Neuronal Hyperexcitability: A Substrate for Central Neuropathic Pain After Spinal Cord Injury

Neuronal hyperexcitability produces enhanced pain transmission in the spinal dorsal horn after spinal cord injury (SCI). Spontaneous and evoked neuronal excitability normally are well controlled by neural circuits. However, SCI produces maladaptive synaptic circuits in the spinal dorsal horn that result in neuronal hyperexcitability. After SCI, activated primary afferent neurons produce enhanced release of glutamate, neuropeptides, adenosine triphosphate, and proinflammatory cytokines, which are known to be major components for pain transmission in the spinal dorsal horn. Enhanced neurochemical events contribute to neuronal hyperexcitability, and neuroanatomical changes also contribute to maladaptive synaptic circuits and neuronal hyperexcitability. These neurochemical and neuroanatomical changes produce enhanced cellular signaling cascades that ensure persistently enhanced pain transmission. This review describes altered neurochemical and neuroanatomical contributions on neuronal hyperexcitability in the spinal dorsal horn, which serve as substrates for central neuropathic pain after SCI.     

Peripheral Nerve Injury–Induced Changes in Spinal α2-Adrenoceptor–Mediated Modulation of Mechanically Evoked Dorsal Horn Neuronal Responses

Peripheral nerve injury has been associated with changes in the modulatory action of noradrenergic pathways on nociceptive traffic through the spinal cord. Thus, the purpose of this study was to assess whether endogenous noradrenergic descending inhibition, acting via spinal α₂-receptors, is altered after peripheral nerve damage. We investigated the effects of spinal administration of a selective α₂-adrenoceptor antagonist, atipamezole, on the evoked activity of deep dorsal horn neurons in animals with selective spinal nerve ligation (SNL) compared with a sham-operated group. Intrathecal administration of atipamezole (1, 10, and 100 μg) did not produce any significant effects on the electrically evoked neuronal responses in either animal group, with the exception of a small but significant enhancement of the postdischarge in the sham control group only. Similarly, no significant effects were observed with the heat-evoked neuronal responses in either group. Interestingly, atipamezole significantly increased the evoked responses of neurons to low-intensity mechanical stimuli in the sham control group but was without effect in the SNL group. Thus, our findings suggest that peripheral nerve injury can result in the suppression of noradrenergic spinal α₂-adrenoceptor–mediated inhibition of spinal dorsal horn neuronal activity evoked by low-intensity mechanical stimuli.PerspectiveThese results suggest that a tonically active noradrenergic inhibition of mechanically evoked spinal dorsal horn neuronal responses is lost after nerve injury. This shift in the balance of noradrenergic controls may be one of the many underlying mechanisms by which behavioral symptoms of hypersensitivity develop after nerve damage.     

Gabapentin Alleviates Facet-Mediated Pain in the Rat Through Reduced Neuronal Hyperexcitability and Astrocytic Activation in the Spinal Cord

Although joint pain is common, its mechanisms remain undefined, with little known about the spinal neuronal responses that contribute to this type of pain. Afferent activity and sustained spinal neuronal hyperexcitability correlate to facet joint loading and the extent of behavioral sensitivity induced after painful facet injury, suggesting that spinal neuronal plasticity is induced in association with facet-mediated pain. This study used a rat model of painful C6-C7 facet joint stretch, together with intrathecal administration of gabapentin, to investigate the effects of one aspect of spinal neuronal function on joint pain. Gabapentin or saline vehicle was given via lumbar puncture prior to and at 1 day after painful joint distraction. Mechanical hyperalgesia was measured in the forepaw for 7 days. Extracellular recordings of neuronal activity and astrocytic and microglial activation in the cervical spinal cord were evaluated at day 7. Gabapentin significantly (P = .0001) attenuated mechanical hyperalgesia, and the frequency of evoked neuronal firing also significantly decreased (P < .047) with gabapentin treatment. Gabapentin also decreased (P < .04) spinal glial fibrillary acidic protein expression. Although spinal Iba1 expression was doubled over sham, gabapentin did not reduce it. Facet joint–mediated pain appears to be sustained through spinal neuronal modifications that are also associated with astrocytic activation.     

Effects of Epidural Spinal Cord Stimulation and Treadmill Training on Locomotion Function and Ultrastructure of Spinal Cord Anterior Horn after Moderate Spinal Cord Injury in Rats

Objective:To investigate the effects of epidural spinal cord stimulation (ESCS) and treadmill training on the locomotion function and ultrastructure of spinal cord anterior horn after moderate spinal cord injury in rats.Method:Nine adult female Sprague-Dawley rats were randomly distributed into three groups: ①spinal cord injury group (SI, n=3). ②spinal cord injury plus ESCS group (SE, n=3). ③spinal cord injury plus treadmill training group (TT, n=3). All rats received a moderate spinal cord injury surgery. Four weeks after surgery, rats in SE group received an electrode implantation procedure, with the electrode field covering spinal cord segments L2—S1. Four weeks after electrode implantation, rats received subthreshold ESCS for 30 min/d. Rats in TT group received 4cm/s treadmill training for 30min/d. Rats in SI group received no intervention, as a control group. All procedures in these three groups lasted four weeks.The open field Basso,Beattie and Bresnahan(BBB) scale was used before and after intervention to evaluate rats′ hindlimb motor function. Result:After four weeks intervention, rats in TT group improved their open field locomotion scores to 20. In contrast, no significant improvement was observed in groups SI and SE. The morphology of synapses and neurons were similar regardless of whether rats had undergone ESCS, treadmill training or not. Conclusion:ESCS alone was not sufficient to improve the walking ability of spinal cord injured rats. ESCS or treadmill training alone might not contribute to the changes of ultrastructure in anterior horn of spinal cord that underlie the recovery of walking ability. Further research is needed to understand the contributions of combination of ESCS and treadmill training to the rehabilitation of spinal cord injured rats.     

Dynorphin and Enkephalin Opioid Peptides and Transcripts in Spinal Cord and Dorsal Root Ganglion During Peripheral Inflammatory Hyperalgesia and Allodynia

Understanding molecular alterations associated with peripheral inflammation is a critical factor in selectively controlling acute and persistent pain. The present report employs in situ hybridization of the 2 opioid precursor mRNAs coupled with quantitative measurements of 2 peptides derived from the prodynorphin and proenkephalin precursor proteins: dynorphin A 1-8 and [Met⁵]-enkephalin-Arg⁶-Gly⁷-Leu⁸. In dorsal spinal cord ipsilateral to the inflammation, dynorphin A 1-8 was elevated after inflammation, and persisted as long as the inflammation was sustained. Qualitative identification by high performance liquid chromatography and gel permeation chromatography revealed the major immunoreactive species in control and inflamed extracts to be dynorphin A 1-8. In situ hybridization in spinal cord after administration of the inflammatory agent, carrageenan, showed increased expression of prodynorphin (Pdyn) mRNA somatotopically in medial superficial dorsal horn neurons. The fold increase in preproenkephalin mRNA (Penk) was comparatively lower, although the basal expression is substantially higher than Pdyn. While Pdyn is not expressed in the dorsal root ganglion (DRG) in basal conditions, it can be induced by nerve injury, but not by inflammation alone. A bioinformatic meta-analysis of multiple nerve injury datasets confirmed Pdyn upregulation in DRG across different nerve injury models. These data support the idea that activation of endogenous opioids, notably dynorphin, is a dynamic indicator of persistent pain states in spinal cord and of nerve injury in DRG.PerspectiveThis is a systematic, quantitative assessment of dynorphin and enkephalin peptides and mRNA in dorsal spinal cord and DRG neurons in response to peripheral inflammation and axotomy. These studies form the foundational framework for understanding how endogenous spinal opioid peptides are involved in nociceptive circuit modulation.     

大鼠脊髓损伤后运动功能的恢复及前角运动神经元功能的改变

目的观察大鼠不同方式脊髓损伤后损伤下段脊髓前角运动神经元内降钙素基因相关肽（CGRP）与乙酰胆碱酯酶（AChE）的变化,并对损伤后后肢运动功能的恢复情况进行比较。方法60只成年Wistar大鼠随机分为假手术组、切割型脊髓损伤组和撞击型脊髓损伤组,采用联合均分（ACOS）神经行为学评定观察损伤后大鼠运动功能的恢复,术后1、2、4、10周,用Karnovsky-Roots直接法染色检测L2～L4段脊髓AChE、免疫组化方法检测CGRP的水平。结果术后1～10周内,撞击组大鼠ACOS得分明显高于切割组,两损伤组大鼠术后前角运动神经元CGRP和AChE的含量均下降,但撞击组10周时有了明显恢复,而切割组一直处于较低水平,且CGRP的改变早于AChE。结论在大鼠不同脊髓损伤后,运动功能变化与前角运动神经元的功能状态具有一定联系;CGRP和AChE可能在对脊髓损伤后运动功能的恢复中起一定作用。     

氯诺昔康对手术致痛大鼠脊髓背角COX-2表达的影响

目的：研究氯诺昔康对手术致痛大鼠脊髓背角COX-2表达的影响。方法：大鼠随机分为：对照组、模型组,三个氯诺昔康预处理模型组（制作手术致痛模型前20 min腹腔注射1、3、9 mg/kg）。3 h后,取出脊髓,采用免疫组化方法观察脊髓背角COX-2的表达。结果：模型组脊髓背角COX-2表达较强,而氯诺昔康可减少手术致痛引起的COX-2表达,并有量效关系。结论：氯诺昔康能对手术致痛引起脊髓背角COX-2的表达产生剂量依赖性的抑制作用。     

Ablating Spinal NK1-Bearing Neurons Eliminates the Development of Pain and Reduces Spinal Neuronal Hyperexcitability and Inflammation From Mechanical Joint Injury in the Rat

The facet joint is a common source of pain, especially from mechanical injury. Although chronic pain is associated with altered spinal glial and neuronal responses, the contribution of specific spinal cells to joint pain is not understood. This study used the neurotoxin [Sar⁹,Met(O₂)¹¹]-substance P-saporin (SSP-SAP) to selectively eliminate spinal cells expressing neurokinin-1 receptor (NK1R) in a rat model of painful facet joint injury to determine the role of those spinal neurons in pain from facet injury. Following spinal administration of SSP-SAP or its control (blank-SAP), a cervical facet injury was imposed and behavioral sensitivity was assessed. Spinal extracellular recordings were made on day 7 to classify neurons and quantify evoked firing. Spinal glial activation and interleukin 1αα (IL1α) expression also were evaluated. SSP-SAP prevented the development of mechanical hyperalgesia that is induced by joint injury and reduced NK1R expression and mechanically evoked neuronal firing in the dorsal horn. SSP-SAP also prevented a shift toward wide dynamic range neurons that is seen after injury. Spinal astrocytic activation and interleukin 1α (IL1α) expression were reduced to sham levels with SSP-SAP treatment. These results suggest that spinal NK1R-bearing cells are critical in initiating spinal nociception and inflammation associated with a painful mechanical joint injury.PerspectiveResults demonstrate that cells expressing NK1R in the spinal cord are critical for the development of joint pain, spinal neuroplasticity, and inflammation after trauma to the joint. These findings have utility for understanding mechanisms of joint pain and developing potential targets to treat pain.     

减重平板训练对脊髓损伤大鼠神经病理性疼痛及脊髓后角谷氨酸脱羧酶-65/67表达的影响

目的 探讨减重平板训练对脊髓损伤大鼠神经病理性疼痛及脊髓后角内谷氨酸脱羧酶-65/67(GAD-65/67)表达的影响.方法 将24只Sprague-Dawley大鼠随机分为假手术组(Sham组)、脊髓损伤-不运动组(SCI-Sed组)和脊髓损伤-运动组(SCI-Ex组),每组8只.采用Allen法制作T10不完全性脊...     

Intravenous Acetylsalicylic Acid Inhibits Central Trigeminal Neurons in the Dorsal Horn of the Upper Cervical Spinal Cord in the Cat

SYNOPSIS
Acetylsalicylic acid (ASA) is one of the most commonly used substances in the treatment of headache and other pain syndromes. It is only recently that its efficacy in the treatment of acute attacks and in the prophylaxis of migraine has been proven in clinical trials. Various peripheral and central mechanisms have been proposed for the analgesic effects of acetyl-salicylic acid and Its mode of action in migraine. The possible actions of acetylsalicylic acid in migraine include local analgesic effects, changes in cerebral serotonin turnover, modulation of antinociceptive neurons in the hypothalamus and inhibition of the release of algogenic peptides during neurogenic inflammation. In this study trigeminal somatosensory evoked potentials and single unit activity of central trigeminal neurons in the dorsolateral C₂ spinal cord were monitored during electrical stimulation of the superior sagittal sinus in the cat. Intravenous administration of the soluble acetylsalicylic salt (acetylsalicylic lysinate, 30mg/kg) reduced the peak-to-peak amplitudes of somatosensory evoked potentials from 219 ± 11mV by 18% after 45 minutes and by 26% after 60 minutes. Naloxone injection (0.5 mg/kg and 1.5 mg/kg) did not reverse the inhibition caused by ASA. The probability of trigeminal cell tiring was reduced in 63% percent of the monitored single units. The effect was not mediated through naloxone-sensitive opioid receptors and was independent from ASA-induced peripheral blockade of neuropeptides during neurogenic inflammation. The non-steroidal anti- inflammatory agent ketorolac (0.4mg/kg, IVI) a new cyclooxygenase inhibitor, also reduced the somatosensory evoked potentials by 30% following the same time course. The data suggest that ASA exerts inhibitory effects on central trigeminal neurons, possibly mediated through inhibition of prostaglandin synthesis and that these may be responsible for its effects in the treatment of migraine.     

Is Sleep Disordered Breathing Confounding Rehabilitation Outcomes in Spinal Cord Injury Research?

The purpose of this article is to highlight the importance of considering sleep-disordered breathing (SDB) as a potential confounder to rehabilitation research interventions in spinal cord injury (SCI). SDB is highly prevalent in SCI, with increased prevalence in individuals with higher and more severe lesions, and the criterion standard treatment with continuous positive airway pressure remains problematic. Despite its high prevalence, SDB is often untested and untreated in individuals with SCI. In individuals without SCI, SDB is known to negatively affect physical function and many of the physiological systems that negatively affect physical rehabilitation in SCI. Thus, owing to the high prevalence, under testing, low treatment adherence, and known negative effect on the physical function, it is contended that underdiagnosed SDB in SCI may be confounding physical rehabilitation research studies in individuals with SCI. Studies investigating the effect of treating SDB and its effect on physical rehabilitation in SCI were unable to be located. Thus, studies investigating the likely integrated relationship among physical rehabilitation, SDB, and proper treatment of SDB in SCI are needed. Owing to rapid growth in both sleep medicine and physical rehabilitation intervention research in SCI, the authors contend it is the appropriate time to begin the conversations and collaborations between these fields. We discuss a general overview of SDB and physical training modalities, as well as how SDB could be affecting these studies.     

Spinal Cord Injuries Containing Asymmetrical Damage in the Ventrolateral Funiculus Is Associated With a Higher Incidence of At-Level Allodynia

Approximately 70% of male rats receiving severe T8 spinal contusions develop allodynia in T5-7 dermatomes (at-level) beginning 2 weeks after injury. In contrast, rats having either complete transections or dorsal hemisections do not develop allodynia at-level after chronic spinal cord injury (SCI). In the present study, incomplete laceration and contusion injuries were made to test for neuroanatomical correlates between areas of white matter damage/sparing at the lesion epicenter and the presence/absence of allodynia. After incomplete laceration lesions and 6 weeks of behavioral testing, histological reconstruction and analysis of the lesion epicenters revealed a significant difference (P < .001) in the amount of ventrolateral funiculus (VLF) asymmetry between rats showing pain-like responses evoked by touch (74.5% ± 8.4% side-to-side difference in VLF damage) versus those not responding to touch (11.3% ± 4.4% side-to-side difference in VLF damage). A 5-week mean allodynia score for each rat that incorporates a full range of forces that are all innocuous in intact controls revealed that the degree of hypersensitivity at level is related to the extent of VLF asymmetry after SCI. No other damaged spinal white matter or gray matter area was correlated with sensitivity to touch. Similar findings were obtained for rats receiving T8 contusions, a more clinically relevant injury. These data suggest that different extents of damage/sparing between the 2 sides of VLF probably are a requisite for the development of allodynia after SCI.PerspectiveA side-to-side lesion asymmetry after chronic SCI in a rodent model was found to be highly correlated with the presence and degree of allodynia. Greater insight of key factors contributing to the development and maintenance of chronic neuropathic pain is important for improving quality of life.     

脊髓损伤后脊髓内神经递质含量的变化及其作用

脊髓损伤后脊髓内神经递质分泌量的变化在一定程度上影响脊髓损伤模型动物或患者神经功能恢复,近年来有关神经递质的研究在脊髓神经恢复中越来越受关注,本文对脊髓损伤后脊髓内主要神经递质及其在不同措施干预下含量的变化进行综述。     

Utilization of Complementary and Integrative Health Care by People With Spinal Cord Injury in the Spinal Cord Injury Model Systems: A Descriptive Study

ObjectiveTo characterize the use of complementary and integrative health care (CIH) by people with spinal cord injury.DesignCross-sectional self-report study.SettingParticipants were recruited from 5 Spinal Cord Injury Model Systems (SCIMS) centers across the United States.InterventionsNot applicable.ParticipantsA total of 411 persons enrolled in the SCIMS completing their SCIMS follow-up interview between January 2017 and July 2019 (N = 411).Main Outcome MeasuresParticipants completed a survey developed for this study that included questions about types of CIH currently and previously used, reasons for current and previous use, reasons for discontinuing use of CIH, and reasons for never using CIH since injury.ResultsOf the 411 respondents, 80.3% were current or previous users of CIH; 19.7% had not used CIH since injury. The most commonly used current types of CIH were multivitamins (40.0%) and massage (32.6%), whereas the most common previously used type of CIH was acupuncture (33.9%). General health and wellness (61.4%) and pain (31.2%) were the most common reasons for using CIH. The primary reason for discontinuing CIH was that it was not helpful (42.1%). The primary reason for not using CIH since injury was not knowing what options are available (40.7%).ConclusionsThese results point to the importance for rehabilitation clinicians to be aware that their patients may be using 1 or more CIH approaches. Providers should be open to starting a dialogue to ensure the health and safety of their patients because there is limited information on safety and efficacy of CIH approaches in this population. These results also set the stage for further analysis of this data set to increase our knowledge in this area.     

脊髓损伤后慢性中枢性疼痛大鼠VEGF及NOS的表达变化研究

目的探讨脊髓损伤后慢性中枢性疼痛VEGF和NOS表达变化。方法 120只大鼠随机分为单纯椎板切除组(对照组)、脊髓损伤组(损伤组)、脊髓损伤后法舒地尔治疗组(治疗组)。免疫组化检测脊髓损伤后1d、3d、7d、14d、21d的VEGF和NOS的表达;WB检测各组各个时间点VEGF的表达。结果 BBB评分:治疗组大鼠BBB评分明显优于损伤组,各组差异有统计学意义。免疫组化结果:脊髓损伤后VEGF的表达升高,于3d达到高峰,然后下降;治疗组VEGF的表达较损伤组降低,各组差异有统计学意义。脊髓损伤后NOS的表达升高,7d达到高峰,然后下降;治疗组NOS的表达较损伤组增高,各组差异有统计学意义。WB结果:脊髓损伤后VEGF的表达升高,于3d达到高峰,然后下降;治疗组VEGF的表达较损伤组降低,各组差异有统计学意义。结论法舒地尔可以下调脊髓损伤后慢性中枢性疼痛VEGF的表达并上调NOS的表达,促进病症恢复。     

脊髓损伤与胆石症关系的研究进展

脊髓损伤患者胆石症发生率较高,与胆囊的交感神经支配受损有关.脂餐试验常用于胆囊功能评价.本文就胆囊的神经支配、超声检测在胆囊功能评估中的应用及脊髓损伤与胆石症的关系作一综述.     

“三法三穴”推拿手法对坐骨神经损伤大鼠痛觉功能和脊髓背角CX3CL1/CX3CR1表达的调节

目的 通过观察脊髓背角趋化因子(C-X3-C基元)配体1 (CX3CL1)/趋化因子(C-X3-C基元)受体1 (CX3CR1)蛋白和mRNA表达变化,探讨“三法三穴”推拿手法对坐骨神经损伤大鼠痛觉功能改善的作用机制。方法 74只雄性Sprague-Dawley大鼠,随机分为正常组(n = 12)、假手术组(n = 24)、模型组(n = 25)和三法三穴组(n = 13)。模型组和三法三穴组制作坐骨神经损伤模型。假手术组仅暴露坐骨神经。三法三穴组造模后第7天起用按摩推拿手法模拟仪按摩殷门、承山、阳陵泉三穴。分别于造模后7 d、干预20 d进行光热耐痛阈测定;造模后7 d、干预10 d、干预20 d进行累积疼痛评分测定;并于造模后7 d和干预20 d取材,对脊髓背角CX3CL1/CX3CR1表达进行Western blotting和RT-PCR检测,干预20 d对脊髓背角小胶质细胞进行免疫荧光观察。结果 造模后7 d,与正常组比较,模型组和假手术组光热耐痛阈升高(P < 0.05);与假手术组比较,模型组和三法三穴组累积疼痛评分升高( P < 0.05);干预10 d后,三法三穴组累积疼痛评分低于模型组( P < 0.05);干预20 d后,三法三穴组光热耐痛阈和累积疼痛评分均低于模型组( P < 0.05)。造模后7 d和干预20 d后,各组CX3CL1/CX3CR1蛋白和mRNA的表达变化均无显著性差异( P > 0.05)。干预20 d后模型组小胶质细胞呈部分活化或完全活化状态,三法三穴组呈未活化或部分活化状态。 结论 “三法三穴”推拿手法对坐骨神经损伤大鼠痛觉功能有改善,可能是通过CX3CL1/CX3CR1以外的途径调节小胶质细胞实现的。     

Prevalence and Determinants of Pain in Spinal Cord Injury During Initial Inpatient Rehabilitation: Data From the Dutch Spinal Cord Injury Database

ObjectiveTo describe the prevalence and characteristics of spinal cord injury (SCI)-related pain during initial inpatient rehabilitation and to investigate relationships with demographic and lesion characteristics.DesignCohort during inpatient rehabilitation.SettingEight specialized SCI rehabilitation centers in the Netherlands.ParticipantsPatients with newly acquired SCI admitted for inpatient rehabilitation between November 2013 and August 2019 (N=1432).InterventionsNot applicable.Main Outcome MeasuresPresence of pain at admission and discharge. Logistic regression analyses were used to study the prevalence of pain related to sex, age, etiology, completeness, and level of injury.ResultsData from 1432 patients were available. Of these patients 64.6% were male, mean age was 56.8 years, 59.9% had a nontraumatic SCI, 63.9% were classified as American Spinal Cord Injury Association Impairment Scale (AIS) D and 56.5% had paraplegia. Prevalence of pain was 61.2% at admission (40.6% nociceptive pain [NocP], 30.2% neuropathic pain [NeuP], 5.4% other pain) and 51.5% at discharge (26.0% NocP, 31.4% NeuP, 5.7% other pain). Having NocP at admission was associated with traumatic SCI. AIS B had a lower risk of NocP than AIS D at admission. Having NocP at discharge was associated with female sex and traumatic SCI. AIS C had a lower risk of NocP at discharge than AIS D. Having NeuP at admission was associated with female sex. Having NeuP at discharge was associated with female sex, age younger than 65 years vs age older than 75 years and tetraplegia.ConclusionsSCI-related pain is highly prevalent during inpatient rehabilitation. Prevalence of NocP decreased during inpatient rehabilitation, and prevalence of NeuP stayed the same. Different patient and lesion characteristics were related to the presence of SCI-related pain. Healthcare professionals should be aware of these differences in screening patients on presence and development of pain during inpatient rehabilitation.