Local translation in primary afferent fibers regulates nociception.
Recent studies have demonstrated the importance of local protein synthesis for neuronal plasticity. In particular, local mRNA translation through the mammalian target of rapamycin (mTOR) has been shown to play a key role in regulating dendrite excitability and modulating long-term synaptic plasticity associated with learning and memory. There is also increased evidence to suggest that intact adult mammalian axons have a functional requirement for local protein synthesis in vivo. Here we show that the translational machinery is present in some myelinated sensory fibers and that active mTOR-dependent pathways participate in maintaining the sensitivity of a subpopulation of fast-conducting nociceptors in vivo. Phosphorylated mTOR together with other downstream components of the translational machinery were localized to a subset of myelinated sensory fibers in rat cutaneous tissue. We then showed with electromyographic studies that the mTOR inhibitor rapamycin reduced the sensitivity of a population of myelinated nociceptors known to be important for the increased mechanical sensitivity that follows injury. Behavioural studies confirmed that local treatment with rapamycin significantly attenuated persistent pain that follows tissue injury, but not acute pain. Specifically, we found that rapamycin blunted the heightened response to mechanical stimulation that develops around a site of injury and reduced the long-term mechanical hypersensitivity that follows partial peripheral nerve damage--a widely used model of chronic pain. Our results show that the sensitivity of a subset of sensory fibers is maintained by ongoing mTOR-mediated local protein synthesis and uncover a novel target for the control of long-term pain states.
Jiménez-Díaz
Lydia
L
Department of Anatomy and Developmental Biology, University College London, London, United Kingdom.
Géranton
Sandrine M
SM
Passmore
Gayle M
GM
Leith
J Lianne
JL
Fisher
Amy S
AS
Berliocchi
Laura
L
Sivasubramaniam
Anantha K
AK
Sheasby
Anne
A
Lumb
Bridget M
BM
Hunt
Stephen P
SP
D000818:Animals; D004576:Electromyography / Q000379:methods*; D004594:Electrophysiology / Q000379:methods; D008297:Male; D009473:Neuronal Plasticity; D009475:Neurons, Afferent / Q000502:physiology*; D009619:Nociceptors / Q000378:metabolism*; D059408:Pain Management; D010147:Pain Measurement; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012680:Sensitivity and Specificity; D058570:TOR Serine-Threonine Kinases
D012333:RNA, Messenger; D011494:Protein Kinases; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases