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The Journal of Neuroscience, February 28, 2007, 27(9):2331-2337; doi:10.1523/JNEUROSCI.4643-06.2007

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Cellular/Molecular
TRPV1 Mediates Histamine-Induced Itching via the Activation of Phospholipase A₂ and 12-Lipoxygenase

Won-Sik Shim, Min-Ho Tak, Mi-Hyun Lee, Minjung Kim, Minkyung Kim, Jae-Yeon Koo, Chang-Hun Lee, Misook Kim, and Uhtaek Oh

Sensory Research Center, College of Pharmacy, Seoul National University, Seoul 151-742, Korea

Correspondence should be addressed to Uhtaek Oh, Kwanak, Shinlim 9-Dong, Seoul 151-742, Korea. Email: utoh{at}plaza.snu.ac.kr

Histamine provokes itching and is a major skin disease complaint. Histamine is known to excite a subset of sensory neurons, predominantly C-fibers. Although histamine is pruritogenic, its signaling pathways that excite sensory neurons have not been identified. Because the metabolic products of lipoxygenases (LOs) activate transient receptor potential vanilloid receptor-1 (TRPV1) in sensory neurons, we hypothesized that histamine excites sensory neurons by activating TRPV1 via phospholipase A₂ (PLA₂) and LO stimulation. In cultured sensory neurons, histamine evoked inward currents that were reduced by capsazepine, a TRPV1 blocker. Moreover, histamine provoked inward currents when histamine receptor subtype 1 (H1R) and TRPV1 were expressed heterologously, but not when H1R or TRPV1 was expressed alone. In addition, histamine caused Ca²⁺ influxes in sensory neurons in wild-type mice but not in TRPV1^–/– mice. Furthermore, histamine caused a 2.5-fold increase in the production of 12-hydroxyeicosatetraenoic acid, a metabolite of LO, in cultured sensory neurons. When injected subcutaneously into the necks of mice, histamine caused bouts of scratching, which were greatly reduced by pretreatment with capsazepine, a TRPV1 blocker, and by inhibitors of PLA₂, LO, and H1R. Furthermore, mice lacking TRPV1 markedly reduced histamine-induced scratching compared with wild type. Together, these results indicate that TRPV1 plays a key role in mediating the pruritogenic action of histamine via the PLA₂/LO pathway.

Key words: histamine; TRPV1; phospholipase A₂; 12-lipoxygenase; itch; pruritus

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Received Oct. 26, 2006; revised Jan. 5, 2007; accepted Jan. 5, 2007.

Correspondence should be addressed to Uhtaek Oh, Kwanak, Shinlim 9-Dong, Seoul 151-742, Korea. Email: utoh{at}plaza.snu.ac.kr

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				B. F. Bessac and S.-E. Jordt Breathtaking TRP Channels: TRPA1 and TRPV1 in Airway Chemosensation and Reflex Control Physiology, December 1, 2008; 23(6): 360 - 370. [Abstract] [Full Text] [PDF]

				S. Davidson, X. Zhang, C. H. Yoon, S. G. Khasabov, D. A. Simone, and G. J. Giesler Jr The Itch-Producing Agents Histamine and Cowhage Activate Separate Populations of Primate Spinothalamic Tract Neurons J. Neurosci., September 12, 2007; 27(37): 10007 - 10014. [Abstract] [Full Text] [PDF]

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