The Itch-Producing Agents Histamine and Cowhage Activate Separate Populations of Primate Spinothalamic Tract Neurons

Abstract

Itch is an everyday sensation, but when associated with disease or infection it can be chronic and debilitating. Several forms of itch can be blocked using antihistamines, but others cannot and these constitute an important clinical problem. Little information is available on the mechanisms underlying itch that is produced by nonhistaminergic mechanisms. We examined the responses of spinothalamic tract neurons to histaminergic and, for the first time, nonhistaminergic forms of itch stimuli. Fifty-seven primate spinothalamic tract (STT) neurons were identified using antidromic activation techniques and examined for their responses to histamine and cowhage, the nonhistaminergic itch-producing spicules covering the pod of the legume Mucuna pruriens. Each examined neuron had a receptive field on the hairy skin of the hindlimb and responded to noxious mechanical stimulation. STT neurons were tested with both pruritogens applied in a random order and we found 12 that responded to histamine and seven to cowhage. Each pruritogen-responsive STT neuron was activated by the chemical algogen capsaicin and two-thirds responded to noxious heat stimuli, demonstrating that these neurons convey chemical, thermal, and mechanical nociceptive information as well. Histamine or cowhage responsive STT neurons were found in both the marginal zone and the deep dorsal horn and were classified as high threshold and wide dynamic range. Unexpectedly, histamine and cowhage never activated the same cell. Our results demonstrate that the spinothalamic tract contains mutually exclusive populations of neurons responsive to histamine or the nonhistaminergic itch-producing agent cowhage.

Cowhage-Evoked Itch Is Mediated by a Novel Cysteine Protease: A Ligand of Protease-Activated Receptors

“…Shelley and Arthur (1955) suggested that the active component, although not isolated, was a protease, which they named mucunain. Cowhage has been used recently to investigate sensory modalities and distinguish between histamine and nonhistamine pathways in humans and monkeys (Johanek et al, 2005(Johanek et al, , 2007Davidson et al, 2007).…”

“…These observations suggest that the mediator of itch from this plant could identify a nonhistamine pathway of pruritus. Cowhage activates subpopulations of nociceptive neurons in cat and monkey (Tuckett and Wei, 1987;Johanek et al, 2005;Davidson et al, 2007). Despite early evidence that cowhage itch might be mediated by a protease called mucunain , neither the active component has been isolated nor has its signaling pathway been established.…”

Le prurit : des avancées physiopathologiques considérables

“…De même, des preuves claires attestent de l'existence d'une voie indépendante de l'histamine, dépendante de l'activation périphérique de PAR-2, et située dans le tractus spinothalamique [23]. Les deux sous-ensembles sont mutuellement exclusifs [10].…”

TRP Channels and Pruritus

“…It is therefore suggested that spinal projection neurons may receive innervation from both itch sensitive and nociceptive primary fibers [13] which supports the selectivity over the specificity hypothesis regarding the relation of itch and pain transmitting pathways. However, in spite of the overlap with the pain sensitive pathways, distinct, non-overlapping populations of spinothalamic tract neurons, transmitting histaminergic and non-histaminergic (cowhage evoked) itch sensations, were described [27]. Indeed, the two sensations can be selectively inhibited, even if they are transmitted by the same spinothalamic tract neurons; it was demonstrated that only the histamine (but not capsaicin) evoked activity of the same spinal projecting neurons can be inhibited by eliciting scratching within the respective cutaneous receptive field [28].…”

“…Among them, PAR2, expressed by sensory neurons, is considered as a key molecule in itch sensation [66][67][68]. In experimental models, by using cowhage spicules (which contain the protease mucunain) to activate PAR2, a histamine-independent parallel itch pathway was identified and found to significantly contribute to chronic itch sensation [10,27,44,69,70]. Interestingly, the activation of PAR2 by kallikrein (a tryptic enzyme) related proteases was also shown in epidermal keratinocytes [71] which further argue for the impact of the pathway in pruriceptive itch.…”