Cross talk between nitric oxide and ERK1/2 signaling pathway in the spinal cord mediates naloxone-precipitated withdrawal in morphine-dependent rats.
Our recent study has shown activation of spinal extracellular signal-regulated kinase-1 and -2 (ERK1/2), a member of the mitogen-activated protein kinase (MAPK) family, contributes to naloxone-precipitated withdrawal and withdrawal-induced spinal neuronal sensitization in morphine-dependent rats. However, the mechanism and significance of the spinal ERK1/2 activation during morphine dependence and withdrawal remain unknown. In this study, we reported that intrathecal (i.t.) pretreatment with either the non-selective nitric oxide synthase (NOS) inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME), neuronal NOS (nNOS) inhibitor 7-nitro indazole (7-NI), or the inducible NOS (iNOS) inhibitor aminoguanidine (AG), could reduce morphine withdrawal-induced increase of phospho-ERK1/2 (pERK1/2) expression in the rat spinal cord. On the other hand, attenuation of the spinal ERK phosphorylation by the MAPK kinase (MEK) inhibitor U0126 also could inhibit the increase of nNOS and iNOS expression in the spinal cord of morphine withdrawal rats. Inhibitory expression of pERK1/2 by i.t. NOS inhibitor L-NAME, 7-NI or AG and of nNOS and iNOS by i.t. U0126 in the spinal cord were accompanied by decreased scores of morphine withdrawal and the inhibited spinal Fos protein (a maker for neuronal excitation or activation) expression induced by morphine withdrawal. These findings suggest cross talk between nitric oxide (NO) and the ERK1/2 signaling pathway mediates morphine withdrawal and withdrawal-induced spinal neuronal sensitization in morphine-dependent rats.
Cao
Jun-Li
JL
Department of Anesthesiology, Affiliated Hospital of Xuzhou Medical College, Jiangsu Institute of Anesthesiology, Jiangsu Province, Xuzhou, Jiangsu 221002, PR China. caojl0310@yahoo.com.cn
Liu
Hai-Lin
HL
Wang
Jun-Ke
JK
Zeng
Yin-Ming
YM
D000818:Animals; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology*; D048052:Mitogen-Activated Protein Kinase 3 / Q000502:physiology*; D009021:Morphine Dependence / Q000378:metabolism* / Q000503:physiopathology; D009270:Naloxone / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000494:pharmacology*; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013116:Spinal Cord / Q000378:metabolism*; D013375:Substance Withdrawal Syndrome / Q000378:metabolism* / Q000503:physiopathology
D009292:Narcotic Antagonists; D009569:Nitric Oxide; D009270:Naloxone; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3