Connexin 43 Contributes to Ectopic Orofacial Pain Following Inferior Alveolar Nerve Injury

Overview

Journal Mol Pain

Date 2016 Apr 1

PMID 27030716

Citations 27

Authors

Kaori Kaji

Masamichi Shinoda

Kuniya Honda

Syumpei Unno

Noriyoshi Shimizu

Koichi Iwata

Affiliations

Soon will be listed here.

Abstract

Background: Clinically, it is well known that injury of mandibular nerve fiber induces persistent ectopic pain which can spread to a wide area of the orofacial region innervated by the uninjured trigeminal nerve branches. However, the exact mechanism of such persistent ectopic orofacial pain is not still known. The present study was undertaken to determine the role of connexin 43 in the trigeminal ganglion on mechanical hypersensitivity in rat whisker pad skin induced by inferior alveolar nerve injury. Here, we examined changes in orofacial mechanical sensitivity following inferior alveolar nerve injury. Furthermore, changes in connexin 43 expression in the trigeminal ganglion and its localization in the trigeminal ganglion were also examined. In addition, we investigated the functional significance of connexin 43 in relation to mechanical allodynia by using a selective gap junction blocker (Gap27).

Results: Long-lasting mechanical allodynia in the whisker pad skin and the upper eyelid skin, and activation of satellite glial cells in the trigeminal ganglion, were induced after inferior alveolar nerve injury. Connexin 43 was expressed in the activated satellite glial cells encircling trigeminal ganglion neurons innervating the whisker pad skin, and the connexin 43 protein expression was significantly increased after inferior alveolar nerve injury. Administration of Gap27 in the trigeminal ganglion significantly reduced satellite glial cell activation and mechanical hypersensitivity in the whisker pad skin. Moreover, the marked activation of satellite glial cells encircling trigeminal ganglion neurons innervating the whisker pad skin following inferior alveolar nerve injury implies that the satellite glial cell activation exerts a major influence on the excitability of nociceptive trigeminal ganglion neurons.

Conclusions: These findings indicate that the propagation of satellite glial cell activation throughout the trigeminal ganglion via gap junctions, which are composed of connexin 43, plays a pivotal role in ectopic mechanical hypersensitivity in whisker pad skin following inferior alveolar nerve injury.

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References

Khawaja N, Renton T . Case studies on implant removal influencing the resolution of inferior alveolar nerve injury. Br Dent J. 2009; 206(7):365-70. DOI: 10.1038/sj.bdj.2009.258. View

Scemes E, Giaume C . Astrocyte calcium waves: what they are and what they do. Glia. 2006; 54(7):716-725. PMC: 2605018. DOI: 10.1002/glia.20374. View

Hanani M . Satellite glial cells in sensory ganglia: from form to function. Brain Res Brain Res Rev. 2005; 48(3):457-76. DOI: 10.1016/j.brainresrev.2004.09.001. View

Nagy J, Dudek F, Rash J . Update on connexins and gap junctions in neurons and glia in the mammalian nervous system. Brain Res Brain Res Rev. 2004; 47(1-3):191-215. DOI: 10.1016/j.brainresrev.2004.05.005. View

Kitagawa J, Takeda M, Suzuki I, Kadoi J, Tsuboi Y, Honda K . Mechanisms involved in modulation of trigeminal primary afferent activity in rats with peripheral mononeuropathy. Eur J Neurosci. 2006; 24(7):1976-86. DOI: 10.1111/j.1460-9568.2006.05065.x. View

Lin P, Shen C, Liao C, Jow G, Chiu C, Chung T . HYS-32, a novel analogue of combretastatin A-4, enhances connexin43 expression and gap junction intercellular communication in rat astrocytes. Neurochem Int. 2013; 62(6):881-92. DOI: 10.1016/j.neuint.2013.02.027. View

Cheng C, Cheng J, Chen C, Rau R, Chang Y, Tsaur M . Nerve growth factor-induced synapse-like structures in contralateral sensory ganglia contribute to chronic mirror-image pain. Pain. 2015; 156(11):2295-2309. DOI: 10.1097/j.pain.0000000000000280. View

Hironaka K, Ozaki N, Hattori H, Nagamine K, Nakashima H, Ueda M . Involvement of glial activation in trigeminal ganglion in a rat model of lower gingival cancer pain. Nagoya J Med Sci. 2015; 76(3-4):323-32. PMC: 4345692. View

Gold M, Gebhart G . Nociceptor sensitization in pain pathogenesis. Nat Med. 2010; 16(11):1248-57. PMC: 5022111. DOI: 10.1038/nm.2235. View

10.

Weick M, Cherkas P, Hartig W, Pannicke T, Uckermann O, Bringmann A . P2 receptors in satellite glial cells in trigeminal ganglia of mice. Neuroscience. 2003; 120(4):969-77. DOI: 10.1016/s0306-4522(03)00388-9. View

11.

Wagner L, Warwick R, Pannicke T, Reichenbach A, Grosche A, Hanani M . Glutamate release from satellite glial cells of the murine trigeminal ganglion. Neurosci Lett. 2014; 578:143-7. DOI: 10.1016/j.neulet.2014.06.047. View

12.

Wang H, Cao Y, Chiang C, Dostrovsky J, Sessle B . The gap junction blocker carbenoxolone attenuates nociceptive behavior and medullary dorsal horn central sensitization induced by partial infraorbital nerve transection in rats. Pain. 2013; 155(2):429-435. PMC: 3901535. DOI: 10.1016/j.pain.2013.11.004. View

13.

Giugliano M . Calcium waves in astrocyte networks: theory and experiments. Front Neurosci. 2010; 3(2):160-1. PMC: 2751621. DOI: 10.3389/neuro.01.019.2009. View

14.

Taves S, Berta T, Chen G, Ji R . Microglia and spinal cord synaptic plasticity in persistent pain. Neural Plast. 2013; 2013:753656. PMC: 3759269. DOI: 10.1155/2013/753656. View

15.

Valerio A, Rizzonelli P, Paterlini M, Moretto G, Knopfel T, Kuhn R . mGluR5 metabotropic glutamate receptor distribution in rat and human spinal cord: a developmental study. Neurosci Res. 1997; 28(1):49-57. DOI: 10.1016/s0168-0102(97)01175-9. View

16.

Campana W, Myers R . Exogenous erythropoietin protects against dorsal root ganglion apoptosis and pain following peripheral nerve injury. Eur J Neurosci. 2003; 18(6):1497-506. DOI: 10.1046/j.1460-9568.2003.02875.x. View

17.

Arguis M, Perez J, Martinez G, Ubre M, Gomar C . Contralateral neuropathic pain following a surgical model of unilateral nerve injury in rats. Reg Anesth Pain Med. 2008; 33(3):211-6. DOI: 10.1016/j.rapm.2007.12.003. View

18.

Hitomi S, Shinoda M, Suzuki I, Iwata K . Involvement of transient receptor potential vanilloid 1 in ectopic pain following inferior alveolar nerve transection in rats. Neurosci Lett. 2012; 513(1):95-9. DOI: 10.1016/j.neulet.2012.02.018. View

19.

Ren K, Dubner R . Activity-triggered tetrapartite neuron-glial interactions following peripheral injury. Curr Opin Pharmacol. 2015; 26:16-25. PMC: 4716885. DOI: 10.1016/j.coph.2015.09.006. View

20.

Renton T, Yilmaz Z, Gaballah K . Evaluation of trigeminal nerve injuries in relation to third molar surgery in a prospective patient cohort. Recommendations for prevention. Int J Oral Maxillofac Surg. 2012; 41(12):1509-18. DOI: 10.1016/j.ijom.2012.06.025. View