Immunohistochemical localization of histamine H3 receptors in rodent skin, dorsal root ganglia, superior cervical ganglia, and spinal cord: Potential antinociceptive targets

Abstract

Activation of histamine H 3 receptors (H 3 Rs) reduces inflammation and nociception, but the existence of H 3 Rs on peripheral innervation has never been demonstrated. Here we use antibodies to locate H 3 Rs in whisker pads, hairy and glabrous hind paw skin, dorsal root ganglia (DRGs), and spinal cords of rats, wild-type mice, and H 3 R knockout (H 3 KO) mice. Although H 3 Rs have been hypothesized to be on C and sympathetic fibers, H 3 R-like immunoreactivity (H 3 R-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 3 R-positive periarterial fibers were thin-caliber and coexpressed immunoreactivity for calcitonin gene-related peptide (CGRP), substance P, acid sensing ion channel 3 and 200kD neurofilament protein (NF). H 3 R-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 3 R-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 3 R-LI ramified extensively in lamina II; many of the former formed a plexus in lamina V. Low levels of H 3 R-LI were also present on Aβ fibers penetrating superficial and into deeper laminae. The distribution of H 3 R-LI was similar in rats and wild-type mice, but was eliminated or strongly reduced in Aδ fibers and Aβ fibers, respectively, in H 3 KO mice. Taken with recently published behavioral results, the present findings suggest that periarterial, peptidergic, H 3 R-containing Aδ fibers may be sources of high threshold mechanical nociception.

The role of histamine in neurogenic inflammation

“…injection of histamine induces CGRP release into the CSF (Bileviciute et al, 1994) and (iii) histamine administered to the nasal mucosa causes CGRP release from the peripheral terminals of trigeminal ganglion in the guinea pig (Tani et al, 1990). Further support for this link between histamine and CGRP is attained from the observed co-localization of the histamine H3 receptor with CGRP on Aδ fibres, with both mediators contributing to a high-threshold mechanical nociceptive effect (Cannon et al, 2007).…”

“…It is possible that these histamine H3 receptor antagonists block the modulatory role of the presynaptic H3 receptor, thus favouring the release of neuropeptides from sensory endings (Cannon et al, 2007). More recently, data obtained with clobenproprit, an H3 receptor antagonist and H4 receptor agonist, suggest that the H4 receptor is also involved in itch.…”

“…injection of histamine induces CGRP release into the CSF (Bileviciute et al, 1994) and (iii) histamine administered to the nasal mucosa causes CGRP release from the peripheral terminals of trigeminal ganglion in the guinea pig (Tani et al, 1990). Further support for this link between histamine and CGRP is attained from the observed co-localization of the histamine H3 receptor with CGRP on Aδ fibres, with both mediators contributing to a high-threshold mechanical nociceptive effect (Cannon et al, 2007).More recently, it has been demonstrated that both the H1 receptor antagonist pyrilamine and the H2 receptor antagonist ranitidine produce dose-dependent antinociceptive responses in the formalin test, and that hyperalgesia induced by intrathecal administration of histamine is attenuated by the GCRP antagonist CGRP 8-37 (Mobarakeh et al, 2011).Studies with histamine H1 receptor knockout mice have demonstrated that both the receptor and its natural ligand are needed to facilitate pain transmission at both the peripheral and central levels (Mobarakeh et al, 2000;. In addition, using histidine decarboxylase (HDC) gene knockout mice, it was shown that NK 1 receptors in the spinal cord mediate the histamine-induced hyperalgesic responses (Yoshida et al, 2005).…”

Histamine H3 Receptor Antagonists Go to Clinics

“…164) In contrast to the latter, GSK334429 is a less rigidized 1,4-diazepane possessing comparable properties to that of GSK189254. It is active in attention and cognition models but what is more important, both, GSK189254 and GSK334429, have recently shown to be efficacious in models of neuropathic pain 165) pointing out a possible additive indication for these short-acting and poor brain penetrating ligands as H 3 R modulates pain reception in the dorsal horn and spinal cord 48) (Fig. 7, Tables 1, 2).…”

“…28) H 3 R expression is not solely restricted to histaminergic neurons: due to its function as a heteroreceptor it can be found on colocalised neurons, and H 3 R activation modulates the release of various important neurotransmitters, i.e. dopamine, [29][30][31][32][33] acetylcholine, [34][35][36][37] norepinephrine, 38,39) serotonin, 40,41) GABA, [42][43][44] glutamate, 45) and substance P. [46][47][48] Therefore, histaminergic neurons and the cross-linkage between major neurotransmitter systems are involved in many (patho)physiological brain functions, including vigilance, memory processes, feeding behaviour and locomotor activity (Fig. 2).…”