Changes in gene expression and neuronal phenotype in brain stem pain modulatory circuitry after inflammation

Kenji Miki, Q. Q. Zhou, W. Guo, Y. Guan, R. Terayama, R. Dubner, K. Ren

Research output: Contribution to journalArticle

116 Citations (Scopus)

Abstract

Recent studies indicate that descending pain modulatory pathways undergo time-dependent changes in excitability following inflammation involving both facilitation and inhibition. The cellular and molecular mechanisms of these phenomena are unclear. In the present study, we examined N-methyl-D-aspartate (NMDA) receptor gene expression and neuronal activity in the rostral ventromedial medulla (RVM), a pivotal structure in pain modulatory circuitry, after complete Freund's adjuvant (CFA)-induced hindpaw inflammation. The reverse transcription polymerase chain reaction analysis indicated that there was an upregulation of mRNAs encoding NMDA receptor subunits in the RVM after inflammation. The increase in the NR1, NR2A, and NR2B receptor mRNAs started at 5 h, maintained for 1-7 days (P < 0.05-0.001) and returned to the control level at 14 days after inflammation. Western blot analysis indicated that the protein translation products of the NR2A subunit were also increased (P < 0.01). In single-unit extracellular recordings, we correlated RVM neuronal activity with the paw withdrawal response in rats with inflammation. We describe these RVM cells as on-, off-, and neutral-like cells because of their similarity to previous studies in which neuronal responses were correlated with tail-flick nocifensive behavior in the absence of inflammation. In contrast to previous studies in the absence of inflammation, using tail flick as a behavioral correlate, fewer off-like cells in naïve animals exhibited a complete pause before the paw withdrawal to a noxious thermal stimulus. The percentage of cells showing a pause of activity after noxious stimulation was further reduced after inflammation (X2 P < 0.0001 vs. naïve rats). Continuous neuronal recordings (3-6.5 h) revealed a phenotypic switch of RVM neurons during the development of inflammation: 11/15 neutral-like cells initially unresponsive to noxious stimuli exhibited and maintained response profiles characteristic of pain modulatory neurons (became off-like: n = 5; became on-like: n = 6). Neutral-like cells recorded in noninflamed animals did not show response profile changes during continuous recordings (5-5.5 h, n = 7). A population study (n = 165) confirmed an increase in on- and off-like cells and a decrease in neutral-like cells at 24 h after inflammation as compared with naïve rats (P < 0.001), These results suggest that enhanced NMDA receptor activation mediates time-dependent changes in excitability of RVM pain modulatory circuitry. The functional phenotypic switch of RVM neurons provides a novel mechanism underlying activity-dependent plasticity and enhanced net descending inhibition after inflammation.

Original languageEnglish (US)
Pages (from-to)750-760
Number of pages11
JournalJournal of Neurophysiology
Volume87
Issue number2
StatePublished - 2002

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Brain Stem
Inflammation
Phenotype
Gene Expression
Pain
N-Methyl-D-Aspartate Receptors
Neurons
Tail
Messenger RNA
Freund's Adjuvant
Protein Biosynthesis
Reverse Transcription
Up-Regulation
Hot Temperature
Western Blotting
Polymerase Chain Reaction

ASJC Scopus subject areas

  • Physiology
  • Neuroscience(all)

Cite this

Miki, K., Zhou, Q. Q., Guo, W., Guan, Y., Terayama, R., Dubner, R., & Ren, K. (2002). Changes in gene expression and neuronal phenotype in brain stem pain modulatory circuitry after inflammation. Journal of Neurophysiology, 87(2), 750-760.

Changes in gene expression and neuronal phenotype in brain stem pain modulatory circuitry after inflammation. / Miki, Kenji; Zhou, Q. Q.; Guo, W.; Guan, Y.; Terayama, R.; Dubner, R.; Ren, K.

In: Journal of Neurophysiology, Vol. 87, No. 2, 2002, p. 750-760.

Research output: Contribution to journalArticle

Miki, K, Zhou, QQ, Guo, W, Guan, Y, Terayama, R, Dubner, R & Ren, K 2002, 'Changes in gene expression and neuronal phenotype in brain stem pain modulatory circuitry after inflammation', Journal of Neurophysiology, vol. 87, no. 2, pp. 750-760.
Miki, Kenji ; Zhou, Q. Q. ; Guo, W. ; Guan, Y. ; Terayama, R. ; Dubner, R. ; Ren, K. / Changes in gene expression and neuronal phenotype in brain stem pain modulatory circuitry after inflammation. In: Journal of Neurophysiology. 2002 ; Vol. 87, No. 2. pp. 750-760.
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