Abstract
Recent reports showed that aquaporin 4 (AQP4) deficiency potentiated morphine analgesia but attenuated chronic morphine-induced tolerance in hot-plate test, predominantly reflecting supraspinal pain response. The present study investigated the effects of AQP4 deficiency on morphine analgesia and tolerance using tail flick test, primarily reflecting spinal response. It was found that (1) chronic morphine treatment resulted in decreased expression of spinal AQP4 in mice detected by Western blotting analysis; (2) in tail flick test, AQP4 knockout mice displayed significant impaired morphine analgesia without influencing the progress of chronic tolerance; and (3) the expressions of mu-opioid receptor (MuOR) and glutamate transporter 1 (GLT-1) in AQP4 knockout mice spinal cord were lower than those in wild-type mice, whereas chronic morphine-induced alteration characteristics of spinal MuOR or GLT-1 expression were not affected by AQP4 deficiency. In conclusion, AQP4 deficiency attenuated morphine acute antinociception but did not affect chronic tolerance in tail flick test, implying a role for spinal AQP4 in morphine analgesia but not in chronic tolerance.
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References
Carmosino M, Procino G, Tamma G, Mannucci R, Svelto M, Valenti G (2007) Trafficking and phosphorylation dynamics of AQP4 in histamine-treated human gastric cells. Biol Cell 99:25–36
Frigeri A, Gropper MA, Turck CW, Verkman AS (1995) Immunolocalization of the mercurial-insensitive water channel and glycerol intrinsic protein in epithelial-cell plasma-membranes. Proc Natl Acad Sci USA 92:4328–4331
Haydon PG, Carmignoto G (2006) Astrocyte control of synaptic transmission and neurovascular coupling. Physiol Rev 86:1009–1031
Johnston IN, Milligan ED, Wieseler-Frank J et al (2004) A role for proinflammatory cytokines and fractalkine in analgesia, tolerance, and subsequent pain facilitation induced by chronic intrathecal morphine. J Neurosci 24:7353–7365
Langerman L, Zakowski MI, Piskoun B, Grant GJ (1995) Hot plate versus tail-flick—evaluation of acute tolerance to continuous morphine infusion in the rat model. J Pharmacol Toxicol Methods 34:23–27
Nagelhus EA, Horio Y, Inanobe A et al (1999) Immunogold evidence suggests that coupling of K + siphoning and water transport in rat retinal Muller cells is mediated by a coenrichment of Kir4.1 and AQP4 in specific membrane domains. Glia 26:47–54
Nagelhus EA, Mathiisen TM, Ottersen OP (2004) Aquaporin-4 in the central nervous system: cellular and subcellular distribution and coexpression with Kir4.1. Neuroscience 129:905–913
Nakahama K, Nagano M, Fujioka A, Shinoda K, Sasaki H (1999) Effect of TPA on aquaporin 4 mRNA expression in cultured rat astrocytes. Glia 25:240–246
Nielsen S, Nagelhus EA, AmiryMoghaddam M, Bourque C, Agre P, Ottersen OP (1997) Specialized membrane domains for water transport in glial cells: high-resolution immunogold cytochemistry of aquaporin-4 in rat brain. J Neurosci 17:171–180
Oshio K, Binder DK, Yang B, Schecter S, Verkman AS, Manley GT (2004) Expression of aquaporin water channels in mouse spinal cord. Neuroscience 127:685–693
Padmawar P, Yao XM, Bloch O, Manley GT, Verkman AS (2005) K + waves in brain cortex visualized using a long-wavelength K+-sensing fluorescent indicator. Nat Methods 2:825–827
Raghavendra V, Rutkowski MD, DeLeo JA (2002) The role of spinal neuroimmune activation in morphine tolerance/hyperalgesia in neuropathic and sham-operated rats. J Neurosci 22:9980–9989
Raghavendra V, Tanga FY, DeLeo JA (2004) Attenuation of morphine tolerance, withdrawal-induced hyperalgesia, and associated spinal inflammatory immune responses by propentofylline in rats. Neuropsychopharmacology 29:327–334
Rash JE, Yasumura T, Hudson CS, Agre P, Nielsen S (1998) Direct immunogold labeling of aquaporin-4 in square arrays of astrocyte and ependymocyte plasma membranes in rat brain and spinal cord. Proc Natl Acad Sci USA 95:11981–11986
Roerig SC, Hoffman RG, Takemori AE, Wilcox GL, Fujimoto JM (1991) Isobolographic analysis of analgesic interactions between intrathecally and intracerebroventricularly administered fentanyl, morphine and D-Ala2-D-Leu5-enkephalin in morphine-tolerant and nontolerant mice. J Pharmacol Exp Ther 257:1091–1099
Song P, Zhao ZQ (2001) The involvement of glial cells in the development of morphine tolerance. Neurosci Res 39:281–286
Vitellaro-Zuccarello L, Mazzetti S, Bosisio P, Monti C, De Blasi S (2005) Distribution of aquaporin 4 in rodent spinal cord: Relationship with astrocyte markers and chondroitin sulfate proteoglycans. Glia 51:148–159
Wang JF, Wang ZY, Wu N, Yan HT, Li J (2009) Effects of aquaporin4 deficiency on opioid receptors characteristics in naive and chronic morphine-treated mice. Neurosci Lett 457:111–114
Watkins LR, Hutchinson MR, Johnston IN, Maier SF (2005) Glia: novel counter-regulators of opioid analgesia. Trends Neurosci 28:661–669
Wu N, Lu XQ, Yan HT et al (2008) Aquaporin 4 deficiency modulates morphine pharmacological actions. Neurosci Lett 448:221–225
Yoburn BC, Lutfy K, Azimuddin S, Sierra V (1990) Differentiation of spinal and supraspinal opioid receptors by morphine-tolerance. Life Sci 46:343–350
Zelenina M, Zelenin S, Bondar AA, Brismar H, Aperia A (2002) Water permeability of aquaporin-4 is decreased by protein kinase C and dopamine. Am J Physiol Renal Physiol 283:F309–F318
Zeng XN, Sun XL, Gao L, Fan Y, Ding JH, Hu G (2007) Aquaporin-4 deficiency down-regulates glutamate uptake and GLT-1 expression in astrocytes. Mol Cell Neurosci 34:34–39
Zimmermann M (1983) Ethical guidelines for investigations of experimental pain in conscious animals. Pain 16:109–110
Acknowledgements
We would like to thank Prof. Gang Hu for his kindness to provide wild-type and AQP4 knockout mice. This work was supported by grant from the National Basic Research Program of China Grant 2006CB500807 and 2007CB512502 and the National Natural Science Fund of China 30830044.
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Meng-Ling Chen and Feng Bao contributed equally to this work.
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Chen, ML., Bao, F., Zhang, YQ. et al. Effects of Aquaporin 4 Deficiency on Morphine Analgesia and Chronic Tolerance: A Study at Spinal Level. J Mol Neurosci 42, 140–144 (2010). https://doi.org/10.1007/s12031-010-9356-7
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DOI: https://doi.org/10.1007/s12031-010-9356-7