase (ERK), a mitogen-activated protein kinases (MAPK), transduces a broad range of extracellular stimuli into diverse intracellular responses. Recent studies have showed that ERK activation in the supraspinal level involved in the development of drug dependence, especially in psychological dependence. In this study, we reported that the spinal ERK signaling pathway was activated by chronic morphine injection. There was a further increase in ERK activation after naloxone-precipitated withdrawal. Furthermore, attenuation of the spinal ERK phosphorylation by intrathecal a MAPK kinase (MEK) inhibitor U0126 or knockdown of the spinal ERK by antisense oligonucleotides not only decreased the scores of morphine withdrawal, but also attenuated withdrawal-induced allodynia, which were accompanied by decreased ERK phosphorylation in the spinal cord. The spinal ERK inhibition or knockdown also reduced morphine withdrawal-induced phosphorylation of cAMP response element binding protein (CREB), which is one of the important downstream substrates of ERK pathway, and Fos expression. The involvement of the spinal ERK in morphine withdrawal was supported by our finding that intrathecal N-methyl-D-aspartate receptor antagonist MK-801 or protein kinase C inhibitor chelerythrine chloride suppressed withdrawal-induced ERK activation in the spinal cord and attenuated morphine withdrawal symptoms. These findings suggest activation of the spinal ERK signaling pathway contributes naloxone-precipitated withdrawal in morphine-dependent rats.
Cao
Jun-Li
JL
Department of Anesthesiology, Affiliated Hospital of Xuzhou Medical College, 99 Huaihai West Road, Xuzhou 221002, People's Republic of China Jiangsu Key Laboratory of Anesthesiology, Jiangsu Institute of Anesthesiology, 99 Huaihai West Road, Xuzhou 221002, People's Republic of China Department of Physiology, University of Texas, Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd, Dallas, TX 75390-9040, USA.
He
Jian-Hua
JH
Ding
Hai-Lei
HL
Zeng
Yin-Ming
YM
D000818:Animals; D002070:Butadienes / Q000008:administration & dosage*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D009021:Morphine Dependence / Q000378:metabolism* / Q000517:prevention & control*; D009270:Naloxone / Q000494:pharmacology*; D009570:Nitriles / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*; D013375:Substance Withdrawal Syndrome / Q000378:metabolism*
D002070:Butadienes; D009570:Nitriles; C113580:U 0126; D009270:Naloxone; D048049:Extracellular Signal-Regulated MAP Kinases