Reopening of ATP-sensitive potassium channels reduces neuropathic pain and regulates astroglial gap junctions in the rat spinal cord

Adenosine triphosphate–sensitive potassium (K_ATP) channels are suggested to be involved in pathogenesis of neuropathic pain, but remain underinvestigated in primary afferents and in the spinal cord. We examined alterations of K_ATP channels in rat spinal cord and tested whether and how they could contribute to neuropathic pain. The results showed that protein expression for K_ATP channel subunits SUR1, SUR2, and Kir6.1, but not Kir6.2, were significantly downregulated and associated with thermal hyperalgesia and mechanical allodynia after sciatic nerve injury. Spinal administration of a K_ATP channel opener cromakalim (CRO, 5, 10, and 20 μg, respectively) prevented or suppressed, in a dose-dependent manner, the hyperalgesia and allodynia. Nerve injury also significantly increased expression and phosphorylation of connexin 43, an astroglial gap junction protein. Such an increase of phosphorylation of connexin 43 was inhibited by CRO treatment. Furthermore, preadministration of an astroglial gap junction decoupler carbenoxolone (10 μg) completely reversed the inhibitory effects of CRO treatment on the hyperalgesia and allodynia and phosphorylation of NR1 and NR2B receptors and the subsequent activation of Ca²⁺-dependent signals Ca²⁺/calmodulin-dependent kinase II and cyclic adenosine monophosphate (cAMP) response element binding protein. These findings suggest that nerve injury–induced downregulation of the K_ATP channels in the spinal cord may interrupt the astroglial gap junctional function and contribute to neuropathic pain, thus the K_ATP channels opener can reduce neuropathic pain probably partly via regulating the astroglial gap junctions. This study may provide a new strategy for treating neuropathic pain using K_ATP channel openers in the clinic.     

脊髓损伤患者神经病理性疼痛现况调查及相关影响因素分析

目的 调查脊髓损伤患者神经病理性疼痛（NP）现况,并分析其相关影响因素。 方法 先用DN4量表在所有诊断为脊髓损伤的患者中筛选出伴有NP的患者,搜集70例脊髓损伤伴NP患者的性别、年龄、文化程度、职业、平均月收入、损伤部位、婚姻状态等一般调查资料,然后再对筛选出来的患者用简化的McGill疼痛问卷表（SF-MPQ）进行NP现况调查,记录患者的疼痛目测类比法（VAS）评分以及疼痛评级指数(PRI),包括PRI-感觉项、PRI-情感项及PEI等平均得分;采用SPSS13.0统计软件对患者的基本资料进行单因素和多因素统计分析,分析患者NP的影响因素。 结果 ①患者的平均疼痛目测类比法（VAS）评分4.37分;SF-MPQ调查的平均PRI得分8.23分,PRI-感觉项平均得分5.2 3分,PRI-情感项平均得分3.00分;现在疼痛强度(PPI)平均程度为1.86,PPI介于轻痛和难受之间,PPI中出现最多的是难受这个描述词。疼痛描述词按出现频率排在前三位的是刺痛、烧灼痛和坠胀痛。有60例（85.7%）患者认为疼痛对其情感状态造成影响,出现最多的是疲惫耗竭感这个描述词。②单因素分析显示损伤程度、文化程度、婚姻状况、家庭人均月收入、家人支持与否以及是否用药是NP的影响因素（P<0.01）,而性别、年龄、病程、损伤部位、职业等因素与VAS评分无明显相关性（P>0.05）;多因素Logistic回归分析显示,未婚、损伤程度重为NP的独立保护因素（OR＜1）,家庭人均月收入低、没有家人支持、没有用药为NP的独立危险因素（OR＞1）。 结论 脊髓损伤患者NP感觉多样,疼痛程度中等,绝大多数患者情感状态受到影响;未婚和损伤程度重为独立保护因素,家庭人均月收入低、没有家人支持及没有用药为其独立危险因素。     

Calcium channel alpha-2-delta-1 protein upregulation in dorsal spinal cord mediates spinal cord injury-induced neuropathic pain states

Spinal cord injury (SCI) commonly results in the development of neuropathic pain, which can dramatically impair the quality of life for SCI patients. SCI-induced neuropathic pain can be manifested as both tactile allodynia (a painful sensation to a non-noxious stimulus) and hyperalgesia (an enhanced sensation to a painful stimulus). The mechanisms underlying these pain states are poorly understood. Clinical studies have shown that gabapentin, a drug that binds to the voltage-gated calcium channel alpha-2-delta-1 subunit (Ca_vα2δ-1) proteins is effective in the management of SCI-induced neuropathic pain. Accordingly, we hypothesized that tactile allodynia post SCI is mediated by an upregulation of Ca_vα2δ-1 in dorsal spinal cord. To test this hypothesis, we examined whether SCI-induced dysregulation of spinal Ca_vα2δ-1 plays a contributory role in below-level allodynia development in a rat spinal T9 contusion injury model. We found that Ca_vα2δ-1 expression levels were significantly increased in L4-6 dorsal, but not ventral, spinal cord of SCI rats that correlated with tactile allodynia development in the hind paw plantar surface. Furthermore, both intrathecal gabapentin treatment and blocking SCI-induced Ca_vα2δ-1 protein upregulation by intrathecal Ca_vα2δ-1 antisense oligodeoxynucleotides could reverse tactile allodynia in SCI rats. These findings support that SCI-induced Ca_vα2δ-1 upregulation in spinal dorsal horn is a key component in mediating below-level neuropathic pain states, and selectively targeting this pathway may provide effective pain relief for SCI patients.     

Combined approaches for the relief of spinal cord injury-induced neuropathic pain

The adequate treatment of spinal cord injury (SCI)-induced neuropathic pain still remains an unresolved problem. The current medications predominantly used in the SCI-induced neuropathic pain therapy are morphine, anticonvulsants, antidepressants, and antiepileptics, which suggests that psychiatric aspects might be important factors in the treatment of neuropathic pain.It is well documented that the modulation of the sensory events is not a unique way for achieving pain relief. In addition, pain patients still express dissatisfaction and complain of unwanted effects of the medications, suggesting that alternative approaches for the treatment of neuropathic pain are essential. In psychiatry, pain relief represents relaxation and a feeling of comfort and satisfaction, which suggests that cognitive and emotional motivations are important factors in the treatment of neuropathic pain. The comorbidity of chronic pain and psychiatric disorders, which is well recognized, suggests that the effective therapeutic relief for neuropathic pain induced by SCI can be achieved in conjunction with the management of the sensory and psychiatric aspects of patient.In this review, we address the feasibility of a combined acupuncture and pharmacotherapy treatment for the relief of neuropathic pain behavior following SCI.     

Loss of calcineurin in the spinal dorsal horn contributes to neuropathic pain,and intrathecal administration of the phosphatase provides prolonged analgesia

Calcineurin (protein phosphatase 3) regulates synaptic plasticity in the brain. The development of neuropathic pain appears dependent on some of the same mechanisms that underlie brain synaptic plasticity. In this study, we examined whether calcineurin regulates chronic constriction injury (CCI)-elicited plasticity in the spinal dorsal horn. CCI animals exhibited mechanical and thermal hypersensitivity 7 days after ligation of the sciatic nerve. Neither control uninjured nor sham-operated animals exhibited pain behavior. Calcineurin activity and content of its Aα isoform were significantly decreased in the ipsilateral postsynaptic density (PSD) of dorsal horn neurons in CCI animals. Calcineurin activity and content in the contralateral PSD of CCI animals or either side of the dorsal horn in sham animals were not modified. The pain behavior in CCI animals was attenuated by intrathecal application of exogenous calcineurin. The treatment was long-lasting as a single injection provided analgesia for 4 days by restoring the phosphatase’s activity and Aα content in the PSD. No signs of toxicity were detected up to 14 days after the single intrathecal injection. Intrathecal application of the calcineurin inhibitor FK-506 elicited pain behavior in control uninjured animals and significantly reduced calcineurin activity in the PSD. CCI may elicit neuropathic pain at least in part as a result of the loss of calcineurin-mediated dephosphorylation in the dorsal horn. Addition of the phosphatase by intrathecal injection reverses the injury-elicited loss and provides prolonged pain relief. Clinical therapy with calcineurin may prove to be a novel, effective, and safe approach in the management of well-established neuropathic pain.     

Functional MRI of the brain detects neuropathic pain in experimental spinal cord injury

Functional magnetic resonance imaging (fMRI) has been used to map cerebral activations related to nociceptive stimuli in rodents. Here, we used fMRI to investigate abnormally increased responses to noxious or innocuous stimuli, in a well-established rat model of chronic neuropathic pain induced by photochemical lumbar spinal cord injury. In this model, a subpopulation of rats exhibits allodynia-like hypersensitivity to mechanical and cold stimulation of the trunk area. In those rats that do not develop overt hypersensitivity after identical spinal cord injury (i.e. non-hypersensitive rats), touch evoked pain can be triggered by the opioid receptor antagonist, naloxone. We show that cerebral activations in contralateral primary somatosensory cortex (SI) are markedly correlated with different behavioural characteristics of these animals. Identical electrical stimulation, applied on trunks of spinally injured hypersensitive and non-hypersensitive rats, evoked significantly higher responses in SI of the former than the latter. Although levels of fMRI signals in SI of the trunk territory were not significantly different between normal and spinally injured non-hypersensitive rats, the administration of naloxone significantly increased fMRI signals in the non-hypersensitive rats, but not in the normal rats. We conclude that increased activation of contralateral SI is a key feature of behavioural neuropathic pain in spinally injured rats and that fMRI is an effective method to monitor experimental neuropathic pain in small animals.     

Injury discharges regulate calcium channel alpha-2-delta-1 subunit upregulation in the dorsal horn that contributes to initiation of neuropathic pain

Previous studies have shown that peripheral nerve injury in rats induces increased expression of the voltage gated calcium channel (VGCC) alpha-2-delta-1 subunit (Ca v alpha2 delta1) in spinal dorsal horn and sensory neurons in dorsal root ganglia (DRG) that correlates to established neuropathic pain states. To determine if injury discharges trigger Ca v alpha2 delta1 induction that contributes to neuropathic pain initiation, we examined allodynia onset and Ca v alpha2 delta1 levels in DRG and spinal dorsal horn of spinal nerve ligated rats after blocking injury induced neural activity with a local brief application of lidocaine on spinal nerves before the ligation. The lidocaine pretreatment blocked ligation-induced discharges in a dose-dependent manner. Similar pretreatment with the effective concentration of lidocaine diminished injury-induced increases of the Ca v alpha2 delta1 in DRG and abolished that in spinal dorsal horn specifically, and resulted in a delayed onset of tactile allodynia post-injury. Both dorsal horn Ca v alpha2 delta1 upregulation and tactile allodynia in the lidocaine pretreated rats returned to levels similar to that in saline pretreated controls 2 weeks post the ligation injury. In addition, preemptive intrathecal Ca v alpha2 delta1 antisense treatments blocked concurrently injury-induced allodynia onset and Ca v alpha2 delta1 upregulation in dorsal spinal cord. These findings indicate that injury induced discharges regulate Ca v alpha2 delta1 expression in the spinal dorsal horn that is critical for neuropathic allodynia initiation. Thus, preemptive blockade of injury-induced neural activity or Ca v alpha2 delta1 upregulation may be a beneficial option in neuropathic pain management.     

Peripheral nerve injury produces a sustained shift in the balance between glutamate release and uptake in the dorsal horn of the spinal cord

Peripheral nerve injury provokes heightened excitability of primary sensory afferents including nociceptors, and elicits ectopic activity in lesioned and neighboring intact nerve fibers. The major transmitter released by sensory afferents in the superficial dorsal horn of the spinal cord is glutamate. Glutamate is critically involved in nociceptive signaling and the development of neuropathic pain. We recorded miniature excitatory postsynaptic currents (mEPSCs) from neurons in lamina II of the rat dorsal horn to assess spontaneous synaptic activity after spared nerve injury (SNI), a model of chronic neuropathic pain. Following SNI, the frequency of mEPSCs doubled, indicating heightened glutamate release from primary afferents or spinal interneurons. Consistent with this finding, glutamate concentrations in the cerebrospinal fluid were elevated at 1 and 4 weeks after SNI. Transmitter uptake was insufficient to prevent the rise in extracellular glutamate as the expression of glutamate transporters remained unchanged or decreased. 2-Methyl-6-(phenylethynyl)pyridine hydrochloride, an antagonist of metabotropic glutamate receptor 5 (mGluR5), reduced the frequency of mEPSCs to its preinjury level, suggesting a positive feedback mechanism that involves facilitation of transmitter release by mGluR5 activation in the presence of high extracellular glutamate. Treatment with the β-lactam antibiotic ceftriaxone increased the expression of glutamate transporter 1 (Glt1) in the dorsal horn after SNI, raised transmitter uptake, and lowered extracellular glutamate. Improving glutamate clearance prevented the facilitation of transmitter release by mGluR5 and attenuated neuropathic pain-like behavior. Balancing glutamate release and uptake after nerve injury should be an important target in the management of chronic neuropathic pain.     

转运蛋白通过激活脊髓背角星形胶质细胞自噬缓解神经病理性疼痛

目的:探讨18kDa转运蛋白(translocator protein,TSPO)是否可以通过激活脊髓背角星形胶质细胞自噬来缓解神经病理性疼痛及其可能的机制.方法:实验分为两部分,第一部分将雄性SD大鼠按随机数字表法分为假手术组(Sham组)、对照组(SNL组)、TSPO受体激动剂Ro5-4864处理组(Ro组);第二...     

Spinal cord stimulation of dorsal columns in a rat model of neuropathic pain: evidence for a segmental spinal mechanism of pain relief

Although spinal cord stimulation (SCS) of the dorsal columns is an established method for treating chronic neuropathic pain, patients still suffer from a substantial level of pain. From a clinical perspective it is known that the location of the SCS is of pivotal importance, thereby suggesting a segmental spinal mode of action. However, experimental studies suggest that SCS acts also through the modulation of supraspinal mechanisms, which might suggest that the location is unimportant. Here we investigated the effect of the rostrocaudal location of SCS stimulation and the effectiveness of pain relief in a rat model of chronic neuropathic pain. Adult male rats (n = 45) were submitted to a partial ligation of the sciatic nerve. The majority of animals developed tactile hypersensitivity in the nerve lesioned paw. All allodynic rats were submitted to SCS (n = 33) for 30 minutes (f = 50 Hz; pulse width 0.2 ms). In one group (n = 16) the electrodes were located at the level where the injured sciatic nerve afferents enter the spinal cord (T13), and in a second group (n = 17) the electrodes were positioned at more rostral levels (T11) as verified by X-ray. A repositioning experiment of electrodes from T12 to T13 was performed in 2 animals. Our data demonstrate that SCS of the dorsal columns at the level where the injured fibers enter the spinal cord dorsal horn result in a much better pain-relieving effect than SCS at more rostral levels. From this we conclude that SCS in treatment of neuropathic pain acts through a segmental spinal site of action.     

EphrinB-EphB receptor signaling contributes to neuropathic pain by regulating neural excitability and spinal synaptic plasticity in rats

Bidirectional signaling between ephrins and Eph receptor tyrosine kinases was first found to play important roles during development, but recently has been implicated in synaptic plasticity and pain processing in the matured nervous system. We show that ephrinB-EphB receptor signaling plays a critical role is induction and maintenance of neuropathic pain by regulating neural excitability and synaptic plasticity in the dorsal root ganglion (DRG) and the spinal dorsal horn (DH). Intrathecal application of blocking reagents for EphB-receptors, EphB1-Fc and EphB2-Fc chimeras inhibits the induction and maintenance of nerve injury-induced thermal hyperalgesia and mechanical allodynia. These blockers also prevent and suppress the nerve injury-induced hyperexcitability of nociceptive small DRG neurons, sensitization of DH neurons and long-term potentiation (LTP) of synapses between C fibers and DH neurons. In naïve, uninjured animals intrathecal administration of EphB-receptor activators ephrinB1-Fc and ephrinB2-Fc, respectively, induces thermal hypersensitivity and lowers the threshold for LTP, while EphB1-Fc prevents induction of the LTP. Western Blot analysis shows that nerve injury triggers an upregulation of the ephrinB1 and EphB1 receptor proteins in DRG and the spinal cord. These results indicate that, by regulating excitability of nociceptive-related neurons in DRG and DH and the synaptic plasticity at the spinal level, ephrinB-EphB receptor signaling contributes to neuropathic pain. This novel role for ephrinB-EphB receptor signaling suggests that these molecules may be useful therapeutic targets for treating pain after nerve injury.     

Upregulation and redistribution of ephrinB and EphB receptor in dorsal root ganglion and spinal dorsal horn neurons after peripheral nerve injury and dorsal rhizotomy

EphrinB–EphB receptor signaling plays diverse roles during development, but recently has been implicated in synaptic plasticity in the matured nervous system and in pain processes. The present study investigated the correlation between expression of ephrinB and EphB receptor proteins and chronic constriction injury (CCI) of the sciatic nerve and dorsal rhizotomy (DR) in dorsal root ganglion (DRG) and spinal cord (SC); and interaction of CCI and DR on expression of these signals. Adult, male Sprague–Dawley rats were employed and thermal sensitivity was determined in the sham operated CCI and DR rats. Western blot and immunobiochemistry analysis and immunofluorescence staining techniques were used to detect the expression and location of the ephrinB–EphB receptor proteins in DRG and SC. The results showed that expression of ephrinB1 and EphB1 receptor proteins was significantly upregulated in DRG and SC in a time‐dependent manner corresponding to the development of thermal hyperalgesia after CCI. The increased expression is predominately located in the medium‐ and small‐sized DRG neurons, the superficial layers of spinal dorsal horn (DH) neurons, and the IB4 positive nociceptive terminals. DR increases ephrinB1 in DRG, not SC and EphB receptor in SC, not DRG. DR suppressed CCI‐induced upregulation of ephrinB1 in SC and EphB1 receptor in DRG and SC. These findings indicate that ephrinB–EphB receptor activation and redistribution in DRG and DH neurons after nerve injury could contribute to neuropathic pain. This study may also provide a new mechanism underlying DR‐induced analgesia in clinic.     

Spread of excitation across modality borders in spinal dorsal horn of neuropathic rats

Under physiological conditions, nociceptive information is mainly processed in superficial laminae of the spinal dorsal horn, whereas non-nociceptive information is processed in deeper laminae. Neuropathic pain patients often suffer from touch-evoked pain (allodynia), suggesting that modality borders are disrupted in their nervous system. We studied whether excitation evoked in deep dorsal horn neurons either via stimulation of primary afferent Abeta-fibres, by direct electrical stimulation or via glutamate microinjection leads to activation of neurons in the superficial dorsal horn. We used Ca(2+)-imaging in transversal spinal cord slices of neuropathic and control animals to monitor spread of excitation from the deep to the superficial spinal dorsal horn. In neuropathic but not control animals, a spread of excitation occurred from the deep to the superficial dorsal horn. The spread of excitation was synaptically mediated as it was blocked by the AMPA receptor antagonist CNQX. In contrast, block of NMDA receptors was ineffective. In control animals, the violation of modality borders could be reproduced by bath application of GABA(A) and glycine receptor antagonists. Furthermore, we could show that neuropathic animals were more prone to synchronous network activity than control animals. Thus, following peripheral nerve injury, excitation generated in dorsal horn areas which process non-nociceptive information can invade superficial dorsal horn areas which normally receive nociceptive input. This may be a spinal mechanism of touch-evoked pain.     

Thalamic activity and biochemical changes in individuals with neuropathic pain after spinal cord injury

There is increasing evidence relating thalamic changes to the generation and/or maintenance of neuropathic pain. We have recently reported that neuropathic orofacial pain is associated with altered thalamic anatomy, biochemistry, and activity, which may result in disturbed thalamocortical oscillatory circuits. Despite this evidence, it is possible that these thalamic changes are not responsible for the presence of pain per se, but result as a consequence of the injury. To clarify this subject, we compared brain activity and biochemistry in 12 people with below-level neuropathic pain after complete thoracic spinal cord injury with 11 people with similar injuries and no neuropathic pain and 21 age- and gender-matched healthy control subjects. Quantitative arterial spinal labelling was used to measure thalamic activity, and magnetic resonance spectroscopy was used to determine changes in neuronal variability quantifying N-acetylaspartate and alterations in inhibitory function quantifying gamma amino butyric acid. This study revealed that the presence of neuropathic pain is associated with significant changes in thalamic biochemistry and neuronal activity. More specifically, the presence of neuropathic pain after spinal cord injury is associated with significant reductions in thalamic N-acetylaspartate, gamma amino butyric acid content, and blood flow in the region of the thalamic reticular nucleus. Spinal cord injury on its own did not account for these changes. These findings support the hypothesis that neuropathic pain is associated with altered thalamic structure and function, which may disturb central processing and play a key role in the experience of neuropathic pain.     

Neuropathic pain- and glial derived neurotrophic factor-associated regulation of cadherins in spinal circuits of the dorsal horn

Neuropathic pain is associated with reorganization of spinal synaptic circuits, implying that adhesion proteins that normally build and modify synapses must be involved. The adhesion proteins E- and N-cadherin delineate different synapses furnished by nociceptive primary afferents, but dynamic aspects of cadherin localization in relationship to onset, maintenance or reversibility of neuropathic pain are uncharacterized. Here, we find very different responses of these cadherins to L5 spinal nerve transection (SNT)-induced mechanical allodynia and to intrathecal glial derived neurotrophic factor (GDNF), which has potent analgesic effects in this pain model. In L5, E-cadherin is rapidly eliminated in patches within lamina IIi contemporaneously with the onset of mechanical allodynia. Intrathecal GDNF in conjunction with, or at 7 days after, L5 SNT prevents or reverses both the loss of E-cadherin and abnormal pain sensation. In contrast, N-cadherin undergoes a delayed and transient increase uniformly across lamina I-II that is insensitive to GDNF. Some N-cadherin-labeled profiles codistribute with GAP-43, suggesting a role in axon sprouting. Patterns of immunolabeling for GDNF receptor components GFRα1, NCAM, and RET after L5 SNT suggest that GFRα1 and NCAM are the principal receptors operative in this model. In addition, GFRα1 codistributes with E-cadherin, but not N-cadherin, profiles. Together, these data indicate strikingly divergent patterns of temporal and molecular regulation of different cadherins at distinct nociceptive circuits in response to spinal nerve injury, suggesting that the two cadherins and the circuits with which they are affiliated participate in different aspects of synaptic and circuit reorganization associated with neuropathic pain.     

脊髓损伤后慢性中枢性疼痛与脊髓背角P物质关系研究

目的探讨脊髓损伤 (SCI)后慢性中枢性疼痛 (CCP)与P物质的关系。方法选取SD大鼠 2 8只 ,分为正常组 (A组 )、假手术组 (B组 ) ,以及用WADE法复制出SCI后无CCP组 (C组 )和CCP组 (D组 )。取大鼠T13 和L2 脊髓节段 ,采用免疫荧光组织化学染色法结合激光共聚焦显微镜技术观察脊髓背角P物质 (SP)的变化。结果各组大鼠T13 和L2 节段脊髓背角SP含量比较为 :D组较C组减少 (P <0 .0 5 ) ,较A组和B组明显减少 (P <0 .0 1) ;C组较A组和B组减少 (P <0 .0 5 ) ;A组与B组无显著性差异。结论SCI后CCP大鼠脊髓背角SP可能对CCP有某种程度的抑制作用。     

Ankle joint mobilization reduces axonotmesis-induced neuropathic pain and glial activation in the spinal cord and enhances nerve regeneration in rats

An important issue in physical rehabilitation is how to protect from or to reduce the effects of peripheral nerve injury. In the present study, we examined whether ankle joint mobilization (AJM) would reduce neuropathic pain and enhance motor functional recovery after nerve injury. In the axonotmesis model, AJM during 15 sessions every other day was conducted in rats. Mechanical and thermal hyperalgesia and motor performance deficit were measured for 5 weeks. After 5 weeks, we performed morphological analysis and quantified the immunoreactivity for CD11b/c and glial fibrillary acidic protein (GFAP), markers of glial activation, in the lumbar spinal cord. Mechanical and thermal hyperalgesia and motor performance deficit were found in the Crush + Anesthesia (Anes) group (P < 0.001), which was significantly decreased after AJM (P < 0.001). In the morphological analysis, the Crush + Anes group presented reduced myelin sheath thickness (P < 0.05), but the AJM group presented enhanced myelin sheath thickness (P < 0.05). Peripheral nerve injury increased the immunoreactivity for CD11b/c and GFAP in the spinal cord (P < 0.05), and AJM markedly reduced CD11b/c and GFAP immunoreactivity (P < 0.01). These results show that AJM in rats produces an antihyperalgesic effect and peripheral nerve regeneration through the inhibition of glial activation in the dorsal horn of the spinal cord. These findings suggest new approaches for physical rehabilitation to protect from or reduce the effects of nerve injury.     

Metabolite concentrations in the anterior cingulate cortex predict high neuropathic pain impact after spinal cord injury

Persistent pain is a common reason for reduced quality of life after a spinal cord injury (SCI). Biomarkers of neuropathic pain may facilitate translational research and the understanding of underlying mechanisms. Research suggests that pain and affective distress are anatomically and functionally integrated in the anterior cingulate cortex and can modulate sensory and affective aspects of pain. We hypothesized that severe neuropathic pain with a significant psychosocial impact would be associated with metabolite concentrations (obtained by magnetic resonance spectroscopy) in the anterior cingulate cortex, indicating neuronal and/or glial dysfunction. Participants with SCI and severe, high-impact neuropathic pain (SCI-HPI; n = 16), SCI and moderate, low-impact neuropathic pain (SCI-LPI; n = 24), SCI without neuropathic pain (SCI-noNP; n = 14), and able-bodied, pain-free control subjects (A-B; n = 22) underwent a 3-T magnetic resonance imaging brain scan. Analyses revealed that the SCI-HPI group had significantly higher levels of myoinositol (Ins) (P < .000), creatine (P = .007), and choline (P = .014), and significantly lower levels of N-acetyl aspartate/Ins (P = .024) and glutamate-glutamine (Glx)/Ins (P = .003) ratios than the SCI-LPI group. The lower Glx/Ins ratio significantly discriminated between SCI-HPI and the A-B (P = .006) and SCI-noNP (P = .026) groups, displayed excellent test-retest reliability, and was significantly related to greater pain severity, interference, and affective distress. This suggests that the combination of lower glutamatergic metabolism and proliferation of glia and glial activation are underlying mechanisms contributing to the maintenance of severe neuropathic pain with significant psychosocial impact in chronic SCI. These findings indicate that the Glx/Ins ratio may be a useful biomarker for severe SCI-related neuropathic pain with significant psychosocial impact.     

重复经颅磁刺激联合针刺治疗脊髓损伤后神经病理性疼痛的临床研究

目的：观察重复经颅磁刺激（rTMS）联合针刺治疗脊髓损伤（SCI）后神经病理性疼痛（NP）的临床疗效。方法：按随机数字表法将99例SCI后NP患者分成对照组、针刺组和联合组,各33例。对照组进行常规基础治疗,针刺组在对照组基础上进行针刺治疗,联合组在针刺组基础上进行rTMS治疗。分别于治疗前及治疗6周后对3组患者进行视觉模拟量表（VAS）、汉密顿抑郁量表（HAMD）、汉密顿焦虑量表(HAMA)及生活质量SF-36量表评估。结果：治疗6周后,3组患者VAS、HAMD和HAMA评分较治疗前均明显降低（P＜0.05）,SF-36量表各项评分较治疗前均明显升高（P＜0.05）;针刺组VAS、HAMD和HAMA评分较对照组均有降低（P＜0.05）,SF-36量表各项评分较对照组均有升高（P＜0.05）;联合组VAS、HAMD和HAMA评分较针刺组和对照组均有降低（P＜0.05）,SF-36量表各项评分较针刺组和对照组均有升高（P＜0.05）。结论：rTMS联合针刺治疗SCI后NP患者,有助于改善患者临床疼痛现象,且在改善患者情绪和生活质量方面疗效显著。     

Interference due to pain following spinal cord injury: important predictors and impact on quality of life

Two studies were designed to examine important predictors of pain following spinal cord injury (SCI), and the impact of pain on self-reported quality of life (QOL). Pain was defined as ‘interference in day-to-day activities secondary to pain’. In order to determine risk factors associated with the development of pain interference, Study 1 examined the predictive validity of multiple demographic, medical, and QOL variables at year 1 post-SCI to self-reported pain interference 2 years post-injury. Results showed that middle age (30–59-year-olds), lower self-reported mental health, and pain interference at 1 year post-SCI were the most important unique predictors of pain interference 2 years post-SCI. In Study 2, participants were separated into four groups; (1) those pain-free at years 1 and 2, (2) those pain-free at year 1 and in pain at year 2, (3) those in pain at year 1 and pain-free at year 2, and (4) those in pain at years 1 and 2. Results showed that only those experiencing a change in pain interference status reported a change in QOL. More specifically, those developing pain interference (group 2) from year 1 to year 2 reported decreased life satisfaction, physical health, and mental health, whereas, those with resolving pain interference from year 1 to year 2 reported an increase in these same domains. Unexpectedly, change in pain interference status was unrelated to change in self-reported handicap. Implications and future directions are discussed.