Pruriception and neuronal coding in nociceptor subtypes in human and nonhuman primates

Abstract

In humans, intradermal administration of β-alanine (ALA) and bovine adrenal medulla peptide 8–22 (BAM8-22) evokes the sensation of itch. Currently, it is unknown which human dorsal root ganglion (DRG) neurons express the receptors of these pruritogens, MRGPRD and MRGPRX1, respectively, and which cutaneous afferents these pruritogens activate in primate. In situ hybridization studies revealed that MRGPRD and MRGPRX1 are co-expressed in a subpopulation of TRPV1+ human DRG neurons. In electrophysiological recordings in nonhuman primates (Macaca nemestrina), subtypes of polymodal C-fiber nociceptors are preferentially activated by ALA and BAM8-22, with significant overlap. When pruritogens ALA, BAM8-22, and histamine, which activate different subclasses of C-fiber afferents, are administered in combination, human volunteers report itch and nociceptive sensations similar to those induced by a single pruritogen. Our results provide evidence for differences in pruriceptive processing between primates and rodents, and do not support the spatial contrast theory of coding of itch and pain.

Spatial transcriptomics reveals unique molecular fingerprints of human nociceptors

“…This is consistent with previous studies that have shown species differences in expression of pruritogen receptor genes such as the IL31 receptor (73). It is also consistent with a recent study comparing macaque and human DRG expression of pruritogen receptors MRGRPD and MRGPRX1 that demonstrated co-expression with TRPV1 (80). This contrasts with mouse experiments where Mrgprd is expressed by a subset of neurons that are devoid of Trpv1 (81).…”

Microinjection of pruritogens in NGF-sensitized human skin

“…We detected flare reactions, one of the hallmarks of HIS-induced CMi activation, after injections of BAM8–22 and ET-1 that were only slightly smaller than the HIS-induced flare, whereas β-ALA did not induce such a reaction. This is in good agreement with previous results from our own and other groups that delivered these chemicals via intradermal microinjection 6 , 8 , 45 – 47 , but differs from studies that administered ET-1 superficially by iontophoresis or BAM8–22 focally into the skin using inactivated cowhage spicules 5 , 48 . The lack of a flare response in the latter studies might indicate that CMi activation and flare reaction after injection of ET-1 or BAM8–22 potentially constitute an indirect effect caused by a pruritogen-induced HIS release from skin mast cells as one plausible scenario.…”

“…In addition, if BAM8–22 is injected and thus delivered deeper into the skin, a HIS-dependent flare develops that does not add to the direct BAM8–22-dependent itch. In agreement with this notion, we could not detect additive effects on itch when we co-injected supra-threshold amounts of BAM8–22 and HIS 8 . Collectively our study substantiates that BAM8–22, β-ALA and ET-1 induce itch in humans via HIS-independent (BAM8–22, β-ALA) or only partially HIS-independent (ET-1) mechanisms.…”

“…In humans and pigs, both of these fiber types are sensitized by rhNGF injection 54 , 55 . We could recently show in monkey that polymodal C-fibers are the class of afferents primarily activated by the MRGPRX1 agonist BAM8–22 8 . Therefore, Aδ-fibers might underlie sensitization of cowhage-induced itch, but it remains unclear whether dermal Aδ-fibers in humans do also express MRGPRX1 receptors as shown for human dental pulp nociceptors 56 .…”

“…These neurons also express transduction proteins normally linked to painful stimulation, e.g. the transient receptor potential cation channel subfamily V member 1 (TRPV1) 8 , 9 . In contrast to intradermal microinjection of the TRPV1 agonist capsaicin, which causes pain, focal capsaicin administration induces itch of similar intensity as histamine 10 or BAM8–22 5 .…”