NMDA receptors are involved in upstream of the spinal JNK activation in morphine antinociceptive tolerance.
N-methyl-d-aspartate (NMDA) receptors and c-Jun N-terminal kinase (JNK) have been shown to be involved in morphine antinociceptive tolerance. However, whether chronic morphine-induced activation of the spinal JNK is NMDA receptor-dependent is unknown. The present study investigated the link between the spinal NMDA receptor NR2B subunit and the JNK activation during morphine antinociceptive tolerance in rats. Our results showed that chronic morphine treatment induced upregulation of the NR2B expression and activation of JNK in the spinal cord. Moreover, the increased NR2B-immunoreactivity (IR) and phosphorylated JNK-IR were observed mainly at the superficial dorsal horn laminae of the spinal cord; the spinal p-JNK was mainly expressed in astrocytes and NR2B in neurons. SP600125, a selective inhibitor of JNK, significantly attenuated morphine tolerance. MK-801, a noncompetitive NMDA receptor antagonist, not only suppressed morphine antinociceptive tolerance and the increase in NR2B, but also reduced the spinal JNK activation induced by chronic morphine treatment. These findings demonstrated for the first time that NMDA receptor-dependent activation of the spinal JNK contributes to morphine antinociceptive tolerance and that MK-801 attenuates morphine tolerance partly due to its inhibition on the spinal JNK activation.
Guo
Rui-Xian
RX
Department of Physiology, Zhongshan Medical College, Sun Yat-sen University, 74, Zhongshan 2nd Road, Guangzhou 510080, PR China.
Zhang
Mei
M
Liu
Wei
W
Zhao
Chun-Mei
CM
Cui
Yu
Y
Wang
Chu-Huai
CH
Feng
Jian-Qiang
JQ
Chen
Pei-Xi
PX
D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004361:Drug Tolerance; D004789:Enzyme Activation; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000502:physiology*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*
D000701:Analgesics, Opioid; D000873:Anthracenes; C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; C432165:pyrazolanthrone; D016291:Dizocilpine Maleate; D009020:Morphine; D048031:JNK Mitogen-Activated Protein Kinases