Neonatal Injury Modulates Incisional Pain Sensitivity in Adulthood: An Animal Study

Kumi Soma, Suzuro Hitomi, Yoshinori Hayashi, Chihiro Soma, Jo Otsuji, Ikuko Shibuta, Akihiko Furukawa, Kentaro Urata, Ryoko Kurisu, Mamiko Yonemoto, Yasushi Hojo, Tetsuo Shirakawa, Koichi Iwata, Masamichi Shinoda

Research output: Contribution to journalArticlepeer-review


Neonatal pain experiences including traumatic injury influence negatively on development of nociceptive circuits, resulting in persistent pain hypersensitivity in adults. However, the detailed mechanism is not yet well understood. In the present study, to clarify the pathogenesis of orofacial pain hypersensitivity associated with neonatal injury, the involvement of the voltage-gated sodium channel (Nav) 1.8 and the C–C chemokine ligand 2 (CCL2)/C–C chemokine receptor 2 (CCR2) signaling in the trigeminal ganglion (TG) in facial skin incisional pain hypersensitivity was examined in 190 neonatal facial-injured and sham male rats. The whisker pad skin was incised on postnatal day 4 and week 7 (Incision–Incision group). Compared to the group without neonatal incision (Sham–Incision group), mechanical hypersensitivity in the whisker pad skin was enhanced in Incision-Incision group. The number of Nav1.8-immunoreactive TG neurons and the amount of CCL2 expressed in the macrophages and satellite glial cells in the TG were increased on day 14 after re-incision in the Incision–Incision group, compared with Sham-Incision group. Blockages of Nav1.8 in the incised region and CCR2 in the TG suppressed the enhancement of mechanical hypersensitivity in the Incision–Incision group. Administration of CCL2 into the TG enhanced mechanical hypersensitivity in the Sham-Sham, Incision-Sham and Sham–Incision group. Our results suggest that neonatal facial injury accelerates the TG neuronal hyperexcitability following orofacial skin injury in adult in association with Nav1.8 overexpression via CCL2 signaling, resulting in the enhancement of orofacial incisional pain hypersensitivity in the adulthood.

Original languageEnglish
Pages (from-to)60-72
Number of pages13
Publication statusPublished - 21 May 2023


  • CCL2
  • Na1.8
  • neonatal injury
  • orofacial pain
  • trigeminal ganglion


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