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.     

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.     

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.     

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.     

神经病理性疼痛大鼠中脑导水管周围灰质腹外侧区NLRP3炎症小体激活水平研究

目的探讨核苷酸结合寡聚化结构域样受体蛋白3(NLRP3)炎症小体在神经病理性疼痛大鼠中脑导水管周围灰质腹外侧区(vlPAG)的表达水平及其作用。方法选取SPF级SD大鼠20只,采用随机数字表法分为假手术组(Sham组)与慢性坐骨神经压迫性损伤组(CCI组),每组10只。于手术前后测定2组机械痛阈与热痛阈;Western blot检测2组NLRP3炎症小体各组分蛋白表达水平;RT-PCR检测2组NLRP3炎症小体各组分基因mRNA表达水平;酶联免疫吸附实验(ELISA)检测2组炎症因子白介素-lβ(IL^-1β)及白介素-18(IL^-18)表达水平;免疫荧光检测2组中NLRP3炎症小体在vlPAG的分布情况,并与小胶质细胞标志物IBA1进行共定位分析。结果与Sham组相比,CCI组术后3 d、7 d、14 d、21 d机械痛阈与热痛阈均明显降低(P<0.001);与Sham组相比,CCI组核心蛋白NLRP3、效应蛋白Caspase-1 p10及前体蛋白pro-Caspase-1表达水平均明显升高(P<0.001);与Sham组相比,CCI组NLRP3(P<0.001)、Caspase-1(P<0.001)及IL^-1β(P<0.01)mRNA表达水平均明显升高,炎症因子IL^-1β(P<0.001)与IL^-18(P<0.01)表达水平也明显升高;与Sham组相比,CCI组在vlPAG的NLRP3阳性细胞数增加,且与IBA1存在共表达。结论神经病理性疼痛大鼠vlPAG中NLRP3炎症小体被激活且表达水平增高,提示NLRP3炎症小体激活水平与神经病理性疼痛大鼠痛阈下降相关。     

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.     

Effect of high trait anxiety on mechanical hypersensitivity in male rats

Recently, we have shown that neuropathic pain is associated with anxiety-like behaviour in rats with sciatic nerve lesion. An enhanced pain perception has also been described in patients with anxiety disorders. However, there is only limited knowledge about the relationship between anxiety and pain in animals. To investigate whether trait anxiety influences nociception, we measured mechanical hypersensitivity following chronic constriction injury (CCI) in rats selectively bred for high (HAB) or low (LAB) anxiety-like behaviour. Pain sensitivity was assessed before surgery and at day 7, 14, 21, 36 and 57 after CCI by determination of withdrawal thresholds. Additionally, we examined pain-induced anxiety-like behaviour using the elevated plus-maze (EPM). HAB and LAB rats exhibited similar levels of mechanical hypersensitivity 7 days post-injury. However, at day 14 and 21 after surgery, mechanical-induced pain thresholds were significantly decreased in HAB rats (p < 0.05) in comparison to LAB rats. From day 21 onward HAB rats displayed a faster return of paw withdrawal threshold to baseline level when compared to LAB rats (p < 0.01). In the EPM anxiety-like behaviour was observed following CCI injury in HAB and LAB rats on top of low and high trait anxiety reflected in a reduced number of entries in open arms. These findings indicate that trait anxiety increases mechanical hypersensitivity in CCI rats during the chronic phase of pain, thereby suggesting that affective processes modulate even simple pain-related behaviour. Furthermore, we demonstrated that neuropathic pain in the CCI model increases anxiety-like behaviour even in LAB rats.     

Upregulation of the GABA-transporter GAT-1 in the spinal cord contributes to pain behaviour in experimental neuropathy

Sciatic nerve ligation in rats (chronic constriction injury (CCI)) induces signs and symptoms that mimic human conditions of neuropathy. The central mechanisms that have been implicated in the pathogenesis of neuropathic pain include increased neuronal excitability, possibly a consequence of decreased availability of spinal GABA. GABA availability is regulated by the presence of the GABA-transporters (GATs). This study investigates the dorsal horn expression of the transporter GAT-1 and its functional involvement towards pain behaviour in the CCI model. Male Lewis rats (total n=37) were subjected to CCI or to a sham procedure. A sub-group of animals was treated with the GAT-1 antagonist NO-711. Behavioural testing was performed pre-surgery and at 7 days post-surgery. Testing included evaluation of mechanical allodynia using Von Frey filaments, thermal allodynia with a hot-plate test and observational testing of spontaneous pain behaviour. Subsequently, spinal protein expression of GAT-1 was assessed by Western blotting. Animals were sacrificed 7 days following surgery. CCI markedly increased mechanical and thermal allodynia and spontaneous pain behaviour after 7 days, while the sham procedure did not. GAT-1 was increased in spinal cord homogenates compared contralateral to the ligation side after 7 days. NO-711 treatment significantly reduced all tested pain behaviour. These data provide evidence for possible functional involvement of GAT-1 in the development of experimental neuropathic pain. The latter can be derived from observed analgesic effects of early treatment with NO-711, a selective GAT-1 inhibitor. The obtained insights support the clinical employment of GAT-1 inhibitors to treat neuropathic pain.     

穴位电针对慢性神经病理性疼痛大鼠脊髓前列腺酸性磷酸酶表达的影响

目的 观察电针对神经病理性痛大鼠脊髓前列腺酸性磷酸酶（PAP）的表达,及腺苷含量及大鼠痛阈变化的影响,探讨电针镇痛机制。方法 21只雄性SD大鼠采用慢性坐骨神经压缩模型(CCI),取“足三里”及“太冲”穴。设假手术组（sham组）、模型组(CCI组）和电针治疗组（EA组）。采用行为学检测大鼠术前、术后第7天和电针治疗后大鼠机械痛敏值和热敏痛阈值变化,采用Real-time PCR技术检测脊髓PAP mRNA的表达,高效液相色谱法检测脊髓腺苷含量。结果 相比CCI组大鼠,电针组大鼠机械痛敏值和热敏痛阈值明显提高（P<0.05, P<0.05）。电针组大鼠脊髓PAP mRNA表达和腺苷含量比CCI组大鼠显著增加（P<0.05）。与CCI组大鼠相比,电针组大鼠脊髓腺苷含量增加（P<0.01）。结论 电针可提高神经病理性痛大鼠机械痛阈值和热敏痛阈值,其机制可能是通过增加脊髓PAP mRNA的表达和腺苷含量发挥作用。     

慢性压迫性神经损伤大鼠中透明质酸合成变化及其在神经源性疼痛中的作用

慢性神经源性疼痛由于其发病机制尚不完全明确,目前还没有十分有效的治疗手段;神经损伤后炎症反应和免疫调节机制在疼痛的发生中发挥着重要作用,透明质酸(HA)近来被认为是炎症和免疫调节中一个重要的调节分子。为了进一步研究HA是否参与到神经损伤后的病理过程中,我们检测了慢性压迫性神经损伤(CC I)大鼠损伤神经的HA含量。结果显示:与正常神经比较,HA的含量在损伤后7 d明显增加,HA合成酶(HAS)的表达也明显上调。4-甲基伞形酮(4-MU)是HAS的一种抑制剂,我们通过给予4-MU抑制HA的合成,研究HA在慢性神经源性疼痛中的作用,发现给药组CC I大鼠损伤足对热痛刺激的敏感性低于未给药组,同时IL-1β的表达量低于未给药组。以上结果提示HA可能通过对炎症因子的调控参与到损伤后的疼痛机制中,这一结果将有助于慢性神经源性疼痛的治疗。     

Expression of spinal cord microRNAs in a rat model of chronic neuropathic pain

Neuropathic pain is accompanied by significant alterations of gene expression patterns in the somatosensory nervous system. The spinal cord is particularly prone to neuroplastic changes. Since the expression of microRNAs (miRNAs) has been linked to numerous pathophysiological processes, a contribution of miRNAs to the maladaptive plasticity of the spinal cord in neuropathic pain is possible. Aim of the present study therefore was to characterize the specific expression pattern of miRNAs in the rat spinal cord. Furthermore, we evaluated the time-dependent changes in expression patterns of spinal miRNAs in the chronic constriction injury (CCI) model of neuropathic pain in rats. Results from miRNA microarrays revealed a distinct expression pattern of miRNAs in the rat spinal cord. MiRNAs-494, -720, -690 and -668 showed the highest signal intensities. Members of the let-7 family as well as miR-124 belong to the group of the most highly expressed miRNAs. Induction of neuropathic pain by CCI did not lead to relevant differences in spinal miRNA expression levels compared to sham-operated animals at any studied time point. Therefore, modulation of miRNAs does not seem to contribute significantly to the changes in gene expression that cause neural plasticity in the spinal cord in this model of chronic neuropathic pain.     

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.     

The role of spinal orexin-1 receptors in posterior hypothalamic modulation of neuropathic pain

The posterior hypothalamus (PH) is known to reduce nociceptive pain, but the effect of PH stimulation on neuropathic pain is not known. Because neurons containing the neurotransmitter orexin-A are located in the PH in some strains of rat and intrathecal injection of orexin-A produces antinociception in a neuropathic pain model, we hypothesized that orexin-A from neurons in the PH modifies nociception in the spinal cord dorsal horn. To test this hypothesis, the cholinergic agonist carbachol or normal saline was microinjected into the PH of lightly anesthetized female Sprague–Dawley rats with chronic constriction injury (CCI) and foot withdrawal latencies (FWL) were measured. Carbachol-induced PH stimulation produced dose dependent antinociception as shown by significantly increased FWL compared to saline controls. To investigate the role of orexin-A in PH-induced antinociception, the orexin-1 receptor antagonist SB-334867 or dimethyl sulfoxide (DMSO) for control, was given intrathecally following carbachol-induced PH stimulation. SB-334867 decreased FWL compared to DMSO controls. These data are suggestive that stimulating the PH produces antinociception in a neuropathic pain model and that the antinociceptive effect is mediated in part by orexin-1 receptors in the spinal cord dorsal horn.     

Botulinum neurotoxin type A counteracts neuropathic pain and facilitates functional recovery after peripheral nerve injury in animal models

A growing interest was recently focused on the use of Botulinum neurotoxin serotype A (BoNT/A) for fighting pain. The aim of this study was to investigate the effects of BoNT/A on neuropathic pain. It was observed that BoNT/A is able to counteract neuropathic pain induced by chronic constriction injury (CCI) to the sciatic nerve both in mice and in rats. This effect is already present after a single intraplantar (i.pl.) or intrathecal (i.t.) neurotoxin administration that significantly reduces the sciatic nerve ligation-induced mechanical allodynia in mice and rats and thermal hyperalgesia in rats. This effect was evident starting 24 h after the administration of BoNT/A and it was long-lasting, being present 81 or 25 days after i.pl. injection of the higher dose in mice (15 pg/paw) and rats (75 pg/paw), respectively, and 35 days after i.t. injection in rats (75 pg/rat). Moreover, BoNT/A-injected mice showed a quicker recovery of the walking pattern and weight bearing compared to control groups. The behavioral improvement was accompanied by structural modifications, as revealed by the expression of cell division cycle 2 (Cdc2) and growth associated protein 43 (GAP-43) regeneration associated proteins, investigated by immunofluorescence and Western blotting in the sciatic nerve, and by the immunofluorescence expression of S100β and glial fibrillary acidic protein (GFAP) Schwann cells proteins. In conclusion, the present research demonstrate long-lasting anti-allodynic and anti-hyperalgesic effects of BoNT/A in animal models of neuropathic pain together with an acceleration of regenerative processes in the injured nerve, as evidenced by both behavioral and immunohistochemistry/blotting analysis. These results may have important implications in the therapy of neuropathic pain.     

MiR-139-3p通过靶向下调TRPV1缓解大鼠神经病理性疼痛

目的:研究miR-139-3p在大鼠神经病理性疼痛发生发展中的作用及其作用机制。方法:将大鼠随机分为假手术组(sham)、坐骨神经慢性压迫损伤模型组(chronic constriction injury group,CCI)、2 mg/kg miR-139-3p模拟物(mimic)鞘内注射组、4 mg/kg miR-139-3p mimic鞘内注射组。术后的第14 d,Real-time PCR法检测大鼠背根神经节(DRG)中miR-139-3p及TRPV1的表达。于注射前及注射后的第1、3、7、14 d,利用von Frey检测大鼠机械性痛阈及热辐射法检测大鼠热痛阈值。Western Blot法检测DRG中TRPV1的表达;ELISA法检测脊髓L4-L5组织中TNF-α及IL-1β的含量;双荧光素酶报告基因法检测miR-139-3p与TRPV1的靶向关系。结果:(1)与sham组相比较,miR-139-3p在CCI大鼠DRG中的表达显著下降,而TRPV1的表达显著上升(P0.05)。(2)与sham组相比较,CCI组中大鼠机械刺激缩足反射阈值及热刺激缩足反射潜伏期显著下降(P0.05);而与CCI组相比较,鞘内注射miR-139-3p mimic可显著促进大鼠机械刺激缩足反射阈值及热刺激缩足反射潜伏期的上升,抑制TRPV1的表达(P0.05)。(3)与sham组相比较,CCI组大鼠TNF-α及IL-1β含量显著上升(P0.05);而与CCI组相比较,鞘内注射miR-139-3p mimic可显著抑制TNF-α及IL-1β的产生(P0.05)。(4)miR-139-3p mimic转染可显著降低荧光素酶报告基因的荧光强度。结论:miR-139-3p通过靶向下调TRPV1的表达缓解大鼠神经病理性疼痛。     

Interleukin-17 levels in rat models of nerve damage and neuropathic pain

In the present study, we assessed IL-17 levels at 3 and 8 days following various forms of injuries to the sciatic nerve and related the cytokine levels to the pain behaviors associated with the injuries. The four experimental models employed were chronic constriction injury (CCI), partial sciatic ligation (PSL), complete sciatic transection (CST) and perineural inflammation (Neuritis). Behavior withdrawal thresholds for mechanical stimulus and withdrawal latency for thermal stimulation were used to measure mechanical allodynia and thermal hyperalgesia. IL-17 levels of the affected, contralateral and naïve rats’ sciatic nerve were assessed employing enzyme-linked immunosorbent assay (ELISA). Rats exposed to CCI and Neuritis displayed significant mechanical allodynia and thermal hyperalgesia 3, 5 and 8 days following the procedure, rats exposed to PSL displayed significant mechanical allodynia 5 and 8 days following the procedure and rats exposed to CST developed significant hypoesthesia. Three days following the procedure, IL-17 levels increased significantly compared to naïve rats only in the PSL model. Eight days following the procedure, IL-17 levels in nerves exposed to CCI, CST, PSL and Neuritis were significantly elevated compare to intact nerve levels. It is likely that IL-17 has a limited role in the acute phase of nerve injury and the associated acute pain, but may have a role in later phases of the processes of the development of neuropathic pain.     

Motor cortex stimulation in rats with chronic constriction injury

Motor cortex stimulation (MCS) has gained a significant role in treatment of neuropathic pain. In order to evaluate effect of MCS in experimental animals we applied MCS to rats with neuropathic pain, which was evoked by chronic constriction injury (CCI) to the left sciatic nerve. Pain thresholds of both hind limbs were measured before, immediately after MCS, 1 h after MCS and 1 day after MCS. Effect of the stimulation was studied with respect to laterality (contralateral and ipsilateral MCS) and duration (short-term 10-min and long-term 1-h stimulation). It was found out that in control rats MCS did not affect thermal nociceptive thresholds. However, in CCI animals following results were obtained: difference score (difference in paw withdrawal latency between ligated and non-ligated hind limb) significantly decreased after both short- and long-term contralateral MCS; the difference score after the long-term ipsilateral MCS (related to the ligated hind limb) was not significantly different from that of intact animals; the effects of the contralateral short-term and the ipsilateral long-term stimulation faded within 1 h after the end of MCS, while the effect of the contralateral long-term MCS remained 1 h after the end of the MCS and faded within 24 h. It is concluded that MCS in experimental animals exerts similar effects as in human suffering from neuropathic pain and that the effect might be evoked from both cerebral cortices.     

Inhibition of GAP-43 by propentofylline in a rat model of neuropathic pain

Neural plasticity within the spinal nociceptive network may be fundamental to the chronic nature of neuropathic pain. The relation of growth-associated protein-43 (GAP-43), a protein involved in the nerve fiber growth and sprouting, to pain hypersensitivity has been investigated. Glial activation and inflammatory cytokines released by microglia and astrocytes are considered to be involved in the neural sprouting and plasticity. In the present study, the anti-nociception effect of propentofylline, a glial modulating agent, was investigated in a rat chronic constriction injury (CCI) model aiming to explore the role of GAP-43 expression. Our results demonstrated that propentofylline could attenuate the CCI-induced mechanical allodynia and thermal hyperalgesia and inhibit the astrocyte activation and production of IL-1β. GAP-43 expression was also down-regulated by intrathecal propentofylline. These findings suggest that astrocyte activation is involved in the regulation of GAP-43 expression and propentofylline might be used in the treatment of neuropathic pain.     

T lymphocytes play a role in neuropathic pain following peripheral nerve injury in rats

A catastrophic consequence of peripheral nerve injury is the development of abnormal, chronic neuropathic pain. The inflammatory response at the injury site is believed to contribute to the generation and maintenance of such persistent pain. However, the physiological significance and potential contribution of T cells to neuropathic pain remains unclear. Here we show that T cells infiltrate injured sciatic nerves following chronic constriction injury (CCI), but not uninjured nerves. Congenitally athymic nude rats, which lack mature T cells, developed a significantly reduced mechanical allodynia and thermal hyperalgesia following CCI, compared with their heterozygous littermates. To understand further the role played by different T-cell subsets, we generated polarized populations of type 1 and type 2 T cells, with different cytokine secretion profiles, from spleens of sciatic nerve-injured heterozygous rats. Passive transfer of type 1 T cells, which produce proinflammatory cytokines, into nude rats enhanced the recipients' pain hypersensitivity to a level similar to that of heterozygous donor rats. In contrast, passive transfer of polarized type 2 T cells, which produce anti-inflammatory cytokines, into heterozygous rats modestly though significantly attenuated their pain hypersensitivity. Thus, injection of type 1 and type 2 T-cell subsets produces opposing effects on neuropathic pain. These findings suggest the modulation of the T-cell immune response as a potential target for the treatment of neuropathic pain.     

Sleep and EEG patterns in the chronic constriction injury model of neuropathic pain

Chronic neuropathic pain patients often report sleep disturbances such as reduced amount of sleep and excessive daytime tiredness. The aim of this study was to evaluate possible abnormalities in sleep patterns in a widely used animal model of neuropathic pain. Adult male Sprague-Dawley rats were chronically implanted with electrodes for electroencephalogram (EEG) and electromyogram (EMG) registrations to allow continuous 24-h polygraphic recording. Subsequently, a chronic constriction injury (CCI) was inflicted on eight rats in accordance with the CCI model of neuropathic pain and a sham operation was performed on another eight rats. The polygraphic recordings were repeated 13, 27, 55, and 146 days after surgery. Although the CCI animals developed significant mechanical and cold allodynia and heat hyperalgesia, there were no significant differences between the CCI rats and the sham-operated control animals in the spontaneous EEG/EMG in homecage-like conditions. It is concluded that in the chronic phase, this neuropathic pain model does not produce clear sleep disturbances. Such an absence of general suffering from sleep disturbances is advantageous to the CCI model as it makes use of the model more acceptable ethically. Nonetheless, this outcome appears to be in contrast with the clinical situation in neuropathic pain and therefore could also be seen as a disadvantage for the face validity of the CCI model.