Chemical Response Pattern of Different Classes of C-Nociceptors to Pruritogens and Algogens

Abstract

Vasoneuroactive substances were applied through intradermal microdialysis membranes and characterized as itch- or pain-inducing in psychophysical experiments. Histamine always provoked itching and rarely pain, capsaicin always pain but never itching. Prostaglandin E(2) (PGE(2)) led preferentially to moderate itching. Serotonin, acetylcholine, and bradykinin induced pain more often than itching. Subsequently the same substances were used in microneurography experiments to characterize the sensitivity profile of human cutaneous C-nociceptors. The responses of 89 mechanoresponsive (CMH, polymodal nociceptors), 52 mechanoinsensitive, histamine-negative (CMi(His-)), and 24 mechanoinsensitive, histamine-positive (CMi(His+)) units were compared. CMi(His+) units were most responsive to histamine and to PGE(2) and less to serotonin, ACh, bradykinin, and capsaicin. CMH units (polymodal nociceptors) and CMi(His-) units showed significantly weaker responses to histamine, PGE(2), and acetylcholine. Capsaicin and bradykinin responses were not significantly different in the two classes of mechano-insensitive units. We conclude that CMi(His+) units are "selective," but not "specific" for pruritogenic substances and that the pruritic potency of a mediator increases with its ability to activate CMi(His+) units but decreases with activation of CMH and CMi(His-) units.

Analysis of cellular and behavioral responses to imiquimod reveals a unique itch pathway in transient receptor potential vanilloid 1 (TRPV1)-expressing neurons

“…In support of this view, several reports have provided evidence for the existence of specific itch neurons at the spinal level to which primary afferents are targeted (5-7). However, histamine-sensitive fibers were found to respond to painful stimuli such as capsaicin or heat (2,8), arguing against the specificity theory. It is possible that some painful stimuli applied to the itch-specific neurons can result in scratching behavior.…”

“…In general, C-fibers have been thought to be involved primarily in nociception. However, as more has been learned about C-fibers, it is increasingly evident that they also appear to mediate itch produced by various types of pruritogens (1)(2)(3)(4). Electrophysiological recording experiments in human skin showed the presence of a small subset of histamine-sensitive fibers among heterogeneous C-fiber nociceptors (1).…”

TRP Channels and Pruritus

“…These unmyelinated, histamine sensitive sensory neurons have large receptive fields and poor discrimination threshold for histamine induced itch. Furthermore, they are characterized by a particularly low conduction velocity and high transcutaneous electrical thresholds [7,[16][17][18][19][20]. These Cfibers are also suggested to be involved in the generation of the axon reflex erythema [17].…”

“…The vasodilative, pro-inflammatory, and pain-inducing mediator, bradykinin also induces itch [20,125,126]. Its mechanism of action involves increased histamine release from mast cells [127], augmentation of histamine evoked responses [128,129] as well as sensitization of sensory afferent fibers and their receptors (e.g.…”

“…The prototypic TRPV1-selective activator capsaicin reportedly activates both histaminereactive and non-reactive mechano-insensitive C-fibers as well as mechano-sensitive ones [20]. With respect to the mechanisms how TRPV1 can contribute to itch sensation, it is noteworthy that histamine was found to be able to activate TRPV1 via the phospholipase A2 (PLA2) -lipoxygenase pathway.…”