Elevated Levels of Calcitonin Gene-related Peptide in Upper Spinal Cord Promotes Sensitization of Primary Trigeminal Nociceptive Neurons

Overview

Journal Neuroscience

Specialty Neurology

Date 2016 Nov 5

PMID 27746346

Citations 23

Authors

Lauren E Cornelison

Jordan L Hawkins

Paul L Durham

Affiliations

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Abstract

Orofacial pain conditions including temporomandibular disorder (TMD) and migraine are characterized by peripheral and central sensitization of trigeminal nociceptive neurons. The goal of this study was to investigate the role of calcitonin gene-related peptide (CGRP) in promoting bidirectional signaling within the trigeminal system to mediate sensitization of primary nociceptive neurons. Adult male Sprague-Dawley rats were injected intercisternally with CGRP or co-injected with the receptor antagonist CGRP or KT 5720, a protein kinase A (PKA) inhibitor. Nocifensive head withdrawal response to mechanical stimulation was investigated using von Frey filaments. Expression of PKA, glial fibrillary acidic protein (GFAP), and ionized calcium-binding adapter molecule 1 (Iba1) in the spinal cord and phosphorylated extracellular signal-regulated kinase (P-ERK) in the ganglion was studied using immunohistochemistry. Some animals were co-injected with CGRP and Fast Blue dye and the ganglion was imaged using fluorescent microscopy. CGRP increased nocifensive responses to mechanical stimulation when compared to control. Co-injection of CGRP or KT 5720 with CGRP inhibited the nocifensive response. CGRP stimulated PKA and GFAP expression in the spinal cord, and P-ERK in ganglion neurons. Seven days post injection, Fast Blue was observed in ganglion neurons and satellite glial cells. Our results demonstrate that elevated levels of CGRP in the upper spinal cord promote sensitization of primary nociceptive neurons via a mechanism that involves activation of PKA centrally and P-ERK in ganglion neurons. Our findings provide evidence of bidirectional signaling within the trigeminal system that facilitate increased neuron-glia communication within the ganglion associated with trigeminal sensitization.

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References

Bossowska A, Crayton R, Radziszewski P, Kmiec Z, Majewski M . Distribution and neurochemical characterization of sensory dorsal root ganglia neurons supplying porcine urinary bladder. J Physiol Pharmacol. 2010; 60 Suppl 4:77-81. View

Gosselin R, Suter M, Ji R, Decosterd I . Glial cells and chronic pain. Neuroscientist. 2010; 16(5):519-31. PMC: 3017463. DOI: 10.1177/1073858409360822. View

Cady R, Glenn J, Smith K, Durham P . Calcitonin gene-related peptide promotes cellular changes in trigeminal neurons and glia implicated in peripheral and central sensitization. Mol Pain. 2011; 7:94. PMC: 3267674. DOI: 10.1186/1744-8069-7-94. View

Sessle B . Peripheral and central mechanisms of orofacial inflammatory pain. Int Rev Neurobiol. 2011; 97:179-206. DOI: 10.1016/B978-0-12-385198-7.00007-2. View

Bernstein C, Burstein R . Sensitization of the trigeminovascular pathway: perspective and implications to migraine pathophysiology. J Clin Neurol. 2012; 8(2):89-99. PMC: 3391624. DOI: 10.3988/jcn.2012.8.2.89. View

Brain S, Cox H . Neuropeptides and their receptors: innovative science providing novel therapeutic targets. Br J Pharmacol. 2006; 147 Suppl 1:S202-11. PMC: 1760747. DOI: 10.1038/sj.bjp.0706461. View

Burstein R, Noseda R, Borsook D . Migraine: multiple processes, complex pathophysiology. J Neurosci. 2015; 35(17):6619-29. PMC: 4412887. DOI: 10.1523/JNEUROSCI.0373-15.2015. View

Adwanikar H, Ji G, Li W, Doods H, Willis W, Neugebauer V . Spinal CGRP1 receptors contribute to supraspinally organized pain behavior and pain-related sensitization of amygdala neurons. Pain. 2007; 132(1-2):53-66. PMC: 2066202. DOI: 10.1016/j.pain.2007.01.024. View

Hawkins J, Denson J, Miley D, Durham P . Nicotine stimulates expression of proteins implicated in peripheral and central sensitization. Neuroscience. 2015; 290:115-25. PMC: 5894823. DOI: 10.1016/j.neuroscience.2015.01.034. View

10.

Han J, Li W, Neugebauer V . Critical role of calcitonin gene-related peptide 1 receptors in the amygdala in synaptic plasticity and pain behavior. J Neurosci. 2005; 25(46):10717-28. PMC: 6725858. DOI: 10.1523/JNEUROSCI.4112-05.2005. View

11.

Aley K, Levine J . Role of protein kinase A in the maintenance of inflammatory pain. J Neurosci. 1999; 19(6):2181-6. PMC: 6782560. View

12.

Garrett F, Hawkins J, Overmyer A, Hayden J, Durham P . Validation of a novel rat-holding device for studying heat- and mechanical-evoked trigeminal nocifensive behavioral responses. J Orofac Pain. 2012; 26(4):337-44. PMC: 5894827. View

13.

Villa G, Ceruti S, Zanardelli M, Magni G, Jasmin L, Ohara P . Temporomandibular joint inflammation activates glial and immune cells in both the trigeminal ganglia and in the spinal trigeminal nucleus. Mol Pain. 2010; 6:89. PMC: 3017032. DOI: 10.1186/1744-8069-6-89. View

14.

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. 2003; 45(1):89-95. DOI: 10.1002/glia.10308. View

15.

Miller R, Jung H, Bhangoo S, White F . Cytokine and chemokine regulation of sensory neuron function. Handb Exp Pharmacol. 2009; (194):417-49. PMC: 2746245. DOI: 10.1007/978-3-540-79090-7_12. View

16.

Chiba T, Yamaguchi A, Yamatani T, Nakamura A, Morishita T, Inui T . Calcitonin gene-related peptide receptor antagonist human CGRP-(8-37). Am J Physiol. 1989; 256(2 Pt 1):E331-5. DOI: 10.1152/ajpendo.1989.256.2.E331. View

17.

Edvinsson L, Nilsson E, Jansen-Olesen I . Inhibitory effect of BIBN4096BS, CGRP(8-37), a CGRP antibody and an RNA-Spiegelmer on CGRP induced vasodilatation in the perfused and non-perfused rat middle cerebral artery. Br J Pharmacol. 2007; 150(5):633-40. PMC: 2189771. DOI: 10.1038/sj.bjp.0707134. View

18.

Hawkins J, Durham P . Prolonged Jaw Opening Promotes Nociception and Enhanced Cytokine Expression. J Oral Facial Pain Headache. 2016; 30(1):34-41. PMC: 5894825. DOI: 10.11607/ofph.1557. View

19.

Olesen J, Burstein R, Ashina M, Tfelt-Hansen P . Origin of pain in migraine: evidence for peripheral sensitisation. Lancet Neurol. 2009; 8(7):679-90. DOI: 10.1016/S1474-4422(09)70090-0. View

20.

Furquim B, Flamengui L, Conti P . TMD and chronic pain: a current view. Dental Press J Orthod. 2015; 20(1):127-33. PMC: 4373025. DOI: 10.1590/2176-9451.20.1.127-133.sar. View