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

Reddy, Vemuri B.; Iuga, Aurel O.; Shimada, Steve G.; LaMotte, Robert H.; Lerner, Ethan A.

doi:10.1523/jneurosci.0716-08.2008

Cited by 219 publications

(212 citation statements)

References 17 publications

Supporting

Mentioning

203

Contrasting

Unclassified

Order By: Relevance

“…The existence of multiple subsets of neurons responding to itch-provoking stimuli is supported by recent reports that histamine-and cowhage-induced itch involve different sensory circuits (26)(27)(28)(29). Histamine-induced calcium responses were observed in 23% of IB ϩ and 7% of the IB4 Ϫ neurons (9).…”

mentioning

confidence: 62%

TRPV1-expressing primary afferents generate behavioral responses to pruritogens via multiple mechanisms

Isowa

Park

Lee

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

391

437

View full text Add to dashboard Cite

The mechanisms that generate itch are poorly understood at both the molecular and cellular levels despite its clinical importance. To explore the peripheral neuronal mechanisms underlying itch, we assessed the behavioral responses (scratching) produced by s.c. injection of various pruritogens in PLC␤3-or TRPV1-deficient mice. We provide evidence that at least 3 different molecular pathways contribute to the transduction of itch responses to different pruritogens: 1) histamine requires the function of both PLC␤3 and the TRPV1 channel; 2) serotonin, or a selective agonist, ␣-methylserotonin (␣-Me-5-HT), requires the presence of PLC␤3 but not TRPV1, and 3) endothelin-1 (ET-1) does not require either PLC␤3 or TRPV1. To determine whether the activity of these molecules is represented in a particular subpopulation of sensory neurons, we examined the behavioral consequences of selectively eliminating 2 nonoverlapping subsets of nociceptors. The genetic ablation of MrgprD ؉ neurons that represent Ϸ90% of cutaneous nonpeptidergic neurons did not affect the scratching responses to a number of pruritogens. In contrast, chemical ablation of the central branch of TRPV1 ؉ nociceptors led to a significant behavioral deficit for pruritogens, including ␣-Me-5-HT and ET-1, that is, the TRPV1-expressing nociceptor was required, whether or not TRPV1 itself was essential. Thus, TRPV1 neurons are equipped with multiple signaling mechanisms that respond to different pruritogens. Some of these require TRPV1 function; others use alternate signal transduction pathways.itch ͉ PLCb3 ͉ scratching

show abstract

mentioning

confidence: 62%

TRPV1-expressing primary afferents generate behavioral responses to pruritogens via multiple mechanisms

Isowa

Park

Lee

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

391

437

View full text Add to dashboard Cite

show abstract

“…59,60) The main pruritogenic component of cowhage is mucunain, which acts on proteinase-activated receptors (PAR) 2 and 4. 61) In humans, cowhage and histamine activate distinctly different C-fibers, 62) and cowhage-induced itching may be signaled by capsaicin-sensitive and histamine-insensitive Cfibers. 63) In the primate dorsal horn, 25% of the spinothalamic tract neurons tested responded to histamine, 15% responded to cowhage, and none responded to both.…”

Section: Pruriceptive Activity Of Primary Sensory Nervesmentioning

confidence: 99%

Methods for Preclinical Assessment of Antipruritic Agents and Itch Mechanisms Independent of Mast-Cell Histamine

Kuraishi

2015

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

Itch is a sensation that provokes a desire to scratch. Mast-cell histamine was thought to be a key itch mediator. However, histamine and mast-cell degranulation were reported not to elicit scratching in animals. It was difficult to investigate the pathophysiology of itching and to evaluate the antipruritic efficacy of chemical agents in the early 1990 s. We showed that hind-paw scratching and biting were elicited by stimulation with pruritogenic agents in mice. Those results demonstrated for the first time that cutaneous itching could be evaluated behaviorally in animals. We established various animal models of pathological itch of the skin (dry skin, mosquito allergy, surfactant-induced pruritus, and herpes zoster) and mucus membranes (pollen allergy). Mast-cell histamine did not play a key role in itching in any animal model examined except for the pollen allergy model. Histamine is not an exclusive itch mediator of mast cells; tryptase and leukotriene B 4 released from mast cells also act as itch mediators. Epidermal keratinocytes release several itch mediators, such as leukotriene B 4 , sphingosylphosphorylcholine, thromboxane A 2 , nociceptin, nitric oxide, and histamine, which may play important roles in pathological itching. Appropriate animal models of pathological itching are needed for pharmacological evaluation of the antipruritic efficacy of chemical agents.

show abstract

“…PARs are implicated in the signaling by other pruritogens. Mucunain, a pruritogenic component from cowhage seedpod, triggers an itch sensation via PAR2 and 4 on sensory neurons [29] . More recently, cathepsin S has been found to induce itch, which is also dependent on PAR2 and 4 [30] .…”

Section: Peripheral Mechanisms Of Itch and Painmentioning

confidence: 99%

Molecular Mechanisms of Itch and Pain: An Overview

Lee

2015

Itch Pain

View full text Add to dashboard Cite

Itch and pain are two distinct sensory modalities elicited by noxious and pruritic stimuli, respectively. The cellular and electrophysiological characteristics of itch and pain are very similar; thus discerning the mechanical difference between these two sensory modalities has long been elusive. Recent advances in this field have revealed various neuronal receptors responsible for itch and pain signal transduction and transmission. These studies have identified a distinct sub-population of sensory neurons responsible for itch signal transduction. In addition, itch and pain information conveyed to the spinal cord are processed and regulated by distinct spinal cord neurons. Although both itch and pain senses are required for our daily lives, chronic and hyper-sensation of itch and pain results in a debilitating disease state. Studies have now begun to elucidate mechanisms for the sensitization of pain and itch and also to unravel counter-regulatory mechanisms between itch and pain at the spinal cord level. Interestingly, toll-like receptors (TLRs), an innate immune receptor, has been implicated in the central sensitization of both pain and itch. In this review, we will briefly provide an overview of the molecular mechanisms of itch and pain. Additionally, we will discuss the recently uncovered role of TLRs in itch and pain sensation.

show abstract

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

Cited by 219 publications

References 17 publications

TRPV1-expressing primary afferents generate behavioral responses to pruritogens via multiple mechanisms

TRPV1-expressing primary afferents generate behavioral responses to pruritogens via multiple mechanisms

Methods for Preclinical Assessment of Antipruritic Agents and Itch Mechanisms Independent of Mast-Cell Histamine

Molecular Mechanisms of Itch and Pain: An Overview

Contact Info

Product

Resources

About