Calcitonin gene-related peptide (CGRP) in the rat central nervous system: patterns of immunoreactivity and receptor binding sites

The distribution of immunoreactive (IR) axons and neurons in the rat central nervous system (CNS) has been studied with an antiserum directed against the C-terminal sequence of rat α-calcitonin gene-related peptide (CGRP) and a durable peroxidase reaction product for detailed analysis in relation to normal cytoarchitecture. These materials were studied and illustrated in the three principal axes in relation to cell-stained adjacent sections in normal as well as colchicine- and capsaicin-treated animals, although no fundamental differences in pattern were evident in neurotoxin-treated rats. The patterns of CGRP-IR were then compared with autoradiograms of specific, high affinity receptor binding sites for ¹²⁵I-human α-CGRP. CGRP-IR labeling in motor systems includes the vast majority of motoneurons, enabling facile identification of isolated 'accessory' populations. Preganglionic parasympathetic nuclei revealed only labeling of a small proportion of neurons. By contrast, the sensory systems revealed a diversity of labeling patterns precluding simple generalizations. Peripheral input ranges from extensive labeling of thin somatic afferents, feeble to moderate gustatory and olfactory afferents to a total absence of auditory afferents, yet IR axons and neurons can be found in selective distribution within each of these sensory systems. Patterns of IR in various integrative centers, e.g. cerebellum, basal ganglia and hypothalamus, reveal selectivity that fails to conform to conventional descriptions of functional systems. Some regions display unexpected patterns, e.g. vertical stripes in cerebellar cortex. CGRP receptor binding sites (RB) are found in many of the sites where IR axons terminate and in some cases, e.g. motor neurons, which express intraneuronal IR. The main sensory systems reveal a variety of RB patterns, only a few of which can be related to sites of IR axon terminals. Many apparent 'mismatches' between IR and RB are illustrated and discussed in the context of functional peptide expression or in quasi-hormonal terms. It is suggested that the principle of CGRP-IR axon distribution in peripheral tissues, where synapses are lacking, might also apply to the CNS and that neither the locus of IR-axon terminals nor RB sites need indicate transmitter action for impulse information transfer. CGRP is a widely distributed neuromodulator probably subserving a role in both synaptic and metabolic regulation, depending on the specific requirements of the diverse distribution of its receptors.