Spinal leptin contributes to the development of morphine antinociceptive tolerance by activating the STAT3-NMDA receptor pathway in rats.
Leptin, an adipokine synthesized mainly by non‑neuronal tissues, has been reported to contribute to the pathogenesis of neuropathic pain. It has been hypothesized that morphine tolerance and neuropathic pain share some common pathological mechanisms. The present study was designed to examine whether spinal leptin is implicated in the development of morphine antinociceptive tolerance, and whether spinal leptin induces the activation of signal transducer and activator of transcription 3 (STAT3) signaling pathway and the NR1 subunit of N‑methyl‑D‑aspartate (NMDA) receptor, in morphine antinociceptive tolerance in rats. The results demonstrated that intrathecal (i.t.) administration of a leptin antagonist (LA) prevented the development of morphine antinociceptive tolerance in rats. Further studies revealed that the levels of the spinal leptin and the leptin receptor (Ob‑R) were time‑dependently increased following chronic morphine treatment. Mechanistic examination indicated that chronic morphine triggered activation of the STAT3 pathway and an increase in the expression of the NR1 subunit of the NMDA receptor, which was ameliorated by i.t. administration of AG490 [a Janus kinase (JAK)‑STAT inhibitor]. The increased activation of STAT3 and the NR1 subunit was markedly attenuated by i.t. treatment with LA. In addition, the spinal administration of AG490 or MK‑801 (a non‑competitive NMDA receptor inhibitor) blocked the development of morphine antinociceptive tolerance. Taken together, these results have demonstrated, for the first time, to the best of our knowledge, that spinal leptin contributes to the development of morphine antinociceptive tolerance by activating the spinal STAT3‑NMDA receptor pathway.
Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China.
Fen
F
Hu
Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China.
Yu
Y
Cui
Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China.
Ruixian
R
Guo
Department of Cardiovasology, The Affiliated Hospital, Guangdong Medical College, Zhanjiang, Guangdong 524001, P.R. China.
Jingfu
J
Chen
Department of Cardiovasology, The Affiliated Hospital, Guangdong Medical College, Zhanjiang, Guangdong 524001, P.R. China.
Runming
R
Guo
Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China.
Ning
N
Shen
Department of Anesthesiology, Huangpu Division of The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510700, P.R. China.
Xiaoxiao
X
Hua
Department of Anesthesiology, Huangpu Division of The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510700, P.R. China.
Liqiu
L
Mo
Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China.
Jianqiang
J
Feng
D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004361:Drug Tolerance; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020738:Leptin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D054411:Receptors, Leptin / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013116:Spinal Cord / Q000378:metabolism*; D020032:Tyrphostins / Q000494:pharmacology
D000701:Analgesics, Opioid; D020738:Leptin; D054411:Receptors, Leptin; D016194:Receptors, N-Methyl-D-Aspartate; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D016291:Dizocilpine Maleate; D009020:Morphine; D048031:JNK Mitogen-Activated Protein Kinases