scholarly journals Inhibition of phosphorylated calcium/calmodulin-dependent protein kinase IIα relieves streptozotocin-induced diabetic neuropathic pain through regulation of P2X3 receptor in dorsal root ganglia

2022 ◽  
Author(s):  
Xiao-fen He ◽  
Yu-rong Kang ◽  
Xue-yu Fei ◽  
Lu-hang Chen ◽  
Xiang Li ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Dorsal Root Ganglia ◽  
Dorsal Root ◽  
Fasting Blood Glucose ◽  
Thermal Hyperalgesia ◽  
Underlying Mechanism ◽  
Diabetic Rats ◽  
Diabetic Neuropathic Pain ◽  
Calcium Calmodulin Dependent ◽  
Patients With Diabetes

Abstract  Diabetic neuropathic pain (DNP) is frequent among patients with diabetes. We previously showed that P2X3 upregulation in dorsal root ganglia (DRG) plays a role in streptozotocin (STZ)-induced DNP but the underlying mechanism is unclear. Here, a rat model of DNP was established by a single injection of STZ (65 mg/kg). Fasting blood glucose was significantly elevated from the 1st to 3rd week. Paw withdrawal thresholds (PWTs) and paw withdrawal latencies (PWLs) in diabetic rats significantly reduced from the 2nd to 3rd week. Western blot analysis revealed that elevated p-CaMKIIα levels in the DRG of DNP rats were accompanied by pain-associated behaviors while CaMKIIα levels were unchanged. Immunofluorescence revealed significant increase in the proportion of p-CaMKIIα immune positive DRG neurons (stained with NeuN) in the 2nd and 3rd week and p-CaMKIIα was co-expressed with P2X3 in DNP rats. KN93, a CaMKII antagonist, significantly reduce mechanical hyperalgesia and thermal hyperalgesia and these effects varied dose-dependently, and suppressed p-CaMKIIα and P2X3 upregulation in the DRGs of DNP rats. These results revealed that the p-CaMKIIα upregulation in DRG is involved in DNP, which possibly mediated P2X3 upregulation, indicating CaMKIIα may be an effective pharmacological target for DNP management.

scholarly journals Progressive Increase of Inflammatory CXCR4 and TNF-Alpha in the Dorsal Root Ganglia and Spinal Cord Maintains Peripheral and Central Sensitization to Diabetic Neuropathic Pain in Rats

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Dan Zhu ◽  
Tingting Fan ◽  
Xinyue Huo ◽  
Jian Cui ◽  
Chi Wai Cheung ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Dorsal Root Ganglia ◽  
Central Sensitization ◽  
Dorsal Root ◽  
Diabetic Rats ◽  
Spinal Cord Dorsal Horn ◽  
Peripheral Sensitization ◽  
Diabetic Neuropathic Pain ◽  
Spinal Cord Dorsal

Diabetic neuropathic pain (DNP) is a common and serious complication of diabetic patients. The pathogenesis of DNP is largely unclear. The proinflammation proteins, CXCR4, and TNF-α play critical roles in the development of pain, while their relative roles in the development of DNP and especially its progression is unknown. We proposed that establishment of diabetic pain models in rodents and evaluating the stability of behavioral tests are necessary approaches to better understand the mechanism of DNP. In this study, Von Frey and Hargreaves Apparatus was used to analyze the behavioral changes of mechanical allodynia and heat hyperalgesia in streptozotocin-induced diabetic rats at different phases of diabetes. Moreover, CXCR4 and TNF-α of spinal cord dorsal and dorsal root ganglia (DRG) were detected by western blotting and immunostaining over time. The values of paw withdrawal threshold (PWT) and paw withdrawal latencies (PWL) were reduced as early as 1 week in diabetic rats and persistently maintained at lower levels during the progression of diabetes as compared to control rats that were concomitant with significant increases of both CXCR4 and TNF-α protein expressions in the DRG at 2 weeks and 5 weeks (the end of the experiments) of diabetes. By contrast, CXCR4 and TNF-α in the spinal cord dorsal horn did not significantly increase at 2 weeks of diabetes while both were significantly upregulated at 5 weeks of diabetes. The results indicate that central sensitization of spinal cord dorsal may result from persistent peripheral sensitization and suggest a potential reference for further treatment of DNP.

scholarly journals Hypersensitivity of Spinothalamic Tract Neurons Associated With Diabetic Neuropathic Pain in Rats

2002 ◽  
Vol 87 (6) ◽  
pp. 2726-2733 ◽  
Author(s):  
Shao-Rui Chen ◽  
Hui-Lin Pan
Keyword(s):  
Neuropathic Pain ◽  
Dorsal Horn ◽  
Spinal Dorsal Horn ◽  
Thermal Hyperalgesia ◽  
Diabetic Rats ◽  
Projection Neurons ◽  
Diabetic Neuropathic Pain ◽  
Spinothalamic Tract ◽  
Functional Changes ◽  
Spinal Dorsal

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.

lncRNA NONRATT021972 siRNA Decreases Diabetic Neuropathic Pain Mediated by the P2X3 Receptor in Dorsal Root Ganglia

2016 ◽  
Vol 54 (1) ◽  
pp. 511-523 ◽  
Author(s):  
Haiying Peng ◽  
Lifang Zou ◽  
Jinyan Xie ◽  
Hong Wu ◽  
Bing Wu ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Dorsal Root Ganglia ◽  
Dorsal Root ◽  
P2x3 Receptor ◽  
Diabetic Neuropathic Pain

scholarly journals The effect of sinomenine in diabetic neuropathic pain mediated by the P2X3 receptor in dorsal root ganglia

2017 ◽  
Vol 13 (2) ◽  
pp. 227-235 ◽  
Author(s):  
Shenqiang Rao ◽  
Shuangmei Liu ◽  
Lifang Zou ◽  
Tianyu Jia ◽  
Shanhong Zhao ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Dorsal Root Ganglia ◽  
Dorsal Root ◽  
P2x3 Receptor ◽  
Diabetic Neuropathic Pain

Anti-neuropathic pain effects of ethyl acetate extract of Ferula asafoetida oleo-gum-resin in streptozotocin-induced diabetic rats

2020 ◽  
Vol 10 ◽  
Author(s):  
Samad Nazemi ◽  
Hamid Rudsarabi ◽  
Bahareh Amin ◽  
Hamid Farahani ◽  
Hasan Azhdari Zarmehri ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Blood Glucose ◽  
Ethyl Acetate ◽  
Ethyl Acetate Extract ◽  
Fasting Blood Glucose ◽  
Thermal Hyperalgesia ◽  
Diabetic Rats ◽  
Tail Flick ◽  
Dependent Manner ◽  
Ferula Asafoetida

Objective: Diabetic neuropathic pain (DNP) is a common complication in both types of diabetes, which does not respond well to the common pain medications. Asafoetida, an oleo-gum-resin extracted from Ferula asafoetida, is used as analgesic, sedative, and antispasmodic in Iranian traditional medicine. Hence, the present study aimed to investigate antineuropathic pain effects of asafoetida in streptozotocin-induced diabetic rats. Methods: Forty male Wistar rats were randomly divided into five groups. In four groups, diabetes was induced by intraperitoneal injection of a single-dose of streptozotocin (60 mg/kg). Three diabetic groups were treated once daily with asafoetida extract at doses 25, 50 and 100 mg/kg for 25 days. In all groups, the neuropathic pain was evaluated using behavioral tail-flick and von-Frey tests on days 0, 7, 14, 21 and 28. In addition, fasting blood glucose was measured at the mentioned days. Key Findings: According to the results obtained from the behavioral tests, neuropathic pain was established in the diabetic rats on day 21. However, in comparison to untreated animals, the intensity of pain (thermal hyperalgesia and mechanical allodynia) was significantly lower in groups receiving asafoetida extract (50 mg/kg, P<0.05 and 100 mg/kg, P<0.01). In addition, the extract could decrease fasting blood glucose in a dose-dependent manner (P<0.05). Conclusion: Ethyl acetate extract of asafoetida can prevent the development of neuropathic pain in diabetic rats. This effect may be, in part, due to glucose lowering effect of asafoetida. However, further studies are needed to determine its possible mechanisms of action in relieving DNP.

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