Mol Pain. 2012 Sep 27;8:75. doi: 10.1186/1744-8069-8-75.

Prostaglandin metabolite induces inhibition of TRPA1 and channel-dependent nociception.

Source

Neuroscience Graduate Program, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA.

Abstract

Somatosensory neurons detect environmental stimuli, converting external cues into neural activity that is relayed first to second-order neurons in the spinal cord. The detection of cold is proposed to be mediated by the ion channels TRPM8 and TRPA1. However, there is significant debate regarding the role of each channel in cold-evoked pain, complicating their potential as drug targets for conditions such as cold allodynia and hyperalgesia. To address this debate, we generated mice lacking functional copies of both channels and examined behaviors and neural activity in response to painful cold and noxious cooling compounds. Whereas normal mice display a robust preference for warmth over cold, both TRPM8-null (TRPM8(-/-)) and TRPM8/TRPA1 double-knockout mice (DKO) display no preference until temperatures reach the extreme noxious range. Additionally, in contrast to wildtype mice that avoid touching cold surfaces, mice lacking TRPM8 channels display no such avoidance and explore noxious cold surfaces, even at 5 degrees C. Furthermore, nocifensive behaviors to the cold-mimetic icilin are absent in TRPM8(-/-) and DKO mice, but are retained in TRPA1-nulls (TRPA1(-/-)). Finally, neural activity, measured by expression of the immediate-early gene c-fos, evoked by hindpaw stimulation with noxious cold, menthol, or icilin is reduced in TRPM8(-/-) and DKO mice, but not in TRPA1(-/-) animals. Thus our results show that noxious cold signaling is exclusive to TRPM8, mediating neural and behavioral responses to cold and cold-mimetics, and that TRPA1 is not required for acute cold pain in mammals.

Copyright (c) 2010 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Source

Department of Neurobiology, Physiology and Behavior, University of California, Davis, CA 95616, USA.

Abstract

Chronic itch is a symptom of many skin conditions and systemic disease, and it has been hypothesized that the chronic itch may result from sensitization of itch-signaling pathways. We induced experimental chronic dry skin on the rostral back of mice, and observed a significant increase in spontaneous hindlimb scratches directed to the dry skin. Spontaneous scratching was significantly attenuated by a PAR-2 antibody and 5-HT2A receptor antagonist, indicating activation of these receptors by endogenous mediators released under dry skin conditions. We also observed a significant increase in the number of scratch bouts evoked by acute intradermal injections of a protease-activated receptor (PAR)-2 agonist and serotonin (5-HT), but not histamine. We additionally investigated if pruritogen-evoked activity of dorsal root ganglion (DRG) neurons is enhanced in this model. DRG cells from dry skin mice exhibited significantly larger responses to the PAR-2 agonist and 5-HT, but not histamine. Spontaneous scratching may reflect ongoing itch, and enhanced pruritogen-evoked scratching may represent hyperknesis (enhanced itch), both potentially due to sensitization of itch-signaling neurons. The correspondence between enhanced behavioral scratching and DRG cell responses suggest that peripheral pruriceptors that respond to proteases and 5-HT, but not histamine, may be sensitized in dry skin itch.

Copyright © 2010 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

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.

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.

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.