Effects of Duloxetine on the Toll-Like Receptor 4 Signaling Pathway in Spinal Dorsal Horn in a Rat Model of Diabetic Neuropathic Pain

Diabetic neuropathic pain is often considered to be caused by peripheral neuropathy. The involvement of the CNS in this pathological condition has not been well documented. Development of hypersensitivity of spinal dorsal horn neurons is involved in neuropathic pain induced by traumatic nerve injury. In the present study, we determined the functional changes of identified spinothalamic tract (STT) neurons and their correlation to diabetic neuropathic pain. Diabetes was induced in rats by intraperitoneal injection of streptozotocin. Hyperalgesia and allodynia were assessed by the withdrawal responses to pressure, radiant heat, and von Frey filaments applied to the hindpaw. Single-unit activity of STT neurons was recorded from the lumbar spinal cord in anesthetized rats. The responses of STT neurons to mechanical and thermal stimuli and the sensitivity to intravenous morphine were determined in diabetic and normal rats. In 12 diabetic rats, mechanical allodynia and hyperalgesia, but not thermal hyperalgesia, developed within 2 wk after streptozotocin injection and lasted for ≥7 wk. Compared to the 32 STT neurons recorded in normal animals, the 37 STT neurons in diabetic rats displayed a higher spontaneous discharge activity and enlarged receptive fields. Also, the STT neurons in diabetic rats exhibited lower thresholds and augmented responses to mechanical stimulation. Intravenous injection of 2.5 mg/kg of morphine suppressed significantly the responses of STT neurons to noxious stimuli in 12 nondiabetic rats. However, such an inhibitory effect of morphine on the evoked response of STT neurons was diminished in 14 diabetic animals. This electrophysiological study provides new information that development of hypersensitivity of spinal dorsal horn projection neurons may be closely related to neuropathic pain symptoms caused by diabetes. Furthermore, the attenuated inhibitory effects of morphine on evoked responses of STT neurons in diabetes likely accounts for its reduced analgesic efficacy in this clinical form of neuropathic pain.

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Sirtuin 1 alleviates diabetic neuropathic pain by regulating synaptic plasticity of spinal dorsal horn neurons

Pain ◽

10.1097/j.pain.0000000000001489 ◽

2019 ◽

Vol 160 (5) ◽

pp. 1082-1092 ◽

Cited By ~ 12

Author(s):

Zongqin Zhang ◽

Xiaobao Ding ◽

Zhiwei Zhou ◽

Zhuang Qiu ◽

Naihao Shi ◽

...

Keyword(s):

Neuropathic Pain ◽

Synaptic Plasticity ◽

Dorsal Horn ◽

Spinal Dorsal Horn ◽

Sirtuin 1 ◽

Diabetic Neuropathic Pain ◽

Dorsal Horn Neurons ◽

Spinal Dorsal ◽

Spinal Dorsal Horn Neurons

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Quercetin attenuates diabetic neuropathic pain by inhibiting mTOR/p70S6K pathway-mediated changes of synaptic morphology and synaptic protein levels in spinal dorsal horn of db/db mice

European Journal of Pharmacology ◽

10.1016/j.ejphar.2020.173266 ◽

2020 ◽

Vol 882 ◽

pp. 173266 ◽

Cited By ~ 5

Author(s):

Ruiyao Wang ◽

Zhuang Qiu ◽

Guizhi Wang ◽

Qian Hu ◽

Naihao Shi ◽

...

Keyword(s):

Neuropathic Pain ◽

Dorsal Horn ◽

Spinal Dorsal Horn ◽

Synaptic Protein ◽

Diabetic Neuropathic Pain ◽

Protein Levels ◽

Spinal Dorsal

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The over-production of TNF-α via Toll-like receptor 4 in spinal dorsal horn contributes to the chronic postsurgical pain in rat

Journal of Anesthesia ◽

10.1007/s00540-015-2011-2 ◽

2015 ◽

Vol 29 (5) ◽

pp. 734-740 ◽

Cited By ~ 12

Author(s):

Yang Sun ◽

Mingmin Yang ◽

Hao Tang ◽

Zhongfu Ma ◽

Yanbing Liang ◽

...

Keyword(s):

Dorsal Horn ◽

Spinal Dorsal Horn ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Postsurgical Pain ◽

Spinal Dorsal ◽

Tnf Α ◽

Chronic Postsurgical Pain

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Resveratrol Mediates Mechanical Allodynia Through Modulating Inflammatory Response via the TREM2-autophagy Axis in SNI Rat Model

10.21203/rs.3.rs-35728/v1 ◽

2020 ◽

Author(s):

Yaping Wang ◽

Yu Shi ◽

Yongquan Huang ◽

Wei Liu ◽

Guiyuan Cai ◽

...

Keyword(s):

Neuropathic Pain ◽

Inflammatory Response ◽

Dorsal Horn ◽

Nerve Injury ◽

Rat Model ◽

Mechanical Allodynia ◽

Spinal Dorsal Horn ◽

Intrathecal Administration ◽

Spared Nerve Injury ◽

Spinal Dorsal

Abstract Background Neuropathic pain (NeuP) is a chronic and challenging clinical problem, with little effective treatment. Resveratrol has shown neuroprotection by inhibiting inflammatory response in NeuP. Recently, the triggering receptor expressed on myeloid cells 2 (TREM2) expressed by microglia was identified as a critical factor of inflammation in nervous system diseases. In this study, we explored whether resveratrol could ameliorate neuroinflammation and produce anti-mechanical allodynia effects via regulating TREM2 in spared nerve injury rats, as well as investigated the underlying mechanisms. Methods A spared nerve injury (SNI) rat model was performed to investigate whether resveratrol could exert anti-mechanism allodynia effects via inhibiting neuroinflammation. To evaluate the role of TREM2 in anti-neuroinflammatory function of resveratrol, Lentivirus coding TREM2 was intrathecal injected into SNI rats to activate TREM2 and the pain behavior was detected by the Von Frey test. Furthermore, 3-Methyladenine (3-MA, an autophagy inhibitor) was performed to analyze the molecular mechanisms of resveratrol-mediated anti-neuroinflammation using Western blot, qPCR, immunofluorescence. Results The TREM2 expression and number of the microglial cell was significantly increased in the ipsilateral spinal dorsal horn after SNI. We found that intrathecal administration of resveratrol (300ug/day) alleviated mechanical allodynia; obviously enhanced autophagy; and markedly reduced the levels of interleukin-1β, interleukin-6, and tumor necrosis factor-α in the ipsilateral spinal dorsal horn after SNI. Moreover, the number of Iba-1+ microglial cells and TREM2 expression were downregulated after resveratrol treatment. Intrathecal administration of lentivirus coding TREM2 and/or 3-methyladenine in those rats induced deficiencies in resveratrol-mediated anti-inflammation, leading to mechanical allodynia that could be rescued via administration of Res. Furthermore, 3-MA treatment contributed to TREM2-mediated mechanical allodynia. Conclusions Taken together, these data reveal that resveratrol relieves neuropathic pain through suppressing microglia-mediated neuroinflammation via regulating the TREM2-autophagy axis in SNI rats.

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Mammalian target of rapamycin signaling pathway is involved in synaptic plasticity of the spinal dorsal horn and neuropathic pain in rats by regulating autophagy

Neuroreport ◽

10.1097/wnr.0000000000001684 ◽

2021 ◽

Vol Publish Ahead of Print ◽

Author(s):

Jijun Hu ◽

Xueling Chen ◽

Jie Cheng ◽

Fanli Kong ◽

Hui Xia ◽

...

Keyword(s):

Neuropathic Pain ◽

Synaptic Plasticity ◽

Signaling Pathway ◽

Dorsal Horn ◽

Spinal Dorsal Horn ◽

Mammalian Target Of Rapamycin ◽

Target Of Rapamycin ◽

Spinal Dorsal

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Resveratrol mediates mechanical allodynia through modulating inflammatory response via the TREM2-autophagy axis in SNI rat model

Journal of Neuroinflammation ◽

10.1186/s12974-020-01991-2 ◽

2020 ◽

Vol 17 (1) ◽

Author(s):

Yaping Wang ◽

Yu Shi ◽

Yongquan Huang ◽

Wei Liu ◽

Guiyuan Cai ◽

...

Keyword(s):

Neuropathic Pain ◽

Inflammatory Response ◽

Dorsal Horn ◽

Nerve Injury ◽

Rat Model ◽

Mechanical Allodynia ◽

Spinal Dorsal Horn ◽

Intrathecal Administration ◽

Spared Nerve Injury ◽

Spinal Dorsal

Abstract Background Neuropathic pain (NeuP) is a chronic and challenging clinical problem, with little effective treatment. Resveratrol has shown neuroprotection by inhibiting inflammatory response in NeuP. Recently, the triggering receptor expressed on myeloid cells 2 (TREM2) expressed by microglia was identified as a critical factor of inflammation in nervous system diseases. In this study, we explored whether resveratrol could ameliorate neuroinflammation and produce anti-mechanical allodynia effects via regulating TREM2 in spared nerve injury rats, as well as investigated the underlying mechanisms. Methods A spared nerve injury (SNI) rat model was performed to investigate whether resveratrol could exert anti-mechanical allodynia effects via inhibiting neuroinflammation. To evaluate the role of TREM2 in anti-neuroinflammatory function of resveratrol, lentivirus coding TREM2 was intrathecally injected into SNI rats to activate TREM2, and the pain behavior was detected by the von Frey test. Furthermore, 3-methyladenine (3-MA, an autophagy inhibitor) was applied to study the molecular mechanisms of resveratrol-mediated anti-neuroinflammation using Western blot, qPCR, and immunofluorescence. Results The TREM2 expression and number of the microglial cells were significantly increased in the ipsilateral spinal dorsal horn after SNI. We found that intrathecal administration of resveratrol (300ug/day) alleviated mechanical allodynia; obviously enhanced autophagy; and markedly reduced the levels of interleukin-1β, interleukin-6, and tumor necrosis factor-α in the ipsilateral spinal dorsal horn after SNI. Moreover, the number of Iba-1+ microglial cells and TREM2 expression were downregulated after resveratrol treatment. Intrathecal administration of lentivirus coding TREM2 and/or 3-MA in those rats induced deficiencies in resveratrol-mediated anti-inflammation, leading to mechanical allodynia that could be rescued via administration of Res. Furthermore, 3-MA treatment contributed to TREM2-mediated mechanical allodynia. Conclusions Taken together, these data reveal that resveratrol relieves neuropathic pain through suppressing microglia-mediated neuroinflammation via regulating the TREM2-autophagy axis in SNI rats.

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