Inhibition of glial activation in rostral ventromedial medulla attenuates mechanical allodynia in a rat model of cancer-induced bone pain

Abstract

Descending nociceptive modulation from the supraspinal structures plays an important role in cancer-induced bone pain (CIBP). Rostral ventromedial medulla (RVM) is a critical component of descending nociceptive facilitation circuitry, but so far the mechanisms are poorly known. In this study, we investigated the role of RVM glial activation in the descending nociceptive facilitation circuitry in a CIBP rat model. CIBP rats showed significant activation of microglia and astrocytes, and also up-regulation of phosphorylated p38 mitogen-activated protein kinase (p38 MAPK) and pro-inflammatory mediators released by glial cells (IL-1β, IL-6, TNF-α and brain-derived neurotrophic factor) in the RVM. Stereotaxic microinjection of the glial inhibitors (minocycline and fluorocitrate) into CIBP rats’ RVM could reverse the glial activation and significantly attenuate mechanical allodynia in a time-dependent manner. RVM microinjection of p38 MAPK inhibitor (SB203580) abolished the activation of microglia, reversed the associated up-regulation of pro-inflammatory mediators and significantly attenuated mechanical allodynia. Taken together, these results suggest that RVM glial activation is involved in the pathogenesis of CIBP. RVM microglial p38 MAPK signaling pathway is activated and leads to the release of downstream pro-inflammatory mediators, which contribute to the descending facilitation of CIBP.

Keywords

cancer-induced bone pain / microglia / astrocyte / p38 MAPK / rostral ventromedial medulla

References

[1] ColvinL., FallonM.. Challenges in cancer pain management—bone pain. Eur J Cancer, 2008, 44(8): 1083-1090

[2] WeilbaecherK.N., GuiseT.A., McCauleyL.K.. Cancer to bone: a fatal attraction. Nat Rev Cancer, 2011, 11(6): 411-425

[3] Jimenez-AndradeJ.M., MantyhW.G., BloomA.P., et al.. Bone cancer pain. Ann N Y Acad Sci, 2010, 1198: 173-181

[4] GoblirschM.J., ZwolakP.P., ClohisyD.R.. Biology of bone cancer pain. Clin Cancer Res, 2006, 12(20): 6231s-6235s

[5] MillanM.J.. Descending control of pain. Prog Neurobiol, 2002, 66(6): 355-474

[6] Vera-PortocarreroL.P., ZhangE.T., OssipovM.H., et al.. Descending facilitation from the rostral ventromedial medulla maintains nerve injury-induced central sensitization. Neuroscience, 2006, 140(4): 1311-1320

[7] PorrecaF., BurgessS.E., GardellL.R., et al.. Inhibition of neuropathic pain by selective ablation of brainstem medullary cells expressing the mu-opioid receptor. J Neurosci, 2001, 21(14): 5281-5288

[8] OssipovM.H., DussorG.O., PorrecaF.. Central modulation of pain. J Clin Invest, 2010, 120(11): 3779-3787

[9] PorrecaF., OssipovM.H., GebhartG.F.. Chronic pain and medullary descending facilitation. Trends Neurosci, 2002, 25(6): 319-325

[10] RobertsJ., OssipovM.H., PorrecaF.. Glial activation in the rostroventromedial medulla promotes descending facilitation to mediate inflammatory hypersensitivity. Eur J Neurosci, 2009, 30(2): 229-241

[11] WeiF., GuoW., ZouS., et al.. Supraspinal glial-neuronal interactions contribute to descending pain facilitation. J Neurosci, 2008, 28(42): 10 482-10 495

[12] JiR.R., SuterM.R.. p38 MAPK, microglial signaling, and neuropathic pain. Mol Pain, 2007, 3: 33

[13] KohnoT.. Neuropathic pain and neuron-glia interactions in the spinal cord. J Anesth, 2010, 24(2): 325-327

[14] GeisC., GraulichM., WissmannA., et al.. Evoked pain behavior and spinal glia activation is dependent on tumor necrosis factor receptor 1 and 2 in a mouse model of bone cancer pain. Neuroscience, 2010, 169(1): 463-474

[15] ZhangR.X., LiuB., WangL., et al.. Spinal glial activation in a new rat model of bone cancer pain produced by prostate cancer cell inoculation of the tibia. Pain, 2005, 118(1–2): 125-136

[16] CaoF., GaoF., XuA.J., et al.. Regulation of spinal neuroimmune responses by prolonged morphine treatment in a rat model of cancer induced bone pain. Brain Res, 2010, 1326: 162-173

[17] LaalouF.Z., de VasconcelosA.P., OberlingP., et al.. Involvement of the basal cholinergic forebrain in the mediation of general (propofol) anesthesia. Anesthesiology, 2008, 108(5): 888-896

[18] WeiF., DubnerR., ZouS., et al.. Molecular depletion of descending serotonin unmasks its novel facilitatory role in the development of persistent pain. J Neurosci, 2010, 30(25): 8624-8636

[19] FoxA., MedhurstS., CouradeJ.P., et al.. Anti-hyperalgesic activity of the cox-2 inhibitor lumiracoxib in a model of bone cancer pain in the rat. Pain, 2004, 107(1–2): 33-40

[20] WangY., LiX., CaoL., et al.. Analgesic effect of diprospan in rats with trigeminal neuralgia. J Huazhong Univ Sci Technolog [Med Sci], 2011, 31(3): 395-399

[21] CaoF., ChenS.S., YanX.F., et al.. Evaluation of side effects through selective ablation of the mu opioid receptor expressing descending nociceptive facilitatory neurons in the rostral ventromedial medulla with dermorphin-saporin. Neurotoxicology, 2009, 30(6): 1096-1106

[22] WangG.M., TianX.B., ChenJ.P., et al.. Prevention of neuropathic pain in an animal model of spare nerve injury following oral immunization with recombinant adenovirus serotype 5-mediated NR2B gene transfer. Gene Ther, 2007, 14(24): 1681-1687

[23] ShimizuK., GuoW., WangH., et al.. Differential involvement of trigeminal transition zone and laminated subnucleus caudalis in orofacial deep and cutaneous hyperalgesia: the effects of interleukin-10 and glial inhibitors. Mol Pain, 2009, 5: 75

[24] HosoiR., OkadaM., HatazawaJ., et al.. Effect of astrocytic energy metabolism depressant on 14C-acetate uptake in intact rat brain. J Cereb Blood Flow Metab, 2004, 24(2): 188-190

[25] Romero-SandovalA., ChaiN., Nutile-McMenemyN., et al.. A comparison of spinal Iba1 and GFAP expression in rodent models of acute and chronic pain. Brain Res, 2008, 1219: 116-126

[26] Mao-YingQ.L., ZhaoJ., DongZ.Q., et al.. A rat model of bone cancer pain induced by intra-tibia inoculation of Walker 256 mammary gland carcinoma cells. Biochem Biophys Res Commun, 2006, 345(4): 1292-1298

[27] ScholzJ., WoolfC.J.. The neuropathic pain triad: neurons, immune cells and glia. Nat Neurosci, 2007, 10(11): 1361-1368

[28] StorksonR.V., KjorsvikA., TjolsenA., et al.. Lumbar catheterization of the spinal subarachnoid space in the rat. J Neurosci Methods, 1996, 65(2): 167-172

[29] KristensenJ.D., PostC., GordhT.Jr, et al.. Spinal cord morphology and antinociception after chronic intrathecal administration of excitatory amino acid antagonists in the rat. Pain, 1993, 54(3): 309-316

[30] TsangB.K., HeZ., MaT., et al.. Decreased paralysis and better motor coordination with microspinal versus PE10 intrathecal catheters in pain study rats. Anesth Analg, 1997, 84(3): 591-594