Decreased nociceptive sensitization in mice lacking the fragile X mental retardation protein: role of mGluR1/5 and mTOR.
Fragile X mental retardation is caused by silencing of the gene (FMR1) that encodes the RNA-binding protein (FMRP) that influences translation in neurons. A prominent feature of the human disorder is self-injurious behavior, suggesting an abnormality in pain processing. Moreover, FMRP regulates group I metabotropic glutamate receptor (mGluR1/5)-dependent plasticity, which is known to contribute to nociceptive sensitization. We demonstrate here, using the Fmr1 knock-out (KO) mouse, that FMRP plays an important role in pain processing because Fmr1 KO mice showed (1) decreased (approximately 50%) responses to ongoing nociception (phase 2, formalin test), (2) a 3 week delay in the development of peripheral nerve injury-induced allodynia, and (3) a near absence of wind-up responses in ascending sensory fibers after repetitive C-fiber stimulation. We provide evidence that the behavioral deficits are related to a mGluR1/5- and mammalian target of rapamycin (mTOR)-mediated mechanism because (1) spinal mGluR5 antagonism failed to inhibit the second phase of the formalin test, and we observed a marked reduction in nociceptive response to an intrathecal injection of an mGluR1/5 agonist (RS)-3,5-dihydroxyphenylglycine (DHPG) in Fmr1 KO mice; (2) peripheral DHPG injection had no effect in KO mice yet evoked thermal hyperalgesia in wild types; and (3) the mTOR inhibitor rapamycin inhibited formalin- and DHPG-induced nociception in wild-type but not Fmr1 KO mice. These experiments show that translation regulation via FMRP and mTOR is an important feature of nociceptive plasticity. These observations also support the hypothesis that the persistence of self-injurious behavior observed in fragile X mental retardation patients could be related to deficits in nociceptive sensitization.
Price
Theodore J
TJ
McGill University, Anesthesia Research Unit, Faculty of Dentistry and McGill Centre for Research on Pain, Montreal, Quebec, Canada H3G 1Y6. tjprice@email.arizona.edu
Rashid
Md Harunor
MH
Millecamps
Magali
M
Sanoja
Raul
R
Entrena
Jose M
JM
Cervero
Fernando
F
D000818:Animals; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics* / Q000502:physiology; D008297:Male; D008734:Methoxyhydroxyphenylglycol / Q000008:administration & dosage / Q000031:analogs & derivatives; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010146:Pain / Q000235:genetics / Q000378:metabolism*; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D011494:Protein Kinases / Q000502:physiology*; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases
D051860:Fragile X Messenger Ribonucleoprotein 1; D008734:Methoxyhydroxyphenylglycol; D011494:Protein Kinases; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D058570:TOR Serine-Threonine Kinases; C497684:Fmr1 protein, mouse; C578935:GRM5 protein, human; C578936:Grm5 protein, mouse; C104077:metabotropic glutamate receptor type 1; C546842:MTOR protein, human; C546843:mTOR protein, mouse; C010117:3,4-dihydroxyphenylglycol