Trpv1Reporter Mice Reveal Highly Restricted Brain Distribution and Functional Expression in Arteriolar Smooth Muscle Cells

Abstract

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 central nervous system (CNS) is debated. As previous evidence is based largely 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 largely 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.

Homeoprotein Phox2b commands a somatic-to-visceral switch in cranial sensory pathways

“…The substantial overlap of transcriptional code among sensory neurons suggests that many are related in development and evolution and represent variations on a generic sensory neuronal type. Pan-sensory effector genes such as the noxious stimulus receptors TrpV1 (35) or Nav1.8 (36) also point to the existence of a generic sensory phenotype and might lie downstream of the shared transcription factors.…”

N-Arachidonoyl Dopamine Modulates Acute Systemic Inflammation via Nonhematopoietic TRPV1

“…TRPV1 is highly expressed in the peripheral nervous system, specifically in a subset of small-diameter primary sensory neurons in trigeminal nerve and dorsal root ganglia that detect noxious stimuli and in the inferior (nodose) ganglion of the vagus nerve (9)(10)(11)(12)(13). The peripheral terminals of TRPV1-expressing nociceptors innervate most organs and tissues.…”

“…TRPV1 is also expressed in the CNS, including the spinal cord, striatum, hippocampus, cerebellum, and amygdala (19)(20)(21)(22)(23). Finally, TRPV1 is found in nonneuronal cells, including leukocytes, smooth muscle cells, and endothelial cells (11,17,(24)(25)(26)(27). In this regard, TRPV1 activation has been reported to regulate the activation and proinflammatory properties of CD4 + T cells (28) NADA and TRPV1 have overlapping distributions, because NADA has been detected in the striatum, cerebellum, hippocampus, thalamus, brainstem, and dorsal root ganglia (7,19,20,23,29).…”

The Expression Pattern of TRPV1 in Brain

“…Because of the therapeutic potential of TRPV1 pharmacology as pain killers, the expression pattern of TRPV1 should be determined more precisely to minimize possible side effects of such therapies on brain. Cavanaugh et al (2011) examined TRPV1 expression using a new genetic tool: a TRPV1 reporter mouse in which two reporter genes, nuclear LacZ and the placental alkaline phosphatase (PLAP), were inserted after an IRES sequence (site for internal entrance of ribosomes). This system allows the expression of separate genes under the control of the same regulatory elements.…”