Estrogens influence female itch sensitivity via the spinal gastrin-releasing peptide receptor neurons

Keiko Takanami, Daisuke Uta, Ken Ichi Matsuda, Mitsuhiro Kawata, Earl Carstens, Tatsuya Sakamoto, Hirotaka Sakamoto

Research output: Contribution to journalArticlepeer-review

14 Citations (Scopus)


There are sex differences in somatosensory sensitivity. Circulating estrogens appear to have a pronociceptive effect that explains why females are reported to be more sensitive to pain than males. Although itch symptoms develop during pregnancy in many women, the underlying mechanism of female-specific pruritus is unknown. Here, we demonstrate that estradiol, but not progesterone, enhances histamine-evoked scratching behavior indicative of itch in female rats. Estradiol increased the expression of the spinal itch mediator, gastrinreleasing peptide (GRP), and increased the histamine-evoked activity of itch-processing neurons that express the GRP receptor (GRPR) in the spinal dorsal horn. The enhancement of itch behavior by estradiol was suppressed by intrathecal administration of a GRPR blocker. In vivo electrophysiological analysis showed that estradiol increased the histamine-evoked firing frequency and prolonged the response of spinal GRP-sensitive neurons in female rats. On the other hand, estradiol did not affect the threshold of noxious thermal pain and decreased touch sensitivity, indicating that estradiol separately affects itch, pain, and touch modalities. Thus, estrogens selectively enhance histamine-evoked itch in females via the spinal GRP/GRPR system. This may explain why itch sensation varies with estrogen levels and provides a basis for treating itch in females by targeting GRPR.

Original languageEnglish
Article numbere2103536118
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number31
Publication statusPublished - Aug 3 2021


  • Estrogens
  • Gastrin-releasing peptide receptor
  • Histamine
  • Itch
  • Spinal cord

ASJC Scopus subject areas

  • General


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