TRPV1-expressing primary afferents generate behavioral responses to pruritogens via multiple mechanisms
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 PLCβ3- 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 PLCβ3 and the TRPV1 channel; 2) serotonin, or a selective agonist, α-methyl-serotonin (α-Me-5-HT), requires the presence of PLCβ3 but not TRPV1, and 3) endothelin-1 (ET-1) does not require either PLCβ3 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 ≈90% 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 α-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.
Additional Information© 2009 by the National Academy of Sciences. Contributed by Melvin I. Simon, May 20, 2009 (received for review May 4, 2009). Published online before print June 29, 2009, doi: 10.1073/pnas.0905605106 We thank Mark Zylka for invaluable help, Heeju Kim and Valeria Mancino for help with the behavioral assays, and Timothy M. Kim for video analyses. This work was supported by National Institutes of Health Grant PO1-NS048499 (to M.I.S., D.J.A., and A.I.B.). H.S.L. is supported by an award from the Christopher and Dana Reeve Foundation. D.J.A. is an investigator of the Howard Hughes Medical Institute. Author contributions: A.I.B. and S.-K.H. designed research; N.I., G.H.P., H.L., and S.-K.H. performed research; S.-K.H. analyzed data; and D.J.A., M.I.S., A.I.B., and S.-K.H. wrote the paper. The authors declare no conflict of interest. This article contains supporting information online at www.pnas.org/cgi/content/full/0905605106/DCSupplemental.
Published - Imamachi2009p5070P_Natl_Acad_Sci_Usa.pdf
Supplemental Material - 0905605106SI.pdf