Spinal Serum- and Glucocorticoid-Regulated Kinase 1 (SGK1) Signaling Contributes to Morphine-Induced Analgesic Tolerance in Rats
| Autor: | Zhong Liu, Yu Cui, Xiao-e Wang, Pu Shen, Yu Chen, Xue Han, Qi Li, Li Xiao |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male Small interfering RNA Pharmacology Protein Serine-Threonine Kinases Receptors N-Methyl-D-Aspartate Immediate-Early Proteins Nociceptive Pain Rats Sprague-Dawley 03 medical and health sciences Random Allocation 0302 clinical medicine Downregulation and upregulation Medicine Animals Phosphorylation Neuronal Plasticity Morphine urogenital system business.industry Kinase musculoskeletal neural and ocular physiology General Neuroscience Transcription Factor RelA Drug Tolerance Analgesics Opioid Posterior Horn Cells 030104 developmental biology Nociception nervous system SGK1 Signal transduction business 030217 neurology & neurosurgery medicine.drug Signal Transduction |
| Zdroj: | Neuroscience. 413 |
| ISSN: | 1873-7544 |
| Popis: | Accumulating evidence indicates that phosphorylated serum- and glucocorticoid-regulated kinase 1 (SGK1) is associated with spinal nociceptive sensitization by modulating glutamatergic N-methyl-D-aspartate receptors (NMDARs). In this study, we determined whether spinal SGK1 signaling contributes to the development of morphine analgesic tolerance. Chronic morphine administration markedly induced phosphorylation of SGK1 in the spinal dorsal horn neurons. Intrathecal injection of SGK1 inhibitor GSK-650394 reduced the development of morphine tolerance with a significant leftward shift in morphine dose-effect curve. Furthermore, spinal inhibition of SGK1 suppressed morphine-induced phosphorylation of nuclear factor kappa B (NF-κB) p65 and upregulation of NMDAR NR1 and NR2B expression in the spinal dorsal horn. In contrast, intrathecal administration of NMDAR antagonist MK-801 had no effect on the phosphorylation of SGK1 in morphine-treated rats. In addition, morphine-induced upregulation of NR2B, but not NR1, was significantly abolished by intrathecal pretreatment with PDTC, a specific NF-κB activation inhibitor. Finally, spinal delivery of SGK1 small interfering RNA exhibited similar inhibitory effects on morphine-induced tolerance, phosphorylation of NF-κB p65, as well as upregulation of NR1 and NR2B expression. Our findings demonstrate that spinal SGK1 contributes to the development of morphine tolerance by enhancing NF-κB p65/NMDAR signaling. Interfering spinal SGK1 signaling pathway could be a potential strategy for prevention of morphine tolerance in chronic pain management. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect