title: Intrathecal administration of rapamycin inhibits the phosphorylation of DRG Nav1.8 and attenuates STZ-induced painful diabetic neuropathy in rats.
abstract: The mammalian target of rapamycin (mTOR) is a key regulator of mRNA translation and protein synthesis, and it is specifically inhibited by rapamycin. In chronic pain conditions, mTOR-mediated local protein synthesis is crucial for neuronal hyperexcitability and synaptic plasticity. The tetrodotoxin-resistant (TTX-R) sodium channel Nav1.8 plays a major role in action potential initiation and propagation and cellular excitability in DRG (dorsal root ganglion) neurons. In this study, we investigated if mTOR modulates the phosphorylation of Nav1.8 that is associated with neuronal hyperexcitability and behavioral hypersensitivity in STZ-induced diabetic rats. Painful diabetic neuropathy (PDN) was induced in Sprague-Dawley rats by intraperitoneal injection with streptozotocin (STZ) at 60mg/kg. After the onset of PDN, the rats received daily intrathecal administrations of rapamycin (1μg, 3μg, or 10μg/day) for 7 days; other diabetic rats received the same volumes of dimethyl sulfoxide (DMSO). Herein, we demonstrate a marked increase in protein expression of total mTOR and phospho-mTOR (p-mTOR) together with the up-regulation of phosphor-Nav1.8 (p-Nav1.8) prior to the mechanical withdrawal threshold reaching a significant reduction in dorsal root ganglions (DRGs). Furthermore, the intrathecal administration of rapamycin, inhibiting the activity of mTOR, suppressed the phosphorylation of DRG Nav1.8, reduced the TTX-R current density, heightened the voltage threshold for activation and lowered the voltage threshold for inactivation and relieved mechanical hypersensitivity in diabetic rats. An intrathecal injection (i.t.) of rapamycin inhibited the phosphorylation and enhanced the functional availability of DRG Nav1.8 attenuated STZ-induced hyperalgesia. These results suggest that rapamycin is a potential therapeutic intervention for clinical PDN.
authors.affiliation: Department of Anesthesiology, The First People's Hospital of Foshan, 81# North of LingNan Road, Foshan 528000, China.
authors.forename: Wan-You
authors.initials: WY
authors.lastname: He
authors.affiliation: Department of Anesthesiology, The First People's Hospital of Foshan, 81# North of LingNan Road, Foshan 528000, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology, The First People's Hospital of Foshan, 81# North of LingNan Road, Foshan 528000, China.
authors.forename: Qing-Ming
authors.initials: QM
authors.lastname: Xiong
authors.affiliation: Department of Anesthesiology, The First People's Hospital of Foshan, 81# North of LingNan Road, Foshan 528000, China.
authors.forename: Cheng-Xiang
authors.initials: CX
authors.lastname: Yang
authors.affiliation: Department of Anesthesiology, The First People's Hospital of Foshan, 81# North of LingNan Road, Foshan 528000, China.
authors.forename: Wei-Cheng
authors.initials: WC
authors.lastname: Zhao
authors.affiliation: Department of Anesthesiology, The First People's Hospital of Foshan, 81# North of LingNan Road, Foshan 528000, China.
authors.forename: Jian
authors.initials: J
authors.lastname: He
authors.affiliation: Department of Anesthesiology, The First People's Hospital of Foshan, 81# North of LingNan Road, Foshan 528000, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Anesthesiology, The First People's Hospital of Foshan, 81# North of LingNan Road, Foshan 528000, China. Electronic address: fswhbing@163.com.
authors.forename: Han-Bing
authors.initials: HB
authors.lastname: Wang
mesh_terms: D000818:Animals; D003928:Diabetic Nephropathies / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D005727:Ganglia, Spinal / Q000378:metabolism*; D006930:Hyperalgesia / Q000503:physiopathology; D007278:Injections, Spinal; D008297:Male; D062559:NAV1.8 Voltage-Gated Sodium Channel / Q000378:metabolism*; D009474:Neurons / Q000502:physiology; D010766:Phosphorylation; D010812:Physical Stimulation; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology*; D013311:Streptozocin; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014110:Touch
chemical_list: D062559:NAV1.8 Voltage-Gated Sodium Channel; C568319:Scn10a protein, rat; D013311:Streptozocin; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: DRG; Intrathecal administration; Nav1.8; Painful diabetic neuropathy; Rapamycin; mTOR