Scientific Understanding of Consciousness
Science 24 May 2013: Vol. 340 no. 6135 pp. 968-971
The Cells and Circuitry for Itch Responses in Mice
Santosh K. Mishra, Mark A. Hoon
Molecular Genetics Unit, Laboratory of Sensory Biology, National Institute of Dental and Craniofacial Research (NIDCR), NIH, Building 49, Room 1A16, 49 Convent Drive, Bethesda, MD 20892, USA.
Itch is triggered by somatosensory neurons expressing the ion channel TRPV1 (transient receptor potential cation channel subfamily V member 1), but the mechanisms underlying this nociceptive response remain poorly understood. Here, we show that the neuropeptide natriuretic polypeptide b (Nppb) is expressed in a subset of TRPV1 neurons and found that Nppb−/− mice selectively lose almost all behavioral responses to itch-inducing agents. Nppb triggered potent scratching when injected intrathecally in wild-type and Nppb−/− mice, showing that this neuropeptide evokes itch when released from somatosensory neurons. Itch responses were blocked by toxin-mediated ablation of Nppb-receptor–expressing cells, but a second neuropeptide, gastrin-releasing peptide, still induced strong responses in the toxin-treated animals. Thus, our results define the primary pruriceptive neurons, characterize Nppb as an itch-selective neuropeptide, and reveal the next two stages of this dedicated neuronal pathway.
We generated Nppb−/− animals and showed that these mutants displayed no detectable expression of Nppb. The mice were healthy, had normal numbers of nociceptive, touch, and proprioceptive neurons, and the distribution and number of dorsal horn interneurons was unaffected by gene disruption. Nppb−/− mice retained normal responses to thermal, nociceptive, touch, and proprioceptive stimulation when tested with standard assays. We performed intradermal injections and recorded numbers of scratching bouts for substances that directly activate pruriceptors and with compound 48/80 that causes itch via an indirect route. All of these agents reliably triggered multiple bouts of scratching in control animals, but Nppb−/− mice were almost completely insensitive to the full range of pruritic substances tested.
Our results molecularly characterize the first three stations of an itch response pathway in mice, demonstrate that Nppb marks the primary sensory neurons, and show that this peptide is both necessary and sufficient for transmission of peripheral signals that induce stereotypic itch responses. Unlike previously characterized receptors and signaling molecules that affect the detection of particular itch-inducing agents, Nppb is necessary for responses to a wide range of pruritogens (compounds classed as inducing histamine- and nonhistamine-related itch). Our data also refine the role GRP and GRP-receptor cells play in the itch-response pathway by placing them at later stages than had been hypothesized previously. Many questions about itch remain unanswered, including its close relationship to sensing pain and its slow kinetics and long duration, as well as reports from human and nonhuman primate studies that different central pathways mediate histamine and nonhistamine itch. Because Nppb is critically required for pruriception in mice, future studies involving ablation and/or activation of the Nppb-expressing somatosensory neurons together with circuit tracing may reveal whether these cells directly trigger a spinal scratch reflex, are selective detectors for the sensation of itch, or are in fact more broadly tuned nociceptors. Such experiments will help reveal the central mechanism (or mechanisms) for itch, explain the interactions between pruriception and other somatosensory signals, and ultimately provide a powerful stimulus for the rational design of novel therapies to alleviate chronic itch.
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