Abstract
Recent studies have indicated that trigeminal neurons exhibit central sensitization, an increase in the excitability of neurons within the central nervous system to the extent that a normally innocuous stimulus begins to produce pain after inflammation or injury, and that glial activities play a vital role in this central sensitization. The involvement of glial cells in trigeminal central sensitization contains multiple mechanisms, including interaction with glutamatergic and purinergic receptors. A better understanding of the trigeminal central sensitization mediated by glial cells will help to find potential therapeutic targets and lead to developing new analgesics for orofacial-specific pain with higher efficiency and fewer side-effects.
Similar content being viewed by others
Article PDF
References
Ji RR, Kohno T, Moore KA, Woolf CJ . Central sensitization and LTP: do pain and memory share similar mechanisms? Trends Neurosci 2003; 26: 696–705.
Tsuda M, Inoue K, Salter MW . Neuropathic pain and spinal microglia: a big problem from molecules in “small” glia. Trends Neurosci 2005; 28: 101–7.
Watkins LR, Maier SF . Glia: a novel drug discovery target for clinical pain. Nat Rev Drug Discov 2003; 2: 973–85.
Watkins LR, Maier SF . Glia and pain: past, present, and future. In Merskey H, Loeser JD, Dubner R, editors. The paths of pain 1975-2005. Seattle: IASP Press; 2005. p 165–175.
Wieseler-Frank J, Maier SF, Watkins LR . Glial activation and pathological pain. Neurochem Int 2004; 45: 389–95.
De Leo JA, Tawfik VL, LaCroix-Fralish ML . The tetrapartite synapse: path to CNS sensitization and chronic pain. Pain 2006; 122: 17–21.
Xie YF . The updated advancements in synaptic plasticity mediated by glial cells. Sheng Li Ke Xue Jin Zhan 2007; 38: 111–5.
Takemura M, Sugiyo S, Moritani M, Kobayashi M, Yonehara N . Mechanisms of orofacial pain control in the central nervous system. Arch Histol Cytol 2006; 69: 79–100.
Bereiter DA, Hirata H, Hu JW . Trigeminal subnucleus caudalis: beyond homologies with the spinal dorsal horn. Pain 2000; 88: 221–4.
Dubner R, Bennett GJ . Spinal and trigeminal mechanisms of nociception. Annu Rev Neurosci 1983; 6: 381–418.
Sessle BJ . Acute and chronic craniofacial pain: brainstem mechanisms of nociceptive transmission and neuroplasticity, and their clinical correlates. Crit Rev Oral Biol Med 2000; 11: 57–91.
Sessle BJ . Peripheral and central mechanisms of orofacial pain and their clinical correlates. Minerva Anestesiol 2005; 71: 117–36.
Fried K, Bongenhielm U, Boissonade FM, Robinson PP . Nerve injury-induced pain in the trigeminal system. Neuroscientist 2001; 7: 155–65.
Dubner R, Ren K . Brainstem mechanisms of persistent pain following injury. J Orofac Pain 2004; 18: 299–305.
Yu XM, Sessle BJ, Hu JW . Differential effects of cutaneous and deep application of inflammatory irritant on mechanoreceptive field properties of trigeminal brain stem nociceptive neurons. J Neurophysiol 1993; 70: 1704–7.
Chiang CY, Zhang S, Xie YF, Hu JW, Dostrovsky JO, Salter MW, et al. Endogenous ATP involvement in mustard-oil-induced central sensitization in trigeminal subnucleus caudalis (medullary dorsal horn). J Neurophysiol 2005; 94: 1751–60.
Chiang CY, Wang J, Xie YF, Zhang S, Hu JW, Dostrovsky JO, et al. Astroglial glutamate-glutamine shuttle is involved in central sensitization of nociceptive neurons in rat medullary dorsal horn. J Neurosci 2007; 27: 9068–76.
Xie YF, Zhang S, Chiang CY, Hu JW, Dostrovsky JO, Sessle BJ . Involvement of glia in central sensitization in trigeminal sub-nucleus caudalis (medullary dorsal horn). Brain Behav Immun 2007; 21: 634–41.
Piao ZG, Cho IH, Park CK, Hong JP, Choi SY, Lee SJ, et al. Activation of glia and microglial p38 MAPK in medullary dorsal horn contributes to tactile hypersensitivity following trigeminal sensory nerve injury. Pain 2006; 121: 219–31.
Juhl GI, Jensen TS, Norholt SE, Svensson P . Central sensitization phenomena after third molar surgery: A quantitative sensory testing study. Eur J Pain 2008; 12: 116–27.
Dodick D, Silberstein S . Central sensitization theory of migraine: clinical implications. Headache 2006; 46 Suppl 4: S182–91.
Vikelis M, Mitsikostas DD . The role of glutamate and its receptors in migraine. CNS Neurol Disord Drug Targets 2007; 6: 251–7.
Yihong Z, Tamada Y, Akai K, Suwa F . Morphological interrelationship between astrocytes and nerve endings in the rat spinal trigeminal nucleus caudalis. Okajimas Folia Anat Jpn 2006; 83: 91–6.
Lan L, Yuan H, Duan L, Cao R, Gao B, Shen J, et al. Blocking the glial function suppresses subcutaneous formalin-induced nociceptive behavior in the rat. Neurosci Res 2007; 57: 112–9.
Araque A, Sanzgiri RP, Parpura V, Haydon PG . Calcium elevation in astrocytes causes an NMDA receptor-dependent increase in the frequency of miniature synaptic currents in cultured hip-pocampal neurons. J Neurosci 1998; 18: 6822–9.
Araque A, Parpura V, Sanzgiri RP, Haydon PG . Glutamate-de-pendent astrocyte modulation of synaptic transmission between cultured hippocampal neurons. Eur J Neurosci 1998; 10: 2129–42.
Parri R, Crunelli V . Astrocytes target presynaptic NMDA receptors to give synapses a boost. Nat Neurosci 2007; 10: 271–3.
Jourdain P, Bergersen LH, Bhaukaurally K, Bezzi P, Santello M, Domercq M, et al. Glutamate exocytosis from astrocytes controls synaptic strength. Nat Neurosci 2007; 10: 331–9.
Chiang CY, Park SJ, Kwan CL, Hu JW, Sessle BJ . NMDA receptor mechanisms contribute to neuroplasticity induced in caudalis nociceptive neurons by tooth pulp stimulation. J Neurophysiol 1998; 80: 2621–31.
Guo W, Wang H, Watanabe M, Shimizu K, Zou S, LaGraize SC, et al. Glial-cytokine-neuronal interactions underlying the mechanisms of persistent pain. J Neurosci 2007; 27: 6006–18.
Takeda M, Tanimoto T, Kadoi J, Nasu M, Takahashi M, Kitagawa J, et al. Enhanced excitability of nociceptive trigeminal ganglion neurons by satellite glial cytokine following peripheral inflammation. Pain 2007; 129: 155–66.
Jin SX, Zhuang ZY, Woolf CJ, Ji RR . p38 mitogen-activated protein kinase is activated after a spinal nerve ligation in spinal cord microglia and dorsal root ganglion neurons and contributes to the generation of neuropathic pain. J Neurosci 2003; 23: 4017–22.
Svensson CI, Marsala M, Westerlund A, Calcutt NA, Campana WM, Freshwater JD, et al. Activation of p38 mitogen-activated protein kinase in spinal microglia is a critical link in inflammation-induced spinal pain processing. J Neurochem 2003; 86: 1534–44.
Svensson CI, Hua XY, Protter AA, Powell HC, Yaksh TL . Spinal p38 MAP kinase is necessary for NMDA-induced spinal PGE(2) release and thermal hyperalgesia. Neuroreport 2003; 14: 1153–7.
Tsuda M, Mizokoshi A, Shigemoto-Mogami Y, Koizumi S, Inoue K . Activation of p38 mitogen-activated protein kinase in spinal hyperactive microglia contributes to pain hypersensitivity following peripheral nerve injury. Glia 2004; 45: 89–95.
Beattie EC, Stellwagen D, Morishita W, Bresnahan JC, Ha BK, Von Zastrow M, et al. Control of synaptic strength by glial TNFalpha. Science 2002; 295: 2282–5.
Coull JA, Beggs S, Boudreau D, Boivin D, Tsuda M, Inoue K, et al. BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature 2005; 438: 1017–21.
Hu B, Chiang CY, Hu JW, Dostrovsky JO, Sessle BJ . P2X receptors in trigeminal subnucleus caudalis modulate central sensitization in trigeminal subnucleus oralis. J Neurophysiol 2002; 88: 1614–24.
Keyser DO, Pellmar TC . Synaptic transmission in the hippocampus: critical role for glial cells. Glia 1994; 10: 237–43.
Pangrsic T, Potokar M, Stenovec M, Kreft M, Fabbretti E, Nistri A, et al. Exocytotic release of AT P from cultured astrocytes. J Biol Chem 2007; 282: 28749–58.
Gordon GR, Baimoukhametova DV, Hewitt SA, Rajapaksha WR, Fisher TE, Bains JS . Norepinephrine triggers release of glial ATP to increase postsynaptic efficacy. Nat Neurosci 2005; 8: 1078–86.
Ceruti S, Fumagalli M, Villa G, Verderio C, Abbracchio MP . Purinoceptor-mediated calcium signaling in primary neuron-glia trigeminal cultures. Cell Calcium 2007; doi: 10. 1016j.ceca.2007. 10.003.
Takano T, Tian GF, Peng W, Lou N, Libionka W, Han X, et al. Astrocyte-mediated control of cerebral blood flow. Nat Neurosci 2006; 9: 260–7.
Bergerot A, Storer RJ, Goadsby PJ . Dopamine inhibits trigeminovascular transmission in the rat. Ann Neurol 2007; 61: 251–62.
Author information
Authors and Affiliations
Corresponding author
Additional information
Project supported by the National Natural Foundation of China (No 30570592, 30670693, and 30700222).
Rights and permissions
About this article
Cite this article
Xie, Yf. Glial involvement in trigeminal central sensitization. Acta Pharmacol Sin 29, 641–645 (2008). https://doi.org/10.1111/j.1745-7254.2008.00801.x
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1111/j.1745-7254.2008.00801.x
Keywords
This article is cited by
-
SHED-derived exosomes attenuate trigeminal neuralgia after CCI of the infraorbital nerve in mice via the miR-24-3p/IL-1R1/p-p38 MAPK pathway
Journal of Nanobiotechnology (2023)
-
Diverse Physiological Roles of Calcitonin Gene-Related Peptide in Migraine Pathology: Modulation of Neuronal-Glial-Immune Cells to Promote Peripheral and Central Sensitization
Current Pain and Headache Reports (2016)
-
New directions in migraine
BMC Medicine (2011)
-
Cerebral cortex modulation of pain
Acta Pharmacologica Sinica (2009)