Spinal cord stimulation induces c-Fos expression in the dorsal horn in rats with neuropathic pain after partial sciatic nerve injury

Background Neuropathic pain following peripheral nerve injury (PNI) is linked to neuroinflammation in the spinal cord marked by astrocyte activation and upregulation of interleukin 6 (IL -6 ), chemokine (C-C motif) ligand 2 (CCL2) and chemokine (C-X-C motif) ligand 1 (CXCL1), with inhibition of each individually being beneficial in pain models. Methods Wild type (WT) mice and mice with global or pGfap-cre- or pGFAP-cre/ERT2-driven Abcc8/SUR1 deletion or global Trpm4 deletion underwent unilateral sciatic nerve cuffing. WT mice received prophylactic (starting on post-operative day [pod]-0) or therapeutic (starting on pod-21) administration of the SUR1 antagonist, glibenclamide (10 µg IP) daily. We measured mechanical and thermal sensitivity using von Frey filaments and an automated Hargreaves method. Spinal cord tissues were evaluated for SUR1-TRPM4, IL-6, CCL2 and CXCL1. Results Sciatic nerve cuffing in WT mice resulted in pain behaviors (mechanical allodynia, thermal hyperalgesia) and newly upregulated SUR1-TRPM4 in dorsal horn astrocytes. Global and pGfap-cre-driven Abcc8 deletion and global Trpm4 deletion prevented development of pain behaviors. In mice with Abcc8 deletion regulated by pGFAP-cre/ERT2, after pain behaviors were established, delayed silencing of Abcc8 by tamoxifen resulted in gradual improvement over the next 14 days. After PNI, leakage of the blood-spinal barrier allowed entry of glibenclamide into the affected dorsal horn. Daily repeated administration of glibenclamide, both prophylactically and after allodynia was established, prevented or reduced allodynia. The salutary effects of glibenclamide on pain behaviors correlated with reduced expression of IL-6, CCL2 and CXCL1 by dorsal horn astrocytes. Conclusion SUR1-TRPM4 may represent a novel non-addicting target for neuropathic pain.

Download Full-text

“Three Methods and Three Points” regulates p38 mitogen-activated protein kinase in the dorsal horn of the spinal cord in a rat model of sciatic nerve injury

Neural Regeneration Research ◽

10.4103/1673-5374.197147 ◽

2016 ◽

Vol 11 (12) ◽

pp. 2018 ◽

Cited By ~ 1

Author(s):

Tian-yuan Yu ◽

Xin Guo ◽

Wong Steven ◽

Wen-duan Jia ◽

Chi Ma ◽

...

Keyword(s):

Spinal Cord ◽

Protein Kinase ◽

Sciatic Nerve ◽

Dorsal Horn ◽

Nerve Injury ◽

Rat Model ◽

Sciatic Nerve Injury ◽

Mitogen Activated Protein Kinase ◽

Mitogen Activated Protein

Download Full-text

Suppression of Superficial Microglial Activation by Spinal Cord Stimulation Attenuates Neuropathic Pain Following Sciatic Nerve Injury in Rats

International Journal of Molecular Sciences ◽

10.3390/ijms21072390 ◽

2020 ◽

Vol 21 (7) ◽

pp. 2390

Author(s):

Masamichi Shinoda ◽

Satoshi Fujita ◽

Shiori Sugawara ◽

Sayaka Asano ◽

Ryo Koyama ◽

...

Keyword(s):

Spinal Cord ◽

Neuropathic Pain ◽

Electrical Stimulation ◽

Dorsal Horn ◽

Nerve Injury ◽

Spinal Cord Stimulation ◽

Microglial Activation ◽

In Vivo Optical Imaging ◽

Stimulation Of

We evaluated the mechanisms underlying the spinal cord stimulation (SCS)-induced analgesic effect on neuropathic pain following spared nerve injury (SNI). On day 3 after SNI, SCS was performed for 6 h by using electrodes paraspinally placed on the L4-S1 spinal cord. The effects of SCS and intraperitoneal minocycline administration on plantar mechanical sensitivity, microglial activation, and neuronal excitability in the L4 dorsal horn were assessed on day 3 after SNI. The somatosensory cortical responses to electrical stimulation of the hind paw on day 3 following SNI were examined by using in vivo optical imaging with a voltage-sensitive dye. On day 3 after SNI, plantar mechanical hypersensitivity and enhanced microglial activation were suppressed by minocycline or SCS, and L4 dorsal horn nociceptive neuronal hyperexcitability was suppressed by SCS. In vivo optical imaging also revealed that electrical stimulation of the hind paw-activated areas in the somatosensory cortex was decreased by SCS. The present findings suggest that SCS could suppress plantar SNI-induced neuropathic pain via inhibition of microglial activation in the L4 dorsal horn, which is involved in spinal neuronal hyperexcitability. SCS is likely to be a potential alternative and complementary medicine therapy to alleviate neuropathic pain following nerve injury.

Download Full-text

Complement and clusterin in the spinal cord dorsal horn and gracile nucleus following sciatic nerve injury in the adult rat

Neuroscience ◽

10.1016/0306-4522(95)00103-p ◽

1995 ◽

Vol 68 (1) ◽

pp. 167-179 ◽

Cited By ~ 61

Author(s):

L. Liu ◽

E. To¨rnqvist ◽

P. Mattsson ◽

N.P. Eriksson ◽

J.K.E. Persson ◽

...

Keyword(s):

Spinal Cord ◽

Sciatic Nerve ◽

Dorsal Horn ◽

Nerve Injury ◽

Sciatic Nerve Injury ◽

Spinal Cord Dorsal Horn ◽

Adult Rat ◽

Gracile Nucleus ◽

Spinal Cord Dorsal

Download Full-text

Dynamic effects of TNF-α on synaptic transmission in mice over time following sciatic nerve chronic constriction injury

Journal of Neurophysiology ◽

10.1152/jn.01088.2012 ◽

2013 ◽

Vol 110 (7) ◽

pp. 1663-1671 ◽

Cited By ~ 23

Author(s):

Hongmei Zhang ◽

Haijun Zhang ◽

Patrick M. Dougherty

Keyword(s):

Spinal Cord ◽

Neuropathic Pain ◽

Sciatic Nerve ◽

Synaptic Transmission ◽

Dorsal Horn ◽

Nerve Injury ◽

Chronic Constriction Injury ◽

Synaptic Signaling ◽

Tnf Α ◽

Over Time

Nerve injury-induced central sensitization can manifest as an increase in excitatory synaptic transmission and/or as a decrease in inhibitory synaptic transmission in spinal dorsal horn neurons. Cytokines such as tumor necrosis factor-α (TNF-α) are induced in the spinal cord under various injury conditions and contribute to neuropathic pain. In this study we examined the effect of TNF-α in modulating excitatory and inhibitory synaptic input to spinal substantia gelatinosa (SG) neurons over time in mice following chronic constriction injury (CCI) of the sciatic nerve. Whole cell patch-clamp studies from SG neurons showed that TNF-α enhanced overall excitability of the spinal cord early in time following nerve injury 3 days after CCI compared with that in sham control mice. In contrast, the effects of TNF were blunted 14 days after CCI in nerve-injured mice compared with sham surgery mice. Immunohistochemical staining showed that the expression of TNF-α receptor 1 (TNFR1) was increased at 3 days but decreased at 14 days following CCI in the ipsilateral vs. the contralateral spinal cord dorsal horn. These results suggest that TNF-α acting at TNFR1 is important in the development of neuropathic pain by facilitating excitatory synaptic signaling in the acute phases after nerve injury but has a reduced effect on spinal neuron signaling in the later phases of nerve injury-induced pain. Failure of the facilatory effects of TNF-α on excitatory synaptic signaling in the dorsal horn to resolve following nerve injury may be an important component in the transition between acute and chronic pain conditions.

Download Full-text

Gabapentin and NMDA receptor antagonists interacts synergistically to alleviate allodynia in two rat models of neuropathic pain

Scandinavian Journal of Pain ◽

10.1515/sjpain-2018-0083 ◽

2018 ◽

Vol 18 (4) ◽

pp. 687-693 ◽

Cited By ~ 4

Author(s):

Tiansheng Shi ◽

Jing-Xia Hao ◽

Zsuzsanna Wiesenfeld-Hallin ◽

Xiao-Jun Xu

Keyword(s):

Spinal Cord ◽

Neuropathic Pain ◽

Nmda Receptor ◽

Side Effects ◽

Sciatic Nerve ◽

Nerve Injury ◽

Sciatic Nerve Injury ◽

Nmda Receptor Antagonists ◽

Receptor Antagonists ◽

Mk 801

Abstract Background and aims The clinical management of neuropathic pain remains a challenge. We examined the interaction between gabapentin and NMDA receptor antagonists dextromethrophan and MK-801 in alleviating neuropathic pain-like behaviors in rats after spinal cord or sciatic nerve injury. Methods Female and male rats were produced with Ischemic spinal cord injury and sciatic nerve injury. Gabapentin, dextromethorphan, MK-801 or drug combinations were injected with increasing doses. Mechanical response thresholds were tested with von Frey hairs to graded mechanical touch/pressure, and ethyl chloride spray was applied to assess the cold sensitivity before and after injuries. Results In spinally injured rats, gabapentin and dextromethorphan did not affect allodynia-like behaviors at doses of 30 and 20 mg/kg, respectively. In contrast, combination of 15 or 30 mg/kg gabapentin with dextromethorphan at 10 mg/kg produced total alleviation of allodynia to mechanical or cold stimulation. Further reducing the dose of gapapentin to 7.5 mg/kg and dextromethorphan to 5 mg/kg still produced significant effect. MK-801, another NMDA receptor antagonist, also enhanced the effect of gabapentin in spinally injured rats. Similar synergistic anti-allodynic effect between dextromethorphan and gabapentin was also observed in a rat model of partial sciatic nerve injury. No increased side effect was seen following the combination between gabapentin and dextromethorphan. Conclusions In conclusion, the present study suggested that combining NMDA receptor antagonists with gabapentin could provide synergistic effect to alleviate neuropathic pain and reduced side effects. Implications Combining NMDA receptor antagonists with gabapentin may provide a new approach in alleviating neuropathic pain with increased efficacy and reduced side effects.

Download Full-text