Increased neuronal expression of neurokinin-1 receptor and stimulus-evoked internalization of the receptor in the rostral ventromedial medulla of the rat after peripheral inflammatory injury

J Comp Neurol. 2014 Sep 1;522(13):3037-51. doi: 10.1002/cne.23564.


This study examined possible mechanisms by which Substance P (Sub P) assumes a pronociceptive role in the rostral ventromedial medulla (RVM) under conditions of peripheral inflammatory injury, in this case produced by intraplantar (ipl) injection of complete Freund's adjuvant (CFA). In saline- and CFA-treated rats, neurokinin-1 receptor (NK1R) immunoreactivity was localized to neurons in the RVM. Four days after ipl injection of CFA, the number of NK1R-immunoreactive neurons in the RVM was increased by 30%, and there was a concomitant increase in NK1R-immunoreactive processes in CFA-treated rats. Although NK1R immunoreactivity was increased, tachykinin-1 receptor (Tacr1) mRNA was not increased in the RVM of CFA-treated rats. To assess changes in Sub P release, the number of RVM neurons that exhibited NK1R internalization was examined in saline- and CFA-treated rats following noxious heat stimulation of the hind paws. Only CFA-treated rats that experienced noxious heat stimulation exhibited a significant increase in the number of neurons showing NK1R internalization. These data suggest that tonic Sub P release is not increased as a simple consequence of peripheral inflammation, but that phasic or evoked release of Sub P in the RVM is increased in response to noxious peripheral stimulation in a persistent inflammatory state. These data support the proposal that an upregulation of the NK1R in the RVM, as well as enhanced release of Sub P following noxious stimulation, underlie the pronociceptive role of Sub P under conditions of persistent inflammatory injury.

Keywords: Substance P; Tacr1; complete Freund's adjuvant; hyperalgesia; nociception.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Analysis of Variance
  • Animals
  • Disease Models, Animal
  • Freund's Adjuvant / toxicity
  • Glial Fibrillary Acidic Protein / metabolism
  • Hyperalgesia / pathology
  • Inflammation / etiology*
  • Inflammation / pathology*
  • Male
  • Medulla Oblongata / metabolism*
  • Medulla Oblongata / pathology
  • Neurons / metabolism
  • Peripheral Nerve Injuries / chemically induced
  • Peripheral Nerve Injuries / complications*
  • Phosphopyruvate Hydratase / metabolism
  • Protein Transport / physiology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Neurokinin-1 / genetics
  • Receptors, Neurokinin-1 / metabolism*
  • Substance P / metabolism


  • Glial Fibrillary Acidic Protein
  • Receptors, Neurokinin-1
  • Substance P
  • Freund's Adjuvant
  • Phosphopyruvate Hydratase