1. Noritaka Imamachi^a,¹,
2. Goon Ho Park^b,
3. Hyosang Lee^c,
4. David J. Anderson^c,
5. Melvin I. Simon^c,²,
6. Allan I. Basbaum^aand
7. Sang-Kyou Han^b,³

+ Author Affiliations

1. 
   
   ^aDepartment of Anatomy, University of California, San Francisco, CA 94143;
2. 
   
   ^bDepartment of Pharmacology, University of California at San Diego, La Jolla, CA 92093; and
3. 
   
   ^cDivision of Biology, California Institute of Technology, Pasadena, CA 91125

1. Contributed by Melvin I. Simon, May 20, 2009 (received for review May 4, 2009)

Abstract

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.

This paper is in honor of Manfred Zimmermann’s 70th birthday.

Abstract

Histamine is known to excite a subset of C-fibers and cause itch sensation. Despite its well-defined excitatory action on sensory neurons, intracellular signaling mechanisms are not understood. Previously, we demonstrated that bradykinin excited sensory neurons by activating TRPV1 via the phospholipase A₂ (PLA₂) and lipoxygenase (LO) pathway. We, thus, hypothesized that histamine excited sensory neurons via the PLA₂/LO/TRPV1 pathway. Application of histamine elicited a rapid increase in intracellular Ca²⁺ ([Ca²⁺]_i) that desensitized slowly in cultured dorsal root ganglion neurons. Histamine-induced [Ca²⁺]_i was dependent on extracellular Ca²⁺ and inhibited by capsazepine and by SC0030, competitive antagonists of TRPV1. Quinacrine and nordihydroguaiaretic acid, a PLA₂ and an LO inhibitor, respectively, blocked the histamine-induced Ca²⁺influx in sensory neurons, while indomethacin (a cyclooxygenase inhibitor) did not. We thus conclude that histamine activates TRPV1 after stimulating the PLA₂/LO pathway, leading to the excitation of sensory neurons. These results further provide an idea for potential use of TRPV1 antagonists as anti-itch drugs.

Nat Commun. 2012 Mar 20;3:746. doi: 10.1038/ncomms1749.

Güler AD, Rainwater A, Parker JG, Jones GL, Argilli E, Arenkiel BR, Ehlers MD, Bonci A, Zweifel LS, Palmiter RD.

Source

Howard Hughes Medical Institute and Department of Biochemistry, University of Washington, 1959 NE Pacific Street, Box 357370, Seattle, Washington 98195, USA.

Abstract

The ability to control the electrical activity of a neuronal subtype is a valuable tool in deciphering the role of discreet cell populations in complex neural circuits. Recent techniques that allow remote control of neurons are either labor intensive and invasive or indirectly coupled to neural electrical potential with low temporal resolution. Here we show the rapid, reversible and direct activation of genetically identified neuronal subpopulations by generating two inducible transgenic mouse models. Confined expression of the capsaicin receptor, TRPV1, allows cell-specific activation after peripheral or oral delivery of ligand in freely moving mice. Capsaicin-induced activation of dopaminergic or serotonergic neurons reversibly alters both physiological and behavioural responses within minutes, and lasts ~10 min. These models showcase a robust and remotely controllable genetic tool that modulates a distinct cell population without the need for invasive and labour-intensive approaches.

Science. 2011 Sep 9;333(6048):1462-6.

Emery EC, Young GT, Berrocoso EM, Chen L, McNaughton PA.

Source

Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, UK.

Abstract

The rate of action potential firing in nociceptors is a major determinant of the intensity of pain. Possible modulators of action potential firing include the HCN ion channels, which generate an inward current, I(h), after hyperpolarization of the membrane. We found that genetic deletion of HCN2removed the cyclic adenosine monophosphate (cAMP)-sensitive component of I(h) and abolished action potential firing caused by an elevation of cAMP in nociceptors. Mice in which HCN2 was specifically deleted in nociceptors expressing Na(V)1.8 had normal pain thresholds, but inflammation did not cause hyperalgesia to heat stimuli. After a nerve lesion, these mice showed no neuropathic pain in response to thermal or mechanical stimuli. Neuropathic pain is therefore initiated by HCN2-driven action potential firing in Na(V)1.8-expressing nociceptors.

PMID:

 21903816

[PubMed – indexed for MEDLINE]