Small RNAs control sodium channel expression, nociceptor excitability, and pain thresholds.
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.
Zhao
Jing
J
Molecular Nociception Group, Wolfson Institute for Biomedical Research, Research Department of Neuroscience, Physiology and Pharmacology, University College London, London WC1E 6BT, United Kingdom. jing02.zhao@ucl.ac.uk
Lee
Man-Cheung
MC
Momin
Ali
A
Cendan
Cruz-Miguel
CM
Shepherd
Samuel T
ST
Baker
Mark D
MD
Asante
Curtis
C
Bee
Lucy
L
Bethry
Audrey
A
Perkins
James R
JR
Nassar
Mohammed A
MA
Abrahamsen
Bjarke
B
Dickenson
Anthony
A
Cobb
Bradly S
BS
Merkenschlager
Matthias
M
Wood
John N
JN
D000704:Analysis of Variance; D000818:Animals; D002531:Cerebellum / Q000166:cytology; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics / Q000378:metabolism; D053487:DEAD-box RNA Helicases / Q000172:deficiency; D004195:Disease Models, Animal; D004722:Endoribonucleases / Q000172:deficiency; D005260:Female; D005620:Freund's Adjuvant / Q000009:adverse effects; D005727:Ganglia, Spinal / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000235:genetics*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000502:physiology; D062559:NAV1.8 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009619:Nociceptors / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D010146:Pain / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology*; D010147:Pain Measurement; D017288:Pain Threshold / Q000502:physiology*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D018048:Receptors, Purinergic P2 / Q000235:genetics / Q000378:metabolism; D058477:Receptors, Purinergic P2X3; D043244:Ribonuclease III; D011984:Sensory Receptor Cells / Q000502:physiology*; D015222:Sodium Channels / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013116:Spinal Cord / Q000503:physiopathology; D013997:Time Factors
D050676:Core Binding Factor Alpha 2 Subunit; D035683:MicroRNAs; D062559:NAV1.8 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C546409:P2rx3 protein, mouse; D016760:Proto-Oncogene Proteins c-fos; D018048:Receptors, Purinergic P2; D058477:Receptors, Purinergic P2X3; C493726:Runx1 protein, mouse; C568318:Scn10a protein, mouse; D015222:Sodium Channels; D005620:Freund's Adjuvant; D004722:Endoribonucleases; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases