Mechanical allodynia (MA) is the main reason that patients with diabetic peripheral neuropathy (DPN) seek medical advice. It severely debilitates the quality of life. Investigating hyperglycemia-induced changes in neural transcription could provide fundamental insights into the complex pathogenesis of painful DPN (PDPN). Gene expression profiles of physiological dorsal root ganglia (DRG) have been studied. However, the transcriptomic changes in DRG neurons in PDPN remain largely unexplored. In this study, by single-cell RNA sequencing on dissociated rat DRG, we identified five physiological neuron types and a novel neuron type MAAC (Fxyd7+/Atp1b1+) in PDPN. The novel neuron type originated from peptidergic neuron cluster and was characterized by highly expressing genes related to neurofilament and cytoskeleton. Based on the inferred gene regulatory networks, we found that activated transcription factors Hobx7 and Larp1 in MAAC could enhance Atp1b1 expression. Moreover, we constructed the cellular communication network of MAAC and revealed its receptor-ligand pairs for transmitting signals with other cells. Our molecular investigation at single-cell resolution advances the understanding of the dynamic peripheral neuron changes and underlying molecular mechanisms during the development of PDPN.
Objectives
To explore the pathological mechanism of peripheral nerve decompression in relieving tactile allodynia in diabetic rats.
Methods
Healthy adult male Sprague Dawley rats were randomly divided into 5 groups for different interventions: group Ⅰ (healthy control, n=10), group Ⅱ (diabetes model, n=20), group Ⅲ (diabetes model with latex tube placement, n=10), group Ⅳ (diabetes model with latex tube placement and nerve decompression, n=10), group V (diabetes model with latex placement and merely operational area exposure, n=10). The diabetes model was induced by intraperitoneal injection of streptozotocin (STZ). Nerve decompression was performed by removal of latex tube encircling the sciatic nerve at 3 weeks post model establishment. The paw withdrawal threshold was tested 3 days after modeling with the use of up-down method. Diabetic rats with tactile allodynia in 4 experimental groups (groups Ⅱ-Ⅳ) were preserved. Morphometric analysis of myelinated and non-myelinated nerve fibers was performed with the use of projection electron microscope. Western blot and immunofluorescence were used to localized and determined the expression of GABAB receptor protein in spinal dorsal horn.
Results
Three weeks after operation, the incidence of tactile allodynia in STZ-induced rats[55.0%(11/20)] was lower than that in diabetic rats with latex tube placement (groups Ⅲ, Ⅳ and Ⅴ) [86.7%(26/30), χ2=6.254, P=0.012]. The paw withdrawal threshold in group Ⅰ (13.41±1.88 g) was higher than those in groups Ⅱ-Ⅳ (4.06±1.28 g, 3.09±1.43 g, 4.02±1.96 g, 4.15±1.87 g respectively, P<0.05). At 5 weeks post operation, the paw withdrawal threshold in group Ⅳ was higher than those of group Ⅱ, Ⅲ and Ⅴ(all P<0.05). When compared with group Ⅰ, smaller myelinated fibers area and density, as well as higher g-ratio were revealed by electron microscope in each experimental group (all P<0.05). Larger myelinated fiber area and density, as well as lower g-ratio were noted in group Ⅳ when compared with those in group Ⅱ and Ⅴ (all P<0.05). The results of western blot showed that lower expression of GABAB receptor was noted in experimental groups (Ⅱ, Ⅲ, Ⅳ and Ⅴ) when compared with group Ⅰ (all P<0.05), and higher expression of GABAB receptor in both NF-200+ areas and neurons of spinal dorsal horn was noted in group Ⅳ when compared with group V (P<0.05) at 3 weeks post nerve decompression. The results of immunofluorescence showed that lower expression of GABAB receptor in both NF-200+ areas and neurons of spinal dorsal horn was noted in experimental groups (Ⅱ, Ⅲ, Ⅳ and Ⅴ) when compared with group Ⅰ (all P<0.05).
Conclusions
Peripheral nerve decompression can relieve the tactile allodynia of diabetic rats mainly by removing the compression damage of myelinated nerve fibers, lifting the GABAB receptor downregulation-mediated central sensitivity, thereby relieving the pathological state of elevated spinal excitability.
Key words:
Diabetes mellitus; Disease models, animal; Tactile allodynia; Nerve decompression
Percutaneous balloon compression (PBC) has become one of the most common and effective minimally invasive treatments for trigeminal neuralgia (TN). However, the initial and long-term pain outcomes, as well as the complication rates of PBC for patients with TN with concomitant continuous pain (CCP) have yet to be specifically documented.In this clinical study, we aimed to evaluate and compare the results of PBC in treating TN with and without CCP.Retrospective study.This research retrospectively analyzed the pain outcomes and complications of 57 patients with TN with CCP and 118 patients with TN without CCP who had undergone PBC at our institution from January 2019 through June 2022. Procedures were performed by one senior neurosurgeon in a single center. The postdischarge follow-up and the collection of clinical data, including immediate and long-term pain relief, time to recurrence, and complications, were completed through phone contact by an independent neurosurgeon blind to the patients' information. Then, the results of the 2 groups were compared; demographic and clinical data were evaluated for possible predictive factors for poor pain outcomes.In this study, PBC immediately resulted in complete pain relief in 70.2% of patients with CCP and significant pain relief in 84.2% of patients with CCP. For patients without CCP, the rates were 73.7% for complete pain relief and 85.6% for significant pain relief. After a minimum 6-month follow-up period, the rates decreased to 52.6% for complete pain relief and 73.7% for significant pain relief in patients with CCP, compared to 54.2% and 75.4% in those without CCP. The initial and long-term pain control rates in patients without CCP were slightly higher than those with CCP, but the differences were not statistically significant (P = 0.878, P = 0.968, respectively). The incidences of postoperative complications were similar between patients with and without CCP (21.1% vs 22.0%, P = 0.883), whereas the remission rate of complications in patients with CCP was significantly lower than that in patients without CCP (25.0% vs 69.2%, P = 0.011). A longer symptoms duration and having a history of neurodestructive procedures were predictive factors for poor outcomes following PBC.The study was performed in a single-center. The nature of this research is retrospective instead of prospective and randomized, with the inability to control completely for variables. Additionally, the follow-up duration was not long enough to observe recurrence in some patients.This is the first specifically reported experience treating TN with CCP with PBC. PBC can result in significant relief of both episodic and constant pain from TN with CCP. Patients with a longer duration of pain and prior neurodestructive procedures have a higher risk of poor outcomes. The presence of CCP is not associated with pain outcomes and should not be considered a contraindication to PBC.
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