title: Elevated levels of calcitonin gene-related peptide in upper spinal cord promotes sensitization of primary trigeminal nociceptive neurons.
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 CGRP8-37or 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 CGRP8-37or 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.
authors.affiliation: Center for Biomedical and Life Sciences, Missouri State University, Springfield, MO, USA.
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Cornelison
authors.affiliation: Center for Biomedical and Life Sciences, Missouri State University, Springfield, MO, USA.
authors.forename: Jordan L
authors.initials: JL
authors.lastname: Hawkins
authors.affiliation: Center for Biomedical and Life Sciences, Missouri State University, Springfield, MO, USA. Electronic address: pauldurham@missouristate.edu.
authors.forename: Paul L
authors.initials: PL
authors.lastname: Durham
mesh_terms: D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000008:administration & dosage / Q000378:metabolism*; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D002135:Calcium-Binding Proteins / Q000378:metabolism; D066193:Cervical Cord / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005157:Facial Pain / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D008297:Male; D008840:Microfilament Proteins / Q000378:metabolism; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D059226:Nociceptive Pain / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D009619:Nociceptors / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000819:agonists / Q000378:metabolism; D012668:Trigeminal Ganglion / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology
chemical_list: C100745:Aif1 protein, rat; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D002135:Calcium-Binding Proteins; C000614142:Gfap protein, rat; D005904:Glial Fibrillary Acidic Protein; D008840:Microfilament Proteins; D047428:Protein Kinase Inhibitors; D018015:Receptors, Calcitonin Gene-Related Peptide; D017868:Cyclic AMP-Dependent Protein Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D015740:Calcitonin Gene-Related Peptide
keywords: calcitonin gene-related peptide; glia; neuronal sensitization; nociception; protein kinase A; trigeminal ganglion