Systems analyses of RNA-Seq transcriptomic responses in dorsal horn during carrageenan-induced inflammation

Authors

• MR Sapio
• SC Goswami
• JR Gross
• GL Gonnella
• JM Keller
• HD Kominsky
• AJ Mannes
• MJ Iadarola

Abstract

Persistent pain states are known to engage new gene expression programs in nociceptive circuits in the dorsal horn. Up-regulation of genes coding for the endogenous opioid peptides was demonstrated in the late 1980’s and various techniques have been used to expand the repertoire of nociception-regulated genes. Recently, a new method based on next generation DNA sequencing, called RNA-Seq, has been developed for measuring gene expression. RNA-Seq provides accurate quantitation and comprehensive assessment of transcript levels of all genes expressed in a cell or tissue. We used RNA-Seq to analyze gene expression in the dorsal horn of the spinal cord 2 and 48 hours after experimental peripheral inflammation. Elevated expression of multiple transcription factors occurred at 2hrs with return to control levels by 48 hrs, these included known transcription factors c-Fos and JunB, and 3 paralogs of NGFI-B (nuclear receptor family). Several neuropeptide transcripts displayed long-term increases including prodynorphin, proenkephalin and protachykinin, as expected. A total of fifty-five genes exhibited 1.5-fold increases or higher; lowering the threshold to 1.25-fold garnered another ~150 significantly elevated transcripts. Many of the most highly expressed and highly differential genes are immune-like and are part of the microglial complement system. This induction occurs in the absence of other inflammation markers, and is long-lived. We conclude that neuronal activity is accompanied by complement-dependent synaptic rearrangement by microglia. The data demonstrate that a cadre of state-dependent drivers and downstream effector molecules are induced to control nociceptive primary and secondary sensitization processes that occur in persistent pain states.

Scientific Focus Area: Neuroscience

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