title: Anatomy and immunochemical characterization of the non-arterial peptidergic diffuse dural innervation of the rat and Rhesus monkey: Implications for functional regulation and treatment in migraine.
abstract: Objective The interplay between neuronal innervation and other cell types underlies the physiological functions of the dura mater and contributes to pathophysiological conditions such as migraine. We characterized the extensive, but understudied, non-arterial diffuse dural innervation (DDI) of the rat and Rhesus monkey. Methods We used a comprehensive integrated multi-molecular immunofluorescence labeling strategy to extensively profile the rat DDI and to a lesser extent that of the Rhesus monkey. Results The DDI was distributed across a dense, pervasive capillary network and included free nerve endings of peptidergic CGRP-expressing C fibers that were closely intertwined with noradrenergic (NA) sympathetic fibers and thin-caliber nonpeptidergic "C/Aδ" fibers. These newly identified C/Aδ fibers were unmyelinated, like C fibers, but expressed NF200, usually indicative of Aδ fibers, and uniquely co-labeled for the CGRP co-receptor, RAMP1. Slightly-larger caliber NF200-positive fibers co-labeled for myelin basic protein (MBP) and terminated as unbranched corpuscular endings. The DDI peptidergic fibers co-labeled for the lectin IB4 and expressed presumably excitatory α1-adrenergic receptors, as well as inhibitory 5HT1D receptors and the delta opioid receptor (δOR), but rarely the mu opioid receptor (µOR). Labeling for P2X3, TRPV1, TRPA1, and parasympathetic markers was not observed in the DDI. Interpretation These results suggest potential functional interactions, wherein peptidergic DDI fibers may be activated by stress-related sympathetic activity, resulting in CGRP release that could be detected in the circulation. CGRP may also activate nonpeptidergic C/Aδ fibers that are likely mechanosensitive or polymodal, leading to activation of post-synaptic pain transmission circuits. The distribution of α1-adrenergic receptors, RAMP1, and the unique expression of the δOR on CGRP-expressing DDI fibers suggest strategies for functional modulation and application to therapy.
authors.affiliation: 1 Integrated Tissue Dynamics LLC, Rensselaer, NY, USA.
authors.forename: Frank L
authors.initials: FL
authors.lastname: Rice
authors.affiliation: 2 Department of Pharmacology, Arizona Health Sciences Center, University of Arizona, Tucson, AZ, USA.
authors.forename: Jennifer Y
authors.initials: JY
authors.lastname: Xie
authors.affiliation: 1 Integrated Tissue Dynamics LLC, Rensselaer, NY, USA.
authors.forename: Phillip J
authors.initials: PJ
authors.lastname: Albrecht
authors.affiliation: 1 Integrated Tissue Dynamics LLC, Rensselaer, NY, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Acker
authors.affiliation: 1 Integrated Tissue Dynamics LLC, Rensselaer, NY, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Bourgeois
authors.affiliation: 2 Department of Pharmacology, Arizona Health Sciences Center, University of Arizona, Tucson, AZ, USA.
authors.forename: Edita
authors.initials: E
authors.lastname: Navratilova
authors.affiliation: 3 Departments of Collaborative Research and Neurology, Mayo Clinic, Scottsdale, AZ, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Dodick
authors.affiliation: 2 Department of Pharmacology, Arizona Health Sciences Center, University of Arizona, Tucson, AZ, USA.|3 Departments of Collaborative Research and Neurology, Mayo Clinic, Scottsdale, AZ, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Porreca
mesh_terms: D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000032:analysis / Q000378:metabolism; D002196:Capillaries / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D004388:Dura Mater / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology*; D008253:Macaca mulatta; D008297:Male; D008881:Migraine Disorders / Q000378:metabolism* / Q000473:pathology* / Q000628:therapy; D036421:Nerve Fibers, Unmyelinated / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D058262:Receptor Activity-Modifying Protein 1 / Q000032:analysis / Q000378:metabolism; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000032:analysis / Q000378:metabolism; D013045:Species Specificity; D050916:TRPV Cation Channels / Q000032:analysis / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: C545508:Ramp1 protein, rat; D058262:Receptor Activity-Modifying Protein 1; D018340:Receptors, Adrenergic, alpha-1; D018015:Receptors, Calcitonin Gene-Related Peptide; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D015740:Calcitonin Gene-Related Peptide
keywords: Headache; dura mater; sensory fibers; sympathetic fibers