Kappa Opioid Receptor Distribution and Function in Primary Afferents

Lindsey M. Snyder, Michael C. Chiang, Emanuel Loeza-Alcocer, Yu Omori, Junichi Hachisuka, Tayler D. Sheahan, Jenna R. Gale, Peter C. Adelman, Elizabeth I. Sypek, Stephanie A. Fulton, Robert L. Friedman, Margaret C. Wright, Melissa Giraldo Duque, Yeon Sun Lee, Zeyu Hu, Huizhen Huang, Xiaoyun Cai, Kimberly A. Meerschaert, Vidhya Nagarajan, Toshiro HiraiGregory Scherrer, Daniel H. Kaplan, Frank Porreca, Brian M. Davis, Michael S. Gold, H. Richard Koerber, Sarah E. Ross

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

Primary afferents are known to be inhibited by kappa opioid receptor (KOR) signaling. However, the specific types of somatosensory neurons that express KOR remain unclear. Here, using a newly developed KOR-cre knockin allele, viral tracing, single-cell RT-PCR, and ex vivo recordings, we show that KOR is expressed in several populations of primary afferents: a subset of peptidergic sensory neurons, as well as low-threshold mechanoreceptors that form lanceolate or circumferential endings around hair follicles. We find that KOR acts centrally to inhibit excitatory neurotransmission from KOR-cre afferents in laminae I and III, and this effect is likely due to KOR-mediated inhibition of Ca2+ influx, which we observed in sensory neurons from both mouse and human. In the periphery, KOR signaling inhibits neurogenic inflammation and nociceptor sensitization by inflammatory mediators. Finally, peripherally restricted KOR agonists selectively reduce pain and itch behaviors, as well as mechanical hypersensitivity associated with a surgical incision. These experiments provide a rationale for the use of peripherally restricted KOR agonists for therapeutic treatment. Snyder et al. identify primary afferents that express the kappa opioid receptor in mouse and human and show that kappa opioid receptor signaling inhibits these cells in physiological and behavioral experiments.

Original languageEnglish (US)
Pages (from-to)1274-1288.e6
JournalNeuron
Volume99
Issue number6
DOIs
StatePublished - Sep 19 2018

Keywords

  • DRG
  • Oprk1
  • dorsal root ganglia
  • dynorphin
  • human
  • itch
  • mouse
  • nalfurafine
  • pain
  • primary afferents

ASJC Scopus subject areas

  • Neuroscience(all)

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    Snyder, L. M., Chiang, M. C., Loeza-Alcocer, E., Omori, Y., Hachisuka, J., Sheahan, T. D., Gale, J. R., Adelman, P. C., Sypek, E. I., Fulton, S. A., Friedman, R. L., Wright, M. C., Duque, M. G., Lee, Y. S., Hu, Z., Huang, H., Cai, X., Meerschaert, K. A., Nagarajan, V., ... Ross, S. E. (2018). Kappa Opioid Receptor Distribution and Function in Primary Afferents. Neuron, 99(6), 1274-1288.e6. https://doi.org/10.1016/j.neuron.2018.08.044