Substance P plays critical roles in itch and neurogenic inflammation. This neuropeptide has been thought to mediate its actions via the NK1 receptor. Unexpectedly, we have found that substance P is a potent agonist of human MrgX2 and mouse MrgA1, homologous members of the Mrgpr family of receptors that been linked strongly to itch and nociception. SP-evoked scratching is reduced to baseline in Mrg knockout mice. We hypothesize that human MrgprX2 and mouse MrgprA1 play critical roles in SP-induced itch. Evaluating this hypothesis has the potential to be transformative by providing new insights into understanding the basic mechanisms of itch while identifying therapeutic targets leading to new medications for those who suffer from itch.

Public Health Relevance

Substance P is a peptide associated with itch and inflammation. We have identified a new way by which this peptide works. These findings have the potential to lead to new drugs to treat itch and inflammation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AR067399-01
Application #
8809168
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Tseng, Hung H
Project Start
2015-02-01
Project End
2017-01-31
Budget Start
2015-02-01
Budget End
2016-01-31
Support Year
1
Fiscal Year
2015
Total Cost
$223,500
Indirect Cost
$91,500
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
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Azimi, Ehsan; Lerner, Ethan A (2017) Implications of MRGPRX2 in human and experimental cardiometabolic diseases. Nat Rev Cardiol 14:124
Azimi, Ehsan; Reddy, Vemuri B; Pereira, Paula Juliana Seadi et al. (2017) Substance P activates Mas-related G protein-coupled receptors to induce itch. J Allergy Clin Immunol 140:447-453.e3
Pereira, Paula J S; Lerner, Ethan A (2017) Gate Control Theory Springs a Leak. Neuron 93:723-724
Reddy, Vemuri B; Azimi, Ehsan; Chu, Lei et al. (2017) Mas-Related G-Protein Coupled Receptors and Cowhage-Induced Itch. J Invest Dermatol :
Haddadi, Nazgol-Sadat; Foroutan, Arash; Ostadhadi, Sattar et al. (2017) Peripheral NMDA Receptor/NO System Blockage Inhibits Itch Responses Induced by Chloroquine in Mice. Acta Derm Venereol 97:571-577
Azimi, Ehsan; Reddy, Vemuri B; Lerner, Ethan A (2017) Brief communication: MRGPRX2, atopic dermatitis and red man syndrome. Itch (Phila) 2:
Reddy, Vemuri B; Graham, Thomas A; Azimi, Ehsan et al. (2017) A single amino acid in MRGPRX2 necessary for binding and activation by pruritogens. J Allergy Clin Immunol 140:1726-1728
Azimi, Ehsan; Reddy, Vemuri B; Shade, Kai-Ting C et al. (2016) Dual action of neurokinin-1 antagonists on Mas-related GPCRs. JCI Insight 1:e89362
Ostadhadi, Sattar; Azimi, Ehsan; Lerner, Ethan A et al. (2016) Are itch and scratching the nausea and vomiting of skin? Exp Dermatol 25:340-3

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