Calcitonin receptor-like receptor (CLR), receptor activity-modifying protein 1 (RAMP1), and calcitonin gene-related peptide (CGRP) immunoreactivity in the rat trigeminovascular system: differences between peripheral and central CGRP receptor distribution

J Comp Neurol. 2008 Mar 20;507(3):1277-99. doi: 10.1002/cne.21607.


Calcitonin gene-related peptide (CGRP) is a key mediator in primary headaches including migraine. Animal models of meningeal nociception demonstrate both peripheral and central CGRP effects; however, the target structures remain unclear. To study the distribution of CGRP receptors in the rat trigeminovascular system we used antibodies recognizing two components of the CGRP receptor, the calcitonin receptor-like receptor (CLR) and the receptor activity-modifying protein 1 (RAMP1). In the cranial dura mater, CLR and RAMP1 immunoreactivity (-ir) was found within arterial blood vessels, mononuclear cells, and Schwann cells, but not sensory axons. In the trigeminal ganglion, besides Schwann and satellite cells, CLR- and RAMP1-ir was found in subpopulations of CGRP-ir neurons where colocalization of CGRP- and RAMP1-ir was very rare ( approximately 0.6%). CLR- and RAMP1-ir was present on central, but not peripheral, axons. In the spinal trigeminal nucleus, CLR- and RAMP1-ir was localized to "glomerular structures," partly colocalized with CGRP-ir. However, CLR- and RAMP1-ir was lacking in central glia and neuronal cell bodies. We conclude that CGRP receptors are associated with structural targets of known CGRP effects (vasodilation, mast cell degranulation) and targets of unknown function (Schwann cells). In the spinal trigeminal nucleus, CGRP receptors are probably located on neuronal processes, including primary afferent endings, suggesting involvement in presynaptic regulation of nociceptive transmission. Thus, in the trigeminovascular system CGRP receptor localization suggests multiple targets for CGRP in the pathogenesis of primary headaches.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcitonin Gene-Related Peptide / metabolism*
  • Dura Mater / blood supply
  • Dura Mater / metabolism
  • Immunohistochemistry
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Male
  • Medulla Oblongata / blood supply
  • Medulla Oblongata / cytology
  • Medulla Oblongata / metabolism
  • Membrane Proteins / metabolism*
  • Migraine Disorders / metabolism
  • Nociceptors / metabolism
  • Rats
  • Rats, Wistar / physiology*
  • Receptor Activity-Modifying Protein 1
  • Receptor Activity-Modifying Proteins
  • Receptors, Calcitonin Gene-Related Peptide / metabolism*
  • Satellite Cells, Perineuronal / metabolism
  • Schwann Cells / metabolism
  • Trigeminal Ganglion / blood supply
  • Trigeminal Ganglion / cytology
  • Trigeminal Ganglion / metabolism*
  • Trigeminal Nucleus, Spinal / blood supply
  • Trigeminal Nucleus, Spinal / cytology
  • Trigeminal Nucleus, Spinal / metabolism*


  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Ramp1 protein, rat
  • Receptor Activity-Modifying Protein 1
  • Receptor Activity-Modifying Proteins
  • Receptors, Calcitonin Gene-Related Peptide
  • Calcitonin Gene-Related Peptide