Immunohistochemical localization of histamine H 3 receptors in rodent skin, dorsal root ganglia, superior cervical ganglia, and spinal cord: Potential antinociceptive targets

Abstract

Activation of histamine H 3 receptors (H 3Rs) reduces inflammation and nociception, but the existence of H 3Rs on peripheral innervation has never been demonstrated. Here we use antibodies to locate H 3Rs in whisker pads, hairy and glabrous hind paw skin, dorsal root ganglia (DRGs), and spinal cords of rats, wild type mice, and H 3R knockout (H 3KO) mice. Although H 3Rs have been hypothesized to be on C and sympathetic fibers, H 3R-like immunoreactivity (H 3R-LI) was only detected on presumptive periarterial Aδ fibers and on Aβ fibers that terminated in Meissner’s corpuscles and as lanceolate endings around hair follicles. The H 3R-positive periarterial fibers were thin-caliber and coexpressed immunoreactivity for calcitonin gene-related peptide (CGRP), substance P, acid sensing ion channel 3, and 200 kDa neurofilament protein (NF). H 3R-LI was also detected on epidermal keratinocytes and Merkel cells, but not on Merkel endings, C fibers, any other Aδ fibers, or sympathetic fibers. In DRGs, H 3R-LI was preponderantly on medium to large neurons coexpressing NF-LI and mostly CGRP-LI. In dorsal horn, CGRP-positive fibers with and without H 3R-LI ramified extensively in lamina II; many of the former formed a plexus in lamina V. Low levels of H 3R-LI were also present on Aβ fibers penetrating superficial and into deeper laminae. The distribution of H 3R-LI was similar in rats and wild type mice, but was eliminated or strongly reduced in Aδ fibers and Aβ fibers, respectively, in H 3KO mice. Taken with recently published behavioral results, the present findings suggest that periarterial, peptidergic, H 3R-containing Aδ fibers may be sources of high threshold mechanical nociception.