Cerebral arterial innervation by nerve fibers containing calcitonin gene-related peptide (CGRP): I. Distribution and origin of CGRP perivascular innervation in the rat

The origin, density and distribution of calcitonin gene-related peptide (CGRP) immunoreactivity in cerebral perivascular nerves and the trigeminal ganglion of rats were examined in this study. CGRP immunoreactive axons were abundant on the walls of the rostral circulation of the major cerebral arteries in the circle of Willis. The fibers form a grid- or meshwork of longitudinal and circumferential axons studded with numerous varicose swellings. The density of CGRP fibers was particularly high at the bifurcation of major arteries. A few CGRP fibers cross the midline to innervate arteries on the contralateral side of the arterial tree. The arteries of the caudal circulation were sparsely innervated by CGRP fibers. In the trigeminal ganglion, about 30% of the ganglion cells had CGRP immunoreactivity. The cell size of most (75%) of CGRP neurons was less than 30 micron in diameter. There was no significant difference in staining density between small and large CGRP neurons. Unilateral transection of the maxillary and mandibular divisions of the trigeminal nerve caused a substantial decrease of CGRP immunoreactivity in the ipsilateral dorsal two-thirds of the trigeminal nucleus and cervical spinal cord but did not noticeably change the diameter of the vascular lumen or the densities of CGRP fibers in the walls of the cerebral arteries. In contrast, unilateral transection that included the ophthalmic division eliminated CGRP fibers on the ipsilateral cerebral arteries and eliminated CGRP immunoreactivity throughout the trigeminal nucleus in the brainstem and rostral cervical cord. In addition, these lesions caused a significant reduction in the diameter of the denervated arteries. The present study demonstrates that CGRP, a putative neurotransmitter/neuromodulator, is especially abundant in the rostral cerebral circulation and is derived from the ipsilateral ophthalmic division of the trigeminal nerve. In addition, the loss of CGRP perivascular nerves is associated with a reduction of the arterial lumen. This suggests that CGRP is a strong candidate as a nerve-derived trophic factor at trigeminal terminals and provides additional evidence that CGRP is a component in the trigeminovascular system influencing vascular diameter.