Trpv1 Reporter Mice Reveal Highly Restricted Brain Distribution and Functional Expression in Arteriolar Smooth Muscle Cells

Department of Anatomy, University of San Francisco, San Francisco, California 94158, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 03/2011; 31(13):5067-77. DOI: 10.1523/JNEUROSCI.6451-10.2011
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The heat and capsaicin receptor, TRPV1, is required for the detection of painful heat by primary afferent pain fibers (nociceptors), but the extent to which functional TRPV1 channels are expressed in the CNS is debated. Because previous evidence is based primarily on indirect physiological responses to capsaicin, here we genetically modified the Trpv1 locus to reveal, with excellent sensitivity and specificity, the distribution of TRPV1 in all neuronal and non-neuronal tissues. In contrast to reports of widespread and robust expression in the CNS, we find that neuronal TRPV1 is primarily restricted to nociceptors in primary sensory ganglia, with minimal expression in a few discrete brain regions, most notably in a contiguous band of cells within and adjacent to the caudal hypothalamus. We confirm hypothalamic expression in the mouse using several complementary approaches, including in situ hybridization, calcium imaging, and electrophysiological recordings. Additional in situ hybridization experiments in rat, monkey, and human brain demonstrate that the restricted expression of TRPV1 in the CNS is conserved across species. Outside of the CNS, we find TRPV1 expression in a subset of arteriolar smooth muscle cells within thermoregulatory tissues. Here, capsaicin increases calcium uptake and induces vasoconstriction, an effect that likely counteracts the vasodilation produced by activation of neuronal TRPV1.

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    • "The role—and indeed the very presence—of TRPV1 in vascular tissue remain highly contentious. While several groups have reported evidence of endothelial TRPV1 expression (Bratz et al. 2008; Fantozzi et al. 2003; Yang et al. 2010), others have failed to reproduce these findings (Cavanaugh et al. 2011; Marrelli et al. 2007). Many studies have relied on mRNA expression alone, and protein quantification has often been conducted in the absence of appropriate controls, or using antibodies that have not been validated in TRPV1 knockout (KO) tissue. "

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    • "Mice with tissue specific deletions of IL-6Rα were created by crossing mice possessing loxP 77 sites flanking exons 4-6 of the interleukin-6 receptor alpha chain (Il6ra) (Jackson Laboratory, 78 Bar Harbor, ME) with mice expressing Cre recombinase from the Nestin promoter (expressed in 79 the central and peripheral nervous system), the endogenous Trpv1 locus (expressed by sensory 80 nerves; Cavanaugh et al., 2011) (both from Jackson), the human tissue plasminogen activator 81 (HtPa) (expressed by neural crest structures; Pietri et al., 2003), or a tamoxifen inducible "
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    • "11 ) . However , pharmacological blockade of TRPV1 causes hypothermia ( Gavva et al . 2007 ) , suggesting a role for TRPV1 in a cross - talk between environmental and body temperature . A capsaicin - insensitive splice variant of TRPV1 is expressed in the neurons of the supraoptic area of hypothalamus ( Sharif Naeini et al . 2006 ) ( however , see Cavanaugh et al . 2011 ) . These neurons exhibit temperature - activated firing and vasopressin release and are tuned to detect minute variations in the normal 37°C body temperature . Both these properties become significantly attenuated upon pharmacological inhibition or genetic ablation of TRPV1 ( Sharif - Naeini et al . 2008 ; Sudbury et al . 2010 ; Sudbur"
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