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Neurobiol Pain. 2019 Apr 24;6:100031. doi: 10.1016/j.ynpai.2019.100031. eCollection 2019 Aug-Dec.

Sex differences in the expression of calcitonin gene-related peptide receptor components in the spinal trigeminal nucleus.

Author information

1
Department of Advanced Oral Sciences and Therapeutics, University of Maryland School of Dentistry, Baltimore, MD, USA.
2
Program in Neuroscience, University of Maryland School of Medicine, Baltimore, MD, USA.
3
Department of Oncology and Diagnostic Sciences, University of Maryland School of Dentistry, Baltimore, MD, USA.
4
Department of Oral Medicine and Diagnostics Sciences, King Saud University, School of Dentistry, Riyadh, Saudi Arabia.
5
Department of Neural Sciences and Pain, University of Maryland School of Dentistry, Baltimore, MD, USA.
6
School of Behavioral and Brain Sciences, The University of Texas at Dallas, Richardson, TX, USA.
7
Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA.

Abstract

Background and purpose:

Calcitonin gene-related peptide (CGRP) plays an important role in migraine pathophysiology. CGRP acts primarily by activating a receptor composed of 3 proteins: calcitonin receptor-like receptor (CLR), receptor activity-modifying protein 1 (RAMP1), and receptor component protein (RCP). We tested the hypothesis that sex differences exist in protein levels of two key components of this CGRP receptor: CLR and RCP.

Methods:

We used specific antibodies to assess baseline protein levels of CLR and RCP in the spinal trigeminal nucleus caudalis (SpVc) and upper cervical spinal cord of both male and female rats. We also tested if manipulations that knock-down the expression of RCP in SpVc, using locally-mediated gene transfer of short hairpin RNA (shRNA), ameliorate pain in an animal model of intracranial migraine-like pain induced by chemical noxious stimulation of the meninges. To assess pain, we used tests of ongoing pain (rat face grimace test and freezing behavior) and tests of facial mechanical hypersensitivity and allodynia.

Results:

There was no difference in CLR levels between male and female animals (p > 0.11) in SpVc and the upper cervical cord. However, female animals exhibited greater baseline levels of RCP (up to 3-fold higher) compared to males (p < 0.002). The knock-down of RCP expression in SpVc attenuated mechanical facial allodynia induced by chemical noxious stimulation of the meninges, but had little effect on ongoing pain behaviors in female and male animals.

Conclusions:

RCP is an integral component of the CGRP receptor and may play a key role in mediating CGRP induced central sensitization after noxious stimulation of the meninges. RCP expression in the SpVc and upper cervical cord is sexually dimorphic, with higher levels of expression in females. This dimorphism may be related to the increased incidence of migraines in females-a hypothesis that should be tested in the future.

KEYWORDS:

ACSF, artificial cerebrospinal fluid; Allodynia; CGRP; CGRP, calcitonin gene-related peptide; CLR, calcitonin receptor-like protein; Headache; IM, inflammatory mediators; Meninges; Migraine; RAMP1, receptor activity-modifying protein 1; RCP, receptor component protein; SpVc, spinal trigeminal nucleus caudalis; Trigeminal; shRNA, short hairpin RNA

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