Effects of vitamin D administration on nociception and spinal cord pro-oxidant and antioxidant markers in a rat model of neuropathic pain

Reactive oxygen species (ROS) are involved in neuropathic pain, a complicated condition after nerve tissue lesion. Vitamin D appears to improve symptoms of pain and exhibits antioxidant properties. We investigated the effects of oral administration of vitamin D₃, the active form of vitamin D, on nociception, the sciatic functional index (SFI), and spinal cord pro-oxidant and antioxidant markers in rats with chronic constriction injury (CCI) of the sciatic nerve, a model of neuropathic pain. Vitamin D₃ (500 IU/kg per day) attenuated the CCI-induced decrease in mechanical withdrawal threshold and thermal withdrawal latency (indicators of antinociception) and SFI. The vitamin prevented increased lipid hydroperoxide levels in injured sciatic nerve without change to total antioxidant capacity (TAC). Vitamin D₃ prevented increased lipid hydroperoxide, superoxide anion generation (SAG), and hydrogen peroxide (H₂O₂) levels in the spinal cord, which were found in rats without treatment at 7 and 28 days post-CCI. A significant negative correlation was found between mechanical threshold and SAG and between mechanical threshold and H₂O₂ at day 7. Vitamin D₃ also prevented decreased spinal cord total thiols content. There was an increase in TAC in the spinal cord of vitamin-treated CCI rats, compared to CCI rats without treatment only at 28 days. No significant changes were found in body weight and blood parameters of hepatic and renal function. These findings demonstrated, for first time, that vitamin D modulated pro-oxidant and antioxidant markers in the spinal cord. Since antinociception occurred in parallel with oxidative changes in the spinal cord, the oxidative changes may have contributed to vitamin D-induced antinociception.     

Effects of repeated administered ghrelin on chronic constriction injury of the sciatic nerve in rats

Chronic constriction injury (CCI) is a peripheral mononeuropathic pain model that is caused by an injury to the peripheral nervous system and refractory to available conventional treatment. Mechanisms involved in neuropathic pain are still unclear. Previous studies reveal that proinflammatory cytokines contribute to CCI-induced peripheral nerve pathology. Ghrelin, a novel identified gastric peptide, has been shown to have antinociceptive activity and also anti-inflammatory properties by decreasing proinflammatory cytokines. Therefore, the aim of the present study was to investigate the effects of ghrelin on the CCI and its relationship with proinflammatory cytokines in rats. Wistar rats underwent sciatic nerve ligation to induce CCI fallowed by repeated ghrelin administrations (50 and 100 μg/kg i.p., once daily) for a period of 14 days. Mechanical hyperalgesia was assessed before surgery and at day 14 after CCI. TNF-α, IL-1β and IL-6 were measured in blood and spinal cord. The changes of sciatic nerve was assessed histologically by both light and electron microscopy. Ghrelin attenuated mechanical hyperalgesia, reduced spinal TNF-α and IL-1β levels and enhanced sciatic nerve injury with correlated morphometric recovery. These results indicate that the protective effect by ghrelin in the spinal cord is mediated through the suppression of TNF-α and IL-1β. Thus ghrelin may be a promising peptide in the management of neuropathic pain.     

Neuropathic pain in aged rats: behavioral responses and astrocytic activation

We used the Bennett and Xie (1988) model of chronic neuropathic pain to study the effect of age on thermal and tactile sensitivity and on astrocytic activation in the dorsal horn of the spinal cord after nerve injury. Fischer 344 FBNF1 hybrid rats in three age groups, 4-6, 14-16, and 24-26 months, were studied. Rats were either unligated (day 0, control) or the left sciatic nerve was loosely ligated to cause a chronic constriction injury (CCI). CCI causes a neuropathic pain condition characterized by tactile allodynia and thermal hyperalgesia. Rats were behaviorally assessed for tactile and thermal sensitivity of their ligated and unligated hind paws up to 35 days postligation. Rats were sacrificed before or at various days postligation, and activated astrocytes were identified at the L4-L5 levels of their spinal cords by use of an antibody to glial fibrillary acid protein (GFAP). The number of GFAP-ir astrocytes in the dorsal horn of the spinal cord in the control, uninjured condition decreased with age (P < or = 0.001) but increased after CCI in all three age groups. After CCI, astrocytic activation in the cord was less robust in aged rats than in younger ones (P < or = 0.01). Not all the CCI rats displayed hyperalgesia to touch and to heat. Rats with an increased sensitivity to heat had increased levels of GFAP-ir in their cords; however, rats with decreased thermal sensitivity also displayed increased GFAP-ir. Thus the presence of activated astrocytes was not correlated with a single behavioral manifestation of neuropathic pain.     

Changes in neuropeptide Y gene expression in the spinal cord of chronic constrictive injury model rats after electroconvulsive stimulation

Some reports have shown that electroconvulsive shock therapy (ECT) is effective for treating refractory neuropathic pain. However, its mechanism of action remains unknown. We have previously shown that electroconvulsive shock (ECS) improved thermal hypersensitivity in chronic constrictive injury (CCI) model rats and simultaneously elevated the neuropeptide Y (NPY) expression in the brain of these rats. In this study, we examined changes in the expression of NPY in the spinal cord of a CCI model. The rat model of CCI was established by ligating the left sciatic nerve. ECS was administered to the rats once daily for six days on days 7-12 after the operation using an electrical stimulator. RT-PCR was used to measure NPY mRNA expression in both the right and left L5 dorsal spinal cords on the 14th day after the operation. NPY gene expression was decreased in the dorsal spinal cords after ECS; however, no differences in NPY expression were observed between the right and left side of dorsal spinal cords, suggesting that the effect of changes in NPY expression after ECS on the improvement of neuropathic pain is not directly related to the spinal cord, but mainly to the upper central nerves.     

医用臭氧通过下调神经病理性痛大鼠核因子κB/核因子κB抑制蛋白α/核因子κB抑制蛋白激酶β的表达发挥镇痛效应

目的观察医用臭氧(OZ)对坐骨神经慢性缩窄性损伤(CCI)致神经病理性痛大鼠的镇痛作用及对核因子κB(NF-κB)、核因子κB抑制蛋白α(IκBα)及核因子κB抑制蛋白激酶β(IKKβ)表达水平的影响。方法采用CCI法复制大鼠神经病理性痛动物模型,同时给予不同剂量(0.8、0.4、0.2ml)的OZ予以干预,用Von Frey纤维丝机械刺激触痛仪及冷板测痛仪测定不同剂量OZ对CCI大鼠的机械缩足反射阈值与冷缩足反射阈值的影响;用RT-PCR法和Western blotting法检测不同剂量OZ对CCI大鼠脊髓组织NF-κB p65、IκBα及IKKβmRNA和蛋白表达水平的影响。结果与CCI神经病理性痛模型组比较,OZ 0.8、0.4ml剂量升高CCI大鼠机械缩足反射阈值,降低冷缩足反射阈值(P0.05,P0.01);OZ 0.8、0.4ml剂量可下调CCI大鼠脊髓组织NF-κB p65、IκBα及IKKβmRNA和蛋白表达水平(P0.05,P0.01)。结论 OZ对CCI致神经病理性痛大鼠有镇痛作用,其机制可能与下调NF-κB p65、IκBα及IKKβ的表达有关。     

氯胺酮鞘内给药对神经病理性痛大鼠脊髓背角小胶质细胞活化、TNF-α和IL-1β产生的影响

目的:探究鞘内注射氯胺酮(ketamine,KTM)对坐骨神经结扎(CCI)神经病理性疼痛大鼠模型行为、脊髓背角肿瘤坏死因子-α(TNF-α)和白介素1β(IL-1β)以及小胶质细胞标记蛋白OX42表达的影响。方法:(1)建立CCI模型大鼠,鞘内注射KTM或MI(米诺四环素)进行干预,测定大鼠机械缩足阈值(MWT)和热缩足潜伏期(TWL)。(2)运用ELISA法检测TNF-α和IL-1β表达水平。(3)使用Western Blot法检测OX42的表达情况。结果:(1)KTM组和MI组大鼠MWT和TWL值较CCI组显著升高;KTM组大鼠MWT和TWL值高于CCI组(P0.05)。(2)KTM组和MI组TNF-α和IL-1β表达水平低于CCI组(P0.05);其中KTM组TNF-α和IL-1β表达水平显著高于MI组(P0.05)。(3)KTM组和MI组OX42表达水平显著低于CCI组;KTM组OX42表达水平高于MI组(P0.05)。结论:鞘内KTM可以抑制脊髓背角小胶质细胞激活,减少TNF-α和IL-1β表达,显著改善坐骨神经结扎引起的神经病理性疼痛。     

Transient early expression of TNF-alpha in sciatic nerve and dorsal root ganglia in a mouse model of painful peripheral neuropathy

The proinflammatory cytokine tumor necrosis factor-alpha (TNF) is an important mediator in neuropathic pain. We investigated the temporal pattern of TNF mRNA expression in the sciatic nerve, in dorsal root ganglia (DRG) and spinal cord in the mouse chronic constriction injury model of neuropathy with quantitative real-time polymerase chain reaction. Neuropathic pain-like behaviour was monitored by evaluating thermal hyperalgesia and mechanical allodynia. Pain-related behaviour and TNF expression were evaluated 6 h, 1, 3, 7 and 14 days after injury. Naive animals and sham-operated mice were used as controls. We found an early upregulation of sciatic nerve TNF mRNA levels in chronic constriction injury (CCI) and sham-operated animals 6 h after surgery: 1 day later TNF overexpression was present in CCI mice only and disappeared 3 days after injury. The mRNA cytokine levels were elevated in DRG 1 and 3 days after surgery in CCI animals only, while the cytokine was not modulated in the spinal cord. A significant hyperalgesia was present in CCI and sham-operated mice at 6 h and 1 day, while at later time point only CCI mice presented lower thresholds. Mechanical allodynia was already present only in CCI animals 6 h from surgery and remained constant up to the 14 th day. The results indicate that a transient early TNF upregulation takes place in peripheral nervous system after CCI that can activate a cascade of proinflammatory/pronociceptive mediators.     

Noradrenergic and opioidergic alterations in neuropathy in different rat strains

The Fischer 344 (F344) rat strain differs from the Lewis strain in the response to neuropathic pain. Recently, we found that F344 rats totally recover from mechanical allodynia induced by chronic constriction injury (CCI) of the sciatic nerve 28 days after surgery whereas Lewis rats are initiating their recovery at this time point. Thus, the use of this neuropathic pain model in these different rat strains constitutes a good strategy to identify possible target genes involved in the development of neuropathic pain. Since differences between Lewis and F344 rats in their response to pain stimuli in acute pain models have been related to differences in the endogenous opioid and noradrenergic systems, we aimed to determine the levels of expression of key genes of both systems in the spinal cord and dorsal root ganglia (DRG) of both strains 28 days after CCI surgery. Real time RT-PCR revealed minimal changes in gene expression in the spinal cord after CCI despite the strain considered, but marked changes in DRG were observed. A significant upregulation of prodynorphin gene expression occurred only in injured DRG of F344 rats, the most resistant strain to neuropathic pain. In addition, we found a significant downregulation of tyrosine hydroxylase and proenkephalin gene expression levels in both strains whereas δ-opioid receptor was found to be significantly downregulated only in injured DRG of Lewis rats although the same trend was observed in F344 rats. The data strongly suggest that dynorphins could be involved in strain differences concerning CCI resistance.     

Changes in GAD- and GABA- immunoreactivity in the spinal dorsal horn after peripheral nerve injury and promotion of recovery by lumbar transplant of immortalized serotonergic precursors

We have utilized RN46A cells, an immortalized neuronal cell line derived from E13 brainstem raphe, as a model for transplant of bioengineered serotonergic cells. RN46A cells require brain-derived neurotrophic factor (BDNF) for increased survival and serotonin (5HT) synthesis in vitro and in vivo. RN46A cells were transfected with the rat BDNF gene, and the 46A-B14 cell line was subcloned. These cells survive longer than 7 weeks after transplantation into the subarachnoid space of the lumbar spinal cord and synthesize 5HT and BDNF. Chronic constriction injury (CCI) of the sciatic nerve was used to induce chronic neuropathic pain in the affected hindpaw in rats. Transplants of 46A-B14 cells placed 1 week after CCI alleviated chronic neuropathic pain, while transplants of 46A-V1 control cells, negative for 5HT and without the BDNF gene, had no effect on the induction of thermal and tactile nociception. When endogenous cells of the dorsal horn which contain the neurotransmitter γ-aminobutyric acid (GABA) and its synthetic enzyme glutamate decarboxylase (GAD) were immunohistochemically quantified in the lumbar spinal cord 3 days and 1–8 weeks after CCI, the number of GABA- and GAD-immunoreactive (ir) cells decreased bilateral to the nerve injury as soon as 3 days after CCI. At 1 week after CCI, the number of GABA-ir cells continued to significantly decline bilaterally, returning to near normal numbers on the side contralateral to the nerve injury by 8 weeks after the nerve injury. The number of GAD-ir cells began to increase bilaterally to the nerve injury at 1 week after CCI and continued to significantly increase in numbers over normal values by 8 weeks after the nerve injury. When examined 2 and 8 weeks after CCI plus cell transplants, the transplants of 46A-B14 cells reversed the increase in GAD-ir cell numbers and the decrease in GABA-ir cells by 1 week after transplantation, while 46A-V1 control cell transplants after CCI had no effect on the changes in numbers of GAD-ir or GABA-ir cells. Collectively, these data suggest that altered 5HT levels, and perhaps BDNF secretion, related to the transplants ameliorate chronic pain and reverse the induction and maintenance of an endogenous pain mechanism in the dorsal horn. This induction mechanism is likely dependent on altered GAD regulation and GABA synthesis, initiated by CCI.     

Noradrenergic and opioidergic alterations in neuropathy in different rat strains

The Fischer 344 (F344) rat strain differs from the Lewis strain in the response to neuropathic pain. Recently, we found that F344 rats totally recover from mechanical allodynia induced by chronic constriction injury (CCI) of the sciatic nerve 28 days after surgery whereas Lewis rats are initiating their recovery at this time point. Thus, the use of this neuropathic pain model in these different rat strains constitutes a good strategy to identify possible target genes involved in the development of neuropathic pain. Since differences between Lewis and F344 rats in their response to pain stimuli in acute pain models have been related to differences in the endogenous opioid and noradrenergic systems, we aimed to determine the levels of expression of key genes of both systems in the spinal cord and dorsal root ganglia (DRG) of both strains 28 days after CCI surgery. Real time RT-PCR revealed minimal changes in gene expression in the spinal cord after CCI despite the strain considered, but marked changes in DRG were observed. A significant upregulation of prodynorphin gene expression occurred only in injured DRG of F344 rats, the most resistant strain to neuropathic pain. In addition, we found a significant downregulation of tyrosine hydroxylase and proenkephalin gene expression levels in both strains whereas delta-opioid receptor was found to be significantly downregulated only in injured DRG of Lewis rats although the same trend was observed in F344 rats. The data strongly suggest that dynorphins could be involved in strain differences concerning CCI resistance.     

Anti-allodynic action of the disease-modifying anti-rheumatic drug iguratimod in a rat model of neuropathic pain

Objective

Patients with rheumatoid arthritis experience nociceptive as well as neuropathic pain. The effect of iguratimod (IGU), a disease-modifying anti-rheumatic drug, on neuropathic pain in a rat model of chronic constriction injury (CCI) was examined in this study.

Methods

CCI was induced by making four ligations on the left sciatic nerve. Rats with stable signs of static allodynia were selected 2 weeks after the surgery and drug treatments were started (day 0). The test drugs were orally administered once daily for 15 days. The threshold of mechanical pain response in the hind paw was evaluated by the von Frey hair test in a blinded manner. To observe histological changes in the spinal cord, the L4 region was subjected to immunohistochemical analysis for the detection of microglial cells.

Results

IGU showed an anti-allodynic effect on CCI-induced neuropathic pain at days 6 and 14, but not at 90 min after the first administration of IGU. This effect of IGU was observed until day 21. Furthermore, IGU decreased the number of Iba-1-positive cells, which had been increased at the ipsilateral side of the dorsal horn by CCI.

Conclusions

These results suggest that IGU suppresses neuropathic pain via a different mechanism from that of current therapeutics.

     

鞘内注射PSD-95 siRNA对神经病理性疼痛大鼠脊髓CaMKⅡα活性的影响

目的 探讨突触后致密蛋白95（PSD-95）基因沉默对神经病理性疼痛模型大鼠脊髓Ca2+ /钙调蛋白依赖的蛋白激酶Ⅱα（CaMKⅡα）表达及活性的影响。方法 用化学合成针对大鼠PSD-95基因的siRNA转染神经母细胞瘤/大鼠神经胶质细胞瘤杂交瘤细胞（NG108-15细胞）,并观察干扰效果。选取91只成年SD大鼠随机分为3组：Naive组、假手术组（sham）与坐骨神经慢性缩窄损伤（CCI）手术组。CCI组大鼠进一步被分为4个亚组,分别于CCI术后第5天开始鞘内注射生理盐水（Control组）、转染试剂（Vehicle组）、阴性对照（mmRNA组）和PSD-95基因特异siRNA（siRNA组）。连续给药3d,各组大鼠分别于鞘内给药后第1、3、7天评估机械缩足反射阈值（MWT）的改变,并留取腰4～6脊髓节段标本,以Western blotting方法观察脊髓背角PSD-95、CaMKⅡα蛋白表达水平及活性的变化。结果 大鼠PSD-95基因特异的siRNA可以有效地沉默NG108-15细胞中PSD-95基因表达。与生理盐水治疗组相比,鞘内注射PSD-95特异siRNA 3d后,大鼠脊髓背角PSD-95蛋白水平明显降低（P <0.05）,CCI大鼠神经病理性疼痛得到明显缓解（P <0.05）,同时脊髓背角pThr286CaMKⅡα蛋白水平受到明显抑制（P <0.05）,而总CaMKⅡα蛋白水平无明显变化（ P >0.05）。结论 PSD-95基因特异的siRNA可被成功导入大鼠中枢神经系统,引起脊髓PSD-95基因沉默,在缓解病理性疼痛的同时可抑制神经损伤导致的脊髓CaMKⅡα磷酸化水平的增加,阻断中枢敏化相关的信号通路。     

Antihyperalgesic and antiallodynic effect of sirolimus in neuropathic pain and the role of cytokines in this effect

Recent studies have revealed that T lymphocytes play a role in neuropathic pain following nerve injury in rats through releasing several cytokines. Sirolimus is an immunosuppressive antibiotic inhibiting T cell activation. This study aimed to determine the effect of sirolimus on hyperalgesia and allodynia and on serum and spinal cord TNF-α, IL-1β and IL-6 levels in rat neuropathic pain. Neuropathic pain was induced by loose ligation of the sciatic nerve and evaluated by tests measuring the mechanical hyperalgesia and allodynia. Sirolimus (0.75 and 1.5 mg/kg) was administered intraperitoneally once every 3 days for 2 weeks (7 doses totally). This dosing regimen revealed acceptable blood concentrations in neuropathic rats. Chronic constriction injury of the sciatic nerve resulted in hyperalgesia and allodynia. Serum levels of cytokines remained unchanged in neuropathic rats. However, TNF-α, but not IL-1β or IL-6, protein level was increased in the spinal cord tissue as evaluated by Western blotting analysis. Treatment with sirolimus resulted in antihyperalgesic and antiallodynic effects and prevented the increased spinal cord TNF-α level. It seems that sirolimus could be a promising immunosuppressive agent in the treatment of neuropathic pain.     

Intrathecally administered Sema3A protein attenuates neuropathic pain behavior in rats with chronic constriction injury of the sciatic nerve

Semaphorins, one of the repulsive axonal guidance factors during development, are produced under pathological conditions in adult animals. In the neuropathic pain state associated with peripheral nerve injury, synaptic reorganization occurs in spinal cord dorsal horn. In the present study, we investigated the roles of intrathecal administration of Sema3A, a secreted semaphorin, in the spinal cord of chronic constriction injury (CCI) model rat. Neuropilin 1 (NPR1) and Plexin A (PlexA), co-receptors of Sema3A, were expressed in the dorsal horn of na?ve rats. NPR1, and not PlexA, protein expression increased in the dorsal spinal cord of CCI rats. Recombinant Sema3A protein attenuated mechanical allodynia and heat hyperalgesia in CCI rats, whereas heat-inactivated Sema3A had no effect. Immunohistochemistry revealed that Sema3A partially restored the decrease of isolectin B4-positive unmyelinated nerve terminals in lamina II of the ipsilateral dorsal horn of CCI rats. Contrary to our expectations, Sema3A did not change the distribution of myelinated fibers in lamina II at 7 days after CCI. Those results suggested that the suppressive role for Sema3A in the development of neuropathic pain associated with peripheral nerve injury in adult rats, which seemed to be independent from prevention of the myelinated fiber sprouting into lamina II.     

Only high concentrations of ethanol affect GABAA receptors of rat cerebellum granule cells in culture

The Fischer 344 (F344) rat inbred strain differs from the inbred Lewis and the outbred Sprague–Dawley (SD) in the response to different pain stimuli, which has been partially attributed to differences in the endogenous opioid and noradrenergic systems. Since brain-derived neutrophic factor (BDNF) modulates both the endogenous opioid and noradrenergic systems, we have now studied specific changes in BDNF gene expression related to the maintenance of neuropathic pain in the three rat strains. F344 rats were found to be the only strain that completely recovered from neuropathic pain (mechanical allodynia) 28 days after chronic constriction injury (CCI) of the sciatic nerve. Real time RT-PCR studies revealed minimal changes in the expression of BDNF in the spinal cord after CCI despite the strain considered, but marked changes in dorsal root ganglia (DRG) were observed. A significant upregulation of BDNF gene expression was found only in injured DRG of F344 rats, thus correlating with higher resistance to neuropathic pain. The data suggest that BDNF could be involved in strain differences concerning CCI resistance.     

Plasticity in the synaptic number associated with neuropathic pain in the rat spinal dorsal horn: A stereological study

This study aimed to determine whether neuropathic pain is associated with a plasticity change in the number of synapses in the spinal dorsal horn. 12 normal adult SD rats were randomly divided into two groups: 7 animals were subjected to unilateral loose ligation (to induce chronic constriction injury) of the sciatic nerve (CCI group) and 5 animals subjected to unilateral sham-operation (sham-operated group). 28 days after operation, the L4–L6 segment of the spinal cord was removed, and paraffin-embedded sections were prepared and stained with Nissl's method and synaptophysin immunohistochemistry. The numbers of neurons and synapses in the spinal dorsal horn were estimated using a contemporary stereological technique—the optical disector. An 86% increase in the number (per unit length of the spinal cord) of synapses or 98% increase in the ratio between the numbers of synapses and neurons in the spinal dorsal horn was found in the middle tissue block but not in both the rostral and caudal tissue blokes cut from L4–L6 segment of the spinal cord. The results suggest that neuropathic pain, as established by the CCI model, is associated with a plasticity change in the spinal dorsal horn: increase in the number of synapses.     

p38MAPK抑制剂对神经病理性疼痛大鼠脊髓TNF-α合成的影响

 摘要：目的：通过建立坐骨神经慢性压迫损伤模型,研究p38丝裂原激活蛋白激酶（p38MAPK,p38）与TNF-α在神经病理性疼痛发生与发展中的相互作用。方法：SD大鼠分5组：1）空白对照组,2）假手术组,3）CCI手术未治疗组,4）CCI手术生理盐水治疗组,5）CCI手术SB203580（p38抑制剂）治疗组。上述治疗组中,生理盐水或SB203580分别于术前1天、术后第1天,和术后第7天鞘内注射。各组大鼠分别于术后3、7、14天测定机械痛阈。采用Western blot和免疫组化方法测定脊髓中TNF-α含量及p38活化水平。结果：与假手术组相比,CCI手术后3、7、14天磷酸化p38（p-p38）水平明显增加（p<0.05）。外周神经损伤后引起机械性触诱发痛,并且使脊髓中TNF-α浓度增加（p<0.05）。预先或术后立即给予SB203580抑制p38活化可以减少脊髓TNF-α合成,从而有效缓解病理性疼痛(p<0.05)。结论：外周神经损伤后,作为信号转导通路之一的p38可能通过促进脊髓TNF-α合成,引发神经病理性疼痛。     

Very low level laser therapy attenuates edema and pain in experimental models

In this study, we tested a new square wave microprocessor-controlled red laser with an extremely low peak power output (<3 mW; very low level laser therapy [vLLLT]) in experimental pain in the rat. Acute inflammation was induced by intraplantar injection of carrageenan, chronic inflammation was induced by complete Freund's adjuvant (CFA) and neuropathic pain was produced by sciatic nerve chronic constriction injury (CCI). In our study vLLLT was effective in reducing edema and hyperalgesia in acute and chronic inflammation if administered at the points usually selected for acupuncture. Moreover, spontaneous pain and thermal hyperalgesia were reduced in CCI rats treated with vLLLT In conclusion, vLLLT reduced edema and induced analgesia in experimental plantar pain in rats. We interpret this to mean that enkephalin mRNA level was strongly upregulated in the external layers of the dorsal horn of the spinal cord in CFA and CCI animals, and that vLLLT further increased the mRNA level in single neurons.     

Analgesic effect of intrathecally γ-aminobutyric acid transporter-1 inhibitor NO-711 administrating on neuropathic pain in rats

To investigate the analgesic effect of intrathecally administered γ-aminobutyric acid (GABA) transporter-1 inhibitor NO-711 on the sciatic nerve chronic constriction injury (CCI) rats. 5 days after intrathecal catheter placement, neuropathic pain model was established by CCI of sciatic nerve on rats. Withdrawal thresholds for mechanical allodynia and latency for thermal hyperalgesia were measured in all animals. All rats operated upon for CCI displayed decreased withdrawal thresholds for mechanical allodynia and latency for thermal hyperalgesia, which has significant difference compared with sham groups. After intrathecal NO-711 administration, withdrawal thresholds and latency were significantly increased on CCI rats compared with control group after 1 day. The results show that GABA transporter-1 inhibitor could effectively develop analgesic effect in sciatic nerve CCI rats’ model.     

Cyclooxygenase inhibitors suppress the expression of P2X3 receptors in the DRG and attenuate hyperalgesia following chronic constriction injury in rats

Recent evidence suggests that P2X₃ receptors express abundantly in nociceptive sensory neurons and play an important role in neuropathic pain. Upregulation of prostaglandin E2 (PGE2) after nerve injure is involved in the pathogenesis of neuropathic pain. An increase of P2X₃ receptors after chronic constriction injury (CCI) to the sciatic nerve has also been reported, the mechanisms are not known clearly. In this study, we examined the effects of systemic administration of cyclooxygenase (COX) inhibitors on analgesia and the expression of P2X₃ receptors in the dorsal root ganglia (DRG) in CCI rats. Rats received 0.9% saline, the nonselective COX inhibitor ibuprofen (40 mg kg⁻¹ day⁻¹) or the selective COX-2 inhibitor celecoxib (30 mg kg⁻¹ day⁻¹) by gavage twice daily from 3 to 14 days after surgery. Mechanical allodynia and thermal hyperalgesia induced by CCI were markedly attenuated by celecoxib from 5 to 14 days after surgery, and relieved by ibuprofen treatment from 7 to 10 days after surgery. The increase of P2X₃ receptors in the DRG in CCI rats on day 14 after surgery was also significantly inhibited; the effect of ibuprofen was stronger than that of celecoxib. These results demonstrate that up-regulated COX/PGE2 after nerve damage may play an important role in neuropathic pain. They are highly involved in the expression of P2X₃ receptors in the DRG in CCI rats.