Distribution studies disclosed that all major cerebral arteries and cortical arterioles of the cat were invested with fme varicose nerve fibers that contained calcitonin generelated peptide (CGRP)-like immunoreactivity; the trigeminal ganglia likewise contained CGRP immunoreactivity. Sequential immunostaining with antibodies to CGRP and to substance P (SP) revealed identical distributions of these two peptides in trigeminal ganglia and cerebrovascular nerve fibers, suggesting that CGRP and SP are colocalized in these nerves. CGRP completely disappeared from ipsilateral blood vessels after unilateral section of the trigeminal nerve. Exogenous CGRP was a potent relaxant of feline middle cerebral arteries in vitro (maximum relaxation, 10.5 ± 1.5 mN; concentration eliciting half-maximal response, 9.6 ± 1.3 nM). Perivascular microapplication of CGRP to individual cortical arterioles of chloralose-anesthetized cats provoked dose-dependent dilatations (maximum increase in diameter, 38 ± 5%; concentration eliciting half-maximal response, '-3 nM). CGRP was signifiw cantly more potent than SP as a cerebrovascular dilator, both in vitro and in situ. Chronic division of the ipsilateral trigeminal nerve in cats did not modify the magnitude of arteriolar responses to perivascular microapplication of either vasoconstrictor or vasodilator agents, but the duration of vasoconstrictor responses to norepinephrine (0.1 mM) or alkaline solutions (pH 7.6) was significantly increased. The cerebrovascular trigeminal neuronal system, in which CGRP is the most potent vasoactive constituent, may participate in a reflex or local response to excessive cerebral vasoconstriction that restores normal vascular diameter.Local cerebral blood flow is normally adjusted to meet local demands for energy generation that is almost exclusively met by the oxidative catabolism of glucose. The vasoactive products of cellular metabolism, with perivascular hydrogen ions, potassium ions, and adenosine being the most favored candidates, have long been considered primarily responsible for this dynamic regulation of cerebral blood flow (1). Cerebral blood vessels are, however, invested by nerve fibers that contain diverse neurotransmitters [norepinephrine, acetylcholine, 5-hydroxytryptamine, vasoactive intestinal polypeptide, peptide histidine isoleucine, neuropeptide Y, substance P (SP) and such]. Although these agents have direct vasomotor effects upon cerebral blood vessels, the explicit function of any of these perivascular neuronal systems in cerebrovascular regulation remains obscure (2, 3).The neuropeptide, calcitonin gene-related peptide (CGRP), has recently been identified from structural analysis of the products of calcitonin gene expression. Alternative processing of RNA transcribed from the calcitonin gene leads to the production, in neuronal tissue, of a 37-amino acid peptide, CGRP (4,5). CGRP-like immunoreactivity is present in many regions of the central nervous system (most notably the spinal cord, medullary and pontine nuclei, amygdala, a...

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Use of alternative location to go to the published version of the article requires journal subscription. AbstractPrimary headaches such as migraine and cluster headache are neurovascular disorders.Migraine is a painful, incapacitating disease that affects a large portion of the adult population with a substantial economic burden on society.

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Summary: The innervation of cerebral blood vessels by nerve fibers containing calcitonin gene-related peptide (CGRP) and the vasomotor effects of this peptide are de scribed for a number of different mammalian species. CGRP-immunoreactive nerve fibers were present in the adventitia of cerebral arteries in all species examined (guinea pig, cat, rabbit, rat, and mouse). Numerous peri karya containing CGRP immunoreactivity are demon strable in the trigeminal ganglion of all species. In the cerebral perivascular nerve fibers and in trigeminal peri karya, CGRP is often colocalized with substance P and neurokinin A. Marked interspecies differences exist both in the density of CGRP-immunoreactive nerve fibers and in the cerebrovascular levels measured with radioimmu noassay. The highest concentrations were observed in ce rebral vessels from guinea pigs, the lowest concentration in rabbit vessels, and intermediate levels in the feline and human cerebral vasculature. CGRP is a potent dilator of Calcitonin gene-related peptide (CGRP) is a 37 amino acid peptide recently identified from struc tural analysis of the products of calcitonin gene ex pression (Amara et al., 1982;Rosenfeld et al. , 1983). CGRP-immunoreactive fibers are abundant in the sensory receiving areas of the spinal cord and to a lesser extent in the sympathetic and parasym pathetic centers. CGRP-containing terminals are also present in sensory nuclei of the lower brain stem, for example, the nucleus tractus solitarius (Gibson et aI. , 1984; Kawai et aI., 1985;Skofitsch and Jacobowitz, 1985). Immunocytochemical studies have revealed that CGRP coexists with sub stance P and neurokinin A in nerve cell bodies of 720cerebral arteries in all species examined (human pial, fe line middle cerebral, rabbit, guinea pig and rat basilar ar teries). The concentration of CGRP eliciting half-max imal responses ranged from 0.4 nM (human pial artery) to 3 nM (rat and rabbit basilar arteries). Pretreatment of ce rebral arteries with low concentrations of either sub stance P (0.1 nM) or neurokinin A (3 nM) attenuated slightly the CGRP-induced relaxations of guinea pig bas ilar arteries. Calcitonin was found to be a very weak di lator of cerebral arteries from human and guinea pig. Thus, cardiovascular nerve fibers containing CGRP ap pear to be present in all mammalian species (although to varying degrees) and CGRP is invariably a potent dilator of the cerebral arteries for all species.