Abstract
To examine the role of small RNAs in peripheral pain pathways, we deleted the enzyme Dicer in mouse postmitotic damage-sensing neurons. We used a Nav1.8-Cre mouse to target those nociceptors important for inflammatory pain. The conditional null mice were healthy with a normal number of sensory neurons and normal acute pain thresholds. Behavioral studies showed that inflammatory pain was attenuated or abolished. Inflammatory mediators failed to enhance excitability of Nav1.8+ sensory neurons from null mutant mice. Acute noxious input into the dorsal horn of the spinal cord was apparently normal, but the increased input associated with inflammatory pain measured using c-Fos staining was diminished. Microarray and quantitative real-time reverse-transcription PCR (qRT-PCR) analysis showed that Dicer deletion lead to the upregulation of many broadly expressed mRNA transcripts in dorsal root ganglia. By contrast, nociceptor-associated mRNA transcripts (e.g., Nav1.8, P2xr3, and Runx-1) were downregulated, resulting in lower levels of protein and functional expression. qRT-PCR analysis also showed lowered levels of expression of nociceptor-specific pre-mRNA transcripts. MicroRNA microarray and deep sequencing identified known and novel nociceptor microRNAs in mouse Nav1.8+ sensory neurons that may regulate nociceptor gene expression.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Analysis of Variance
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Animals
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Cerebellum / cytology
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Core Binding Factor Alpha 2 Subunit / genetics
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Core Binding Factor Alpha 2 Subunit / metabolism
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DEAD-box RNA Helicases / deficiency
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Disease Models, Animal
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Endoribonucleases / deficiency
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Female
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Freund's Adjuvant / adverse effects
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Ganglia, Spinal / metabolism
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Gene Expression Profiling / methods
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Gene Expression Regulation / genetics*
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Male
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Mice
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Mice, Knockout
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MicroRNAs / physiology
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NAV1.8 Voltage-Gated Sodium Channel
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Nerve Tissue Proteins / metabolism
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Nociceptors / metabolism*
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Oligonucleotide Array Sequence Analysis / methods
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Pain / chemically induced
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Pain / genetics
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Pain / physiopathology*
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Pain Measurement
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Pain Threshold / physiology*
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Proto-Oncogene Proteins c-fos / metabolism
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Receptors, Purinergic P2 / genetics
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Receptors, Purinergic P2 / metabolism
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Receptors, Purinergic P2X3
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Ribonuclease III
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Sensory Receptor Cells / physiology*
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Sodium Channels / deficiency
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Sodium Channels / genetics
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Sodium Channels / metabolism*
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Spinal Cord / physiopathology
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Time Factors
Substances
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Core Binding Factor Alpha 2 Subunit
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MicroRNAs
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NAV1.8 Voltage-Gated Sodium Channel
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Nerve Tissue Proteins
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P2rx3 protein, mouse
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Proto-Oncogene Proteins c-fos
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Receptors, Purinergic P2
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Receptors, Purinergic P2X3
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Runx1 protein, mouse
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Scn10a protein, mouse
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Sodium Channels
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Freund's Adjuvant
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Endoribonucleases
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Dicer1 protein, mouse
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Ribonuclease III
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DEAD-box RNA Helicases