Drugs That Target Small RNAs May Alleviate Chronic Pain

The nervous response to chronic inflammatory pain is regulated by a series of small RNA molecules that control nociceptor gene expression and may be targeted by a new generation of pain killing drugs.

A nociceptor is a sensory receptor that responds to potentially damaging stimuli by sending nerve signals to the spinal cord and brain. This process, called nociception, usually causes the perception of pain.

To study how chronic pain is processed at the molecular level investigators at University College London (United Kingdom) genetically engineered a line of mice to lack the gene for the enzyme Dicer in their damage-sensing neurons. Dicer is an endoribonuclease in the RNase III family that cleaves double-stranded RNA (dsRNA) and pre-microRNA (miRNA) into short double-stranded RNA fragments called small interfering RNA (siRNA) that are about 20-25 nucleotides long.

Results published in the August 11, 2010, online edition of the Journal of Neuroscience revealed that the genetically engineered mice were healthy with a normal number of sensory neurons and normal acute pain thresholds. Behavioral studies showed that chronic inflammatory pain was attenuated or abolished.

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. In contrast, nociceptor-associated mRNA transcripts 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.

"Knowing that small RNAs are so important in chronic inflammatory pain provides a new avenue for developing drugs for some of the most debilitating and life-long conditions out there,” said senior author Dr. John Wood, professor of molecular biology at University College London. "We have identified small RNAs, which are possible drug targets. What we would really like to be able to do is return the pain thresholds to normal in a person who has chronic inflammatory pain, rather than just numbing the whole body. This would mean that they still get the protection of acute pain. Currently, aspirin-like drugs that can do this have a number of side effects but the present discovery might make it possible to invent a class of drugs that act in a completely novel way.”

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