title: Activation of the Mammalian Target of Rapamycin in the Rostral Ventromedial Medulla Contributes to the Maintenance of Nerve Injury-Induced Neuropathic Pain in Rat.
abstract: The mammalian target of rapamycin (mTOR), a serine-threonine protein kinase, integrates extracellular signals, thereby modulating several physiological and pathological processes, including pain. Previous studies have suggested that rapamycin (an mTOR inhibitor) can attenuate nociceptive behaviors in many pain models, most likely at the spinal cord level. However, the mechanisms of mTOR at the supraspinal level, particularly at the level of the rostral ventromedial medulla (RVM), remain unclear. Thus, the aim of this study was to elucidate the role of mTOR in the RVM, a key relay region for the descending pain control pathway, under neuropathic pain conditions. Phosphorylated mTOR was mainly expressed in serotonergic spinally projecting neurons and was significantly increased in the RVM after spared nerve injury- (SNI-) induced neuropathic pain. Moreover, in SNI rat brain slices, rapamycin infusion both decreased the amplitude instead of the frequency of spontaneous excitatory postsynaptic currents and reduced the numbers of action potentials in serotonergic neurons. Finally, intra-RVM microinjection of rapamycin effectively alleviated established mechanical allodynia but failed to affect the development of neuropathic pain. In conclusion, our data provide strong evidence for the role of mTOR in the RVM in nerve injury-induced neuropathic pain, indicating a novel mechanism of mTOR inhibitor-induced analgesia.
authors.affiliation: Department of Anatomy and K. K. Leung Brain Research Centre, Fourth Military Medical University, Xi'an 710000, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi'an 710000, China.
authors.forename: Da-Yun
authors.initials: DY
authors.lastname: Feng
authors.affiliation: Basic Medical College, Zhengzhou University, Zhengzhou 450001, China.
authors.forename: Zhi-Hua
authors.initials: ZH
authors.lastname: Li
authors.affiliation: Department of Anatomy and K. K. Leung Brain Research Centre, Fourth Military Medical University, Xi'an 710000, China.
authors.forename: Ban
authors.initials: B
authors.lastname: Feng
authors.affiliation: Department of Anatomy and K. K. Leung Brain Research Centre, Fourth Military Medical University, Xi'an 710000, China.
authors.forename: Han
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Anatomy and K. K. Leung Brain Research Centre, Fourth Military Medical University, Xi'an 710000, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Department of Anatomy and K. K. Leung Brain Research Centre, Fourth Military Medical University, Xi'an 710000, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Chen
authors.affiliation: Department of Anatomy and K. K. Leung Brain Research Centre, Fourth Military Medical University, Xi'an 710000, China; Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, China.
authors.forename: Yun-Qing
authors.initials: YQ
authors.lastname: Li
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D006930:Hyperalgesia / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008526:Medulla Oblongata / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D009437:Neuralgia / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D017288:Pain Threshold / Q000502:physiology; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000293:injuries*; D059326:Serotonergic Neurons / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology
chemical_list: C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus