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The Journal of Neuroscience, December 19, 2007, 27(51):13958-13967; doi:10.1523/JNEUROSCI.4383-07.2007

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Neurobiology of Disease
Decreased Nociceptive Sensitization in Mice Lacking the Fragile X Mental Retardation Protein: Role of mGluR1/5 and mTOR

Theodore J. Price,¹ Md Harunor Rashid,¹ Magali Millecamps,¹ Raul Sanoja,¹ Jose M. Entrena,² and Fernando Cervero¹

¹McGill University, Anesthesia Research Unit, Faculty of Dentistry and McGill Centre for Research on Pain, Montreal, Quebec, Canada H3G 1Y6, and ²Department of Pharmacology and Neurosciences Institute, University of Granada Faculty of Medicine, E-18012 Granada, Spain

Correspondence should be addressed to Dr. Theodore J. Price at his present address: University of Arizona, Department of Pharmacology, Medical Research Building Room 218, 1656 East Mabel, Tucson, AZ 85719. Email: tjprice{at}email.arizona.edu

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 (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.

Key words: pain; translation regulation; nociceptor; FMRP; mGluR; neuropathic pain; mTOR

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Received April 10, 2007; revised Oct. 17, 2007; accepted Oct. 24, 2007.

Correspondence should be addressed to Dr. Theodore J. Price at his present address: University of Arizona, Department of Pharmacology, Medical Research Building Room 218, 1656 East Mabel, Tucson, AZ 85719. Email: tjprice{at}email.arizona.edu

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