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Article

Spinal leptin contributes to the development of morphine antinociceptive tolerance by activating the STAT3-NMDA receptor pathway in rats

  • Authors:
    • Fen Hu
    • Yu Cui
    • Ruixian Guo
    • Jingfu Chen
    • Runming Guo
    • Ning Shen
    • Xiaoxiao Hua
    • Liqiu Mo
    • Jianqiang Feng
  • View Affiliations / Copyright

    Affiliations: Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China, Department of Cardiovasology, The Affiliated Hospital, Guangdong Medical College, Zhanjiang, Guangdong 524001, P.R. China, Department of Anesthesiology, Huangpu Division of The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510700, P.R. China
  • Pages: 923-930
    |
    Published online on: May 20, 2014
       https://doi.org/10.3892/mmr.2014.2250
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Abstract

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.
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1 

Trujillo KA and Akil H: Inhibition of morphine tolerance and dependence by the NMDA receptor antagonist MK-801. Science. 251:85–87. 1991. View Article : Google Scholar : PubMed/NCBI

2 

Guo RX, Zhang M, Liu W, Zhao CM, Cui Y, Wang CH, Feng JQ and Chen PX: NMDA receptors are involved in upstream of the spinal JNK activation in morphine antinociceptive tolerance. Neurosci Lett. 467:95–99. 2009. View Article : Google Scholar : PubMed/NCBI

3 

Raghavendra V, Rutkowski MD and DeLeo JA: The role of spinal neuroimmune activation in morphine tolerance/hyperalgesia in neuropathic and sham-operated rats. J Neurosci. 22:9980–9989. 2002.PubMed/NCBI

4 

Johnston IN, Milligan ED, Wieseler-Frank J, Frank MG, Zapata V, Campisi J, Langer S, Martin D, Green P, Fleshner M, et al: A role for proinflammatory cytokines and fractalkine in analgesia, tolerance, and subsequent pain facilitation induced by chronic i.t morphine. J Neurosci. 24:7353–7365. 2004. View Article : Google Scholar : PubMed/NCBI

5 

Wang Z, Ma W, Chabot JG and Quirion R: Calcitonin gene-related peptide as a regulator of neuronal CaMKII-CREB, microglial p38-NFκB and astroglial ERK-Stat1/3 cascades mediating the development of tolerance to morphine-induced analgesia. Pain. 151:194–205. 2010.PubMed/NCBI

6 

Cui Y, Liao XX, Liu W, Guo RX, Wu ZZ, Zhao CM, Chen PX and Feng JQ: A novel role of minocycline: attenuating morphine antinociceptive tolerance by inhibition of p38 MAPK in the activated spinal microglia. Brain Behav Immun. 22:114–123. 2008. View Article : Google Scholar : PubMed/NCBI

7 

Cui Y, Chen Y, Zhi JL, Guo RX, Feng JQ and Chen PX: Activation of p38 mitogen-activated protein kinase in spinal microglia mediates morphine antinociceptive tolerance. Brain Res. 1069:235–243. 2006. View Article : Google Scholar : PubMed/NCBI

8 

Zhang Y, Proenca R, Maffei M, Barone M, Leopold L and Friedman JM: Positional cloning of the mouse obese gene and its human homologue. Nature. 372:425–432. 1994. View Article : Google Scholar : PubMed/NCBI

9 

Bjørbaek C, Uotani S, da Silva B and Flier JS: Divergent signaling capacities of the long and short isoforms of the leptin receptor. J Biol Chem. 272:32686–32695. 1997.PubMed/NCBI

10 

Maeda T, Kiguchi N, Kobayashi Y, Ikuta T, Ozaki M and Kishioka S: Leptin derived from adipocytes in injured peripheral nerves facilitates development of neuropathic pain via macrophage stimulation. Proc Natl Acad Sci USA. 106:13076–13081. 2009. View Article : Google Scholar : PubMed/NCBI

11 

Lim G, Wang S, Zhang Y, Tian Y and Mao J: Spinal leptin contributes to the pathogenesis of neuropathic pain in rodents. J Clin Invest. 119:295–304. 2009.PubMed/NCBI

12 

Tian Y, Wang S, Ma Y, Lim G, Kim H and Mao J: Leptin enhances NMDA-induced spinal excitation in rats: A functional link between adipocytokine and neuropathic pain. Pain. 152:1263–1271. 2011. View Article : Google Scholar : PubMed/NCBI

13 

Mao J, Price DD and Mayer DJ: Mechanisms of hyperalgesia and morphine tolerance: a current view of their possible interactions. Pain. 62:259–274. 1995. View Article : Google Scholar : PubMed/NCBI

14 

Mayer DJ, Mao J, Holt J and Price DD: Cellular mechanisms of neuropathic pain, morphine tolerance, and their interactions. Proc Natl Acad Sci USA. 96:7731–7736. 1999. View Article : Google Scholar : PubMed/NCBI

15 

Harvey J: Leptin: a diverse regulator of neuronal function. J Neurochem. 100:307–313. 2007. View Article : Google Scholar : PubMed/NCBI

16 

Tartaglia LA, Dembski M, Weng X, et al: Identification and expression cloning of a leptin receptor, OB-R. Cell. 83:1263–1271. 1995. View Article : Google Scholar : PubMed/NCBI

17 

Myers MG Jr: Leptin receptor signaling and the regulation of mammalian physiology. Recent Prog Horm Res. 59:287–304. 2004. View Article : Google Scholar : PubMed/NCBI

18 

Ahima RS, Qi Y, Singhal NS, Jackson MB and Scherer PE: Brain adipocytokine action and metabolic regulation. Diabetes. 55(Suppl 2): S145–154. 2006. View Article : Google Scholar : PubMed/NCBI

19 

Wolsk E, Mygind H, Grøndahl TS, Pedersen BK and van Hall G: Human skeletal muscle releases leptin in vivo. Cytokine. 60:667–673. 2012. View Article : Google Scholar : PubMed/NCBI

20 

Purdham DM, Zou MX, Rajapurohitam V and Karmazyn M: Rat heart is a site of leptin production and action. Am J Physiol Heart Circ Physiol. 287:H2877–H2884. 2004. View Article : Google Scholar : PubMed/NCBI

21 

Morash B, Li A, Murphy PR, Wilkinson M and Ur E: Leptin gene expression in the brain and pituitary gland. Endocrinology. 140:5995–5998. 1999. View Article : Google Scholar : PubMed/NCBI

22 

Ur E, Wilkinson DA, Morash BA and Wilkinson M: Leptin immunoreactivity is localized to neurons in rat brain. Neuroendocrinology. 75:264–272. 2002. View Article : Google Scholar : PubMed/NCBI

23 

Bjorbaek C: Central leptin receptor action and resistance in obesity. J Investig Med. 57:789–794. 2009.PubMed/NCBI

24 

Robertson SA, Leinninger GM and Myers MG Jr: Molecular and neural mediators of leptin action. Physiol Behav. 94:637–642. 2008. View Article : Google Scholar : PubMed/NCBI

25 

Fisher K, Coderre TJ and Hagen NA: Targeting the N-methyl-D-aspartate receptor for chronic pain management. Preclinical animal studies, recent clinical experience and future research directions. J Pain Symptom Manage. 20:358–373. 2000. View Article : Google Scholar

26 

Hewitt DJ: The use of NMDA-receptor antagonist in the treatment of chronic pain. Clin J Pain. 16(Suppl): s73–79. 2000. View Article : Google Scholar : PubMed/NCBI

27 

Houghton AK, Parsons CG and Headley PM: Mrz 2/579, a fast kinetic NMDA channel blocker, reduces the development of morphine tolerance in awake rats. Pain. 91:201–207. 2001. View Article : Google Scholar : PubMed/NCBI

28 

Goldin M, Segal M and Avignone E: Functional plasticity triggers formation and pruning of dendritic spines in cultured hippocampal networks. J Neurosci. 21:186–193. 2001.PubMed/NCBI

29 

Elmquist JK, Maratos-Flier E, Saper CB and Flier JS: Unraveling the central nervous system pathways underlying responses to leptin. Nat Neurosci. 1:445–450. 1998. View Article : Google Scholar : PubMed/NCBI

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Copy and paste a formatted citation
Spandidos Publications style
Hu F, Cui Y, Guo R, Chen J, Guo R, Shen N, Hua X, Mo L and Feng J: Spinal leptin contributes to the development of morphine antinociceptive tolerance by activating the STAT3-NMDA receptor pathway in rats. Mol Med Rep 10: 923-930, 2014.
APA
Hu, F., Cui, Y., Guo, R., Chen, J., Guo, R., Shen, N. ... Feng, J. (2014). Spinal leptin contributes to the development of morphine antinociceptive tolerance by activating the STAT3-NMDA receptor pathway in rats. Molecular Medicine Reports, 10, 923-930. https://doi.org/10.3892/mmr.2014.2250
MLA
Hu, F., Cui, Y., Guo, R., Chen, J., Guo, R., Shen, N., Hua, X., Mo, L., Feng, J."Spinal leptin contributes to the development of morphine antinociceptive tolerance by activating the STAT3-NMDA receptor pathway in rats". Molecular Medicine Reports 10.2 (2014): 923-930.
Chicago
Hu, F., Cui, Y., Guo, R., Chen, J., Guo, R., Shen, N., Hua, X., Mo, L., Feng, J."Spinal leptin contributes to the development of morphine antinociceptive tolerance by activating the STAT3-NMDA receptor pathway in rats". Molecular Medicine Reports 10, no. 2 (2014): 923-930. https://doi.org/10.3892/mmr.2014.2250
Copy and paste a formatted citation
x
Spandidos Publications style
Hu F, Cui Y, Guo R, Chen J, Guo R, Shen N, Hua X, Mo L and Feng J: Spinal leptin contributes to the development of morphine antinociceptive tolerance by activating the STAT3-NMDA receptor pathway in rats. Mol Med Rep 10: 923-930, 2014.
APA
Hu, F., Cui, Y., Guo, R., Chen, J., Guo, R., Shen, N. ... Feng, J. (2014). Spinal leptin contributes to the development of morphine antinociceptive tolerance by activating the STAT3-NMDA receptor pathway in rats. Molecular Medicine Reports, 10, 923-930. https://doi.org/10.3892/mmr.2014.2250
MLA
Hu, F., Cui, Y., Guo, R., Chen, J., Guo, R., Shen, N., Hua, X., Mo, L., Feng, J."Spinal leptin contributes to the development of morphine antinociceptive tolerance by activating the STAT3-NMDA receptor pathway in rats". Molecular Medicine Reports 10.2 (2014): 923-930.
Chicago
Hu, F., Cui, Y., Guo, R., Chen, J., Guo, R., Shen, N., Hua, X., Mo, L., Feng, J."Spinal leptin contributes to the development of morphine antinociceptive tolerance by activating the STAT3-NMDA receptor pathway in rats". Molecular Medicine Reports 10, no. 2 (2014): 923-930. https://doi.org/10.3892/mmr.2014.2250
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