Optogenetic activation of brainstem serotonergic neurons induces persistent pain sensitization

Mol Pain. 2014 Nov 19:10:70. doi: 10.1186/1744-8069-10-70.


Background: The rostral ventromedial medulla (RVM) is a key brainstem structure that conveys powerful descending influence of the central pain-modulating system on spinal pain transmission and processing. Serotonergic (5-HT) neurons are a major component in the heterogeneous populations of RVM neurons and in the descending pathways from RVM. However, the descending influence of RVM 5-HT neurons on pain behaviors remains unclear.

Results: In this study using optogenetic stimulation in tryptophan hydroxylase 2 (TPH2)- Channelrhodopsin 2 (ChR2) transgenic mice, we determined the behavioral effects of selective activation of RVM 5-HT neurons on mechanical and thermal pain behaviors in vivo. We found that ChR2-EYFP-positive neurons strongly co-localized with TPH2-positive (5-HT) neurons in RVM. Optogenetic stimulation significantly increased c-fos expression in 5-HT cells in the RVM of TPH2-ChR2 mice, but not in wild type mice. Behaviorally, the optogenetic stimulation decreased both mechanical and thermal pain threshold in an intensity-dependent manner, with repeated stimulation producing sensitized pain behavior for up to two weeks.

Conclusions: These results suggest that selective activation of RVM 5-HT neurons exerts a predominant effect of pain facilitation under control conditions.

Publication types

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

MeSH terms

  • Analysis of Variance
  • Animals
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism
  • Channelrhodopsins
  • Female
  • Hyperalgesia / pathology*
  • Luminescent Proteins / genetics
  • Luminescent Proteins / metabolism
  • Male
  • Medulla Oblongata / pathology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Optogenetics*
  • Pain Threshold / physiology
  • Serotonergic Neurons / metabolism*
  • Tryptophan Hydroxylase / genetics
  • Tryptophan Hydroxylase / metabolism*


  • Bacterial Proteins
  • Channelrhodopsins
  • Luminescent Proteins
  • yellow fluorescent protein, Bacteria
  • Tph2 protein, mouse
  • Tryptophan Hydroxylase