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.

Tanshinone IIA Improves Painful Diabetic Neuropathy by Suppressing the Expression and Activity of Voltage-Gated Sodium Channel in Rat Dorsal Root Ganglia

“…Previous trail has reported that the protein expression of Na v 1.8 in DRGs was decreased in PDN rats [25]. However, there was no significant changes of Na v 1.8 expression were detected in our experiment, which was consistent with some other experiments [26,27]. Although the importance of Nav1.9 in painful process was gradually confirmed, most studies of PDN have not mentioned too much.…”

Combination of Ginsenoside Rg1 and Astragaloside IV reduces oxidative stress and inhibits TGF-β1/Smads signaling cascade on renal fibrosis in rats with diabetic nephropathy

“…Then, eight rats were randomly chosen and designated as N group, and the rest were intraperitoneally administered 60 mg/kg of STZ with 0.1 mol/L sodium citrate solution (pH 4.50). 17 – 19 The blood glucose levels of all the rats, except N group, were measured at 72 hours after STZ injection (first experimental day). Only the rats with a blood glucose concentration higher than 13.8 mmol/L were chosen as model rats and used further in our study.…”

Characterization of changes of pain behavior and signal transduction system in food-deprived mice

“…Several lines of evidence have demonstrated that the AMPK and mTOR systems are also closely related with nociception. For example, the expression of mTOR protein in DRG or the spinal cord are altered in several types pain models such as neuropathic pain (Zhang et al 2013 ; Cui et al 2014 ), diabetic neuropathy (He et al 2016 ), and inflammation-induced pain (Asante et al 2009 ; Xu et al 2011 ) models. In addition, the activation of AMPK signal in general reduces nociception, allodynia or hyperalgesia observed in several types of pain models (Russe et al 2013 ; Ma et al 2015 ; Song et al 2015 ; Hasanvand et al 2016 ), suggesting that AMPK is an ultimate target molecules for relieving pain (Melemedjian et al 2011 ; Asiedu et al 2016 ; Price et al 2016 ).…”