Optical coherence tomography reveals in vivo cortical plasticity of adult mice in response to peripheral neuropathic pain

We examined neural plasticity in mice in vivo using optical coherence tomography (OCT) of primary somatosensory (S1) and motor (M1) cortices of mice under the influence of sciatic nerve chronic constriction injury (CCI), a model of neuropathic pain widely utilized in rats. The OCT system used in this study provided cross-sectional images of the cortical tissue of mice up to a depth of about 1mm with longitudinal resolution up to 11 microm. This is the first study to evaluate neural plasticity in vivo using OCT. CCI mice exhibited cold allodynia and spontaneous pain behaviors, which are signs of neuropathic pain, 30 days after sciatic nerve ligation, when OCT observation of S1 and M1 cortices was carried out. The scattering intensity of near-infrared light within the hind paw area of S1 and M1 regions in the contralateral hemisphere was significantly higher than in the ipsilateral hemisphere. These CCI-induced increases in scattering intensity within cortical regions associated with the hind paw probably reflect elevated neural activity associated with neuropathic pain. Synapses and mitochondria are believed to have high light scattering coefficients, since they contain remarkably high concentrations of proteins and complicated membrane structure. Number densities of mitochondria and synapses are known to increase in parallel with increases in neural activity. Our findings thus suggest that neuropathic pain gives rise to neural plasticity within the hind paw area of S1 and M1 contralateral to the ligated sciatic nerve.     

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。     

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.     

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.     

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.     

Short- but not long-lasting treadmill running reduces allodynia and improves functional recovery after peripheral nerve injury

We analyzed the effects of different treadmill running protocols on the functional recovery after chronic constriction injury (CCI) of the sciatic nerve in mice. We found that a treadmill protocol of short-lasting running (1 h/d for 5 days after CCI) reduced the neuropathy-induced mechanical allodynia and normalized the weight bearing and the sciatic static index of the injured hindpaw. At difference, a treadmill protocol of long-lasting running (1 h/d for more than 5 days after CCI) was unfavorable both for allodynia and for functional recovery. Behavioral results were correlated with immunofluorescence assays of microglia and astrocytes activation in L4/L5 lumbar spinal cord sections. We found a differential pattern of activation characterized by: (i) reduced microglia expression, after both short- and long-lasting treadmill running; (ii) reduced astrocytes expression after short-lasting treadmill running; and, (iii) persistence of astrocytes expression after long-lasting treadmill running. Finally, in sections of injured sciatic nerves, we analyzed the expression of Cdc2 and GAP-43 proteins that are both up-regulated during peripheral regenerative processes. Compared to mice subjected to long-lasting treadmill running, mice subjected to short-lasting treadmill running showed an acceleration of the regenerative processes at the injured sciatic nerve. Our data demonstrate that short-lasting treadmill running, by reducing the neuropathic pain symptoms and facilitating the regenerative processes of the injured nerve, have beneficial rehabilitative effects on the functional recovery after peripheral nerve injury.     

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.     

Peripheral nerve injury evokes disabilities and sensory dysfunction in a subpopulation of rats: a closer model to human chronic neuropathic pain?

Chronic pain conditions for which treatment is sought are characterized usually by complex behavioural disturbances as well as pain. We review here evidence that although chronic constriction injury (CCI) of the sciatic nerve evokes allodynia and hyperalgesia in all rats, persistent social behavioural and sleep disruption occurs only in a subpopulation of animals. The finding that the 'degree of pain', as defined by allodynia and hyperalgesia, is the same in all animals suggests that the complex behavioural disabilities are independent of the level of sensory dysfunction. An absence of correlation between disability and sensory dysfunction is characteristic also of human neuropathic pain. These findings indicate that: (i). in a subpopulation of rats sciatic injury evokes disabilities characteristic of human neuropathic pain conditions; and (ii). testing for sensory dysfunction alone cannot detect this subpopulation.     

Effects of 17β-estradiol on glucose transporter 1 expression and endothelial cell survival following focal ischemia in the rats

To characterize various animal models of neuropathic pain, we compared three previously developed rat models using the same behavioral testing methods. These models involve: (1) chronic constriction injury by loose ligation of the sciatic nerve (CCI); (2) tight ligation of the partial sciatic nerve (PSL); and (3) tight ligation of spinal nerves (SNL). Comparisons were made for the time course of behavioral signs representing various components of neuropathic pain as well as for the effects of surgical sympathectomy. In general, all three methods of peripheral nerve injury produced behavioral signs of both ongoing and evoked pain with similar time courses. However, there was a considerable difference in the magnitude of each pain component between models. Signs of mechanical allodynia were largest in the SNL injury and smallest in the CCI model. On the other hand, behavioral signs representing ongoing pain were much more prominent in the CCI model than in the other two. Although the behavioral signs of neuropathic pain tended to decrease after sympathectomy in all three models, the change was most evident in the SNL model. The results of the present study suggest that the three rat models tested have contrasting features, yet all are useful neuropathic pain models, possibly representing different populations of human neuropathic pain patients.     

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.     

Gender dependent effect of DHCR24 polymorphism on the risk for Alzheimer's disease

Although neuroimmune interactions associated with the development of pain sensitization in models of neuropathic pain have been widely studied, there are some aspects that require further investigation. Thus, we aimed to evaluate whether the local intraneural or perineural injections of dexamethasone, an efficacious anti-inflammatory and immunosuppressant drug, delays the development of both thermal hyperalgesia and mechanical allodynia in an experimental model of neuropathic pain in rats. Hargreaves and electronic von Frey tests were applied. The chronic constriction injury (CCI) of right sciatic nerve was performed. Single intraneural dexamethasone administration at the moment of constriction delayed the development of sensitization for thermal hyperalgesia and mechanical allodynia. However, perineural administration of dexamethasone, at the highest dose, did not delay experimental pain development. These results show that inflammation/immune response at the site of nerve lesion is an essential trigger for the pathological changes that lead to both hyperalgesia and allodynia. In conclusion, this approach opens new opportunities to study cellular and molecular neuroimmune interactions associated with the development of pain derived from peripheral neuropathies.     

Local application of capsaicin alleviates mechanical hyperalgesia after spinal nerve transection

Whether modulation of C afferent fiber activities could relieve peripheral neuropathic pain was tested. After establishment of neuropathic pain induced by L5 and 6 spinal nerve transection (SNT), the sciatic nerve was treated with 2% capsaicin at the level of the midthigh. Mechanical hyperalgesia (von Frey filaments) was significantly alleviated from 7 days to 4 weeks after capsaicin treatment, but cold allodynia (acetone) was unchanged. Immunohistochemical studies showed a significant increase in the number of calcitonin gene-related peptide (CGRP)-positive neurons, but not TRPV1-positive neurons in intact L4 dorsal root ganglia after SNT. Capsaicin treatment decreased TRPV1- and CGRP-positive neurons in L4 DRG of the treated side, but not the opposite side. These results suggest that local application of capsaicin onto the sciatic nerve can alleviate mechanical hyperalgesia, but not cold allodynia, in a peripheral neuropathic pain model and the pain alleviation may result from a decrease of TRPV1- and CGRP-positive sensory neurons of which fibers pass through the sciatic nerve.     

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.     

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.     

CC-chemokine MIP-1α in the spinal cord contributes to nerve injury-induced neuropathic pain

We investigated the involvement of spinal macrophage inflammatory protein-1α (MIP-1α), an inflammatory chemokine, in partial sciatic nerve ligation (PSL)-induced neuropathic pain in mice. PSL increased MIP-1α mRNA levels as well as levels of the MIP-1α receptor, CCR1, but not CCR5 in the spinal dorsal horn. PSL-induced tactile allodynia and thermal hyperalgesia were prevented by intrathecal (i.t.) injection of a neutralizing antibody of MIP-1α (2 ng). Recombinant MIP-1α (10 pmol, i.t.) elicited long-lasting tactile allodynia and thermal hyperalgesia in naïve mice. These results suggest that peripheral nerve injury elicits the up-regulation of spinal MIP-1α and CCR1 to participate in neuropathic pain.     

Stability of neuropathic pain symptoms in partial sciatic nerve ligation in rats is affected by suture material

Many factors affect the development of neuropathic pain behavior in animal models. In this letter, we describe the differences in the development of neuropathic pain behavior observed when the partial sciatic nerve ligation (PNL) is performed with either a synthetic silk or chromic catgut ligation. To characterize nociceptive changes over time after surgery, neutral plate, hot plate, Von Frey, pinprick, acetone spray and cold plate testing was performed. The results indicated that a chromic catgut ligature caused cold allodynia, chemical hyperreactivity, mechanical hyperalgesia and hypersensitivity that remained present for the entire 56 days post-surgical observation period. With the synthetic silk ligature, comparable functional deficits were present in the initial phase after surgery, but several of these deficits diminished over time 21-28 days post-surgery. In conclusion, performing the PNL using chromic catgut suture thread gives rise to more robust sensory deficits than when synthetic silk is used. Therefore, the material that is used for the ligature in the partial sciatic ligation model has an effect on the outcome of the observed sensory abnormalities.     

Antihyperalgesic and Anti-inflammatory Effects of Atorvastatin in Chronic Constriction Injury-Induced Neuropathic Pain in Rats

Atorvastatin is a 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitor used in treatment of hypercholesterolemia and prevention of coronary heart disease. The aim of this study is to investigate the antihyperalgesic and anti-inflammatory effects of atorvastatin (3, 10, and 30 mg/kg by oral gavages for 14 days) in chronic constriction injury (CCI) model of neuropathic pain in rats. CCI caused significant increase in tumor necrosis factor-α, interleukin 1 beta, prostaglandin E2, along with matrix metalloproteases (MMP-2) and nerve growth factor (NGF) levels in sciatic nerve and spinal cord concomitant with mechanical and thermal hyperalgesia, which were significantly reduced by oral administration of atorvastatin for 14 days as compared to CCI rats. Our study demonstrated that atorvastatin attenuates neuropathic pain through inhibition of cytokines, MMP-2, and NGF in sciatic nerve and spinal cord suggesting that atorvastatin could be an additional therapeutic strategy in management of neuropathic pain.     

Bone marrow stromal cells induce changes in pain behavior after sciatic nerve constriction

Peripheral nerve injury, i.e. a single ligature nerve constriction (SLNC), triggers neuropathic pain. Bone marrow stromal cells (MSCs) have been observed to migrate to the injured tissues and mediate functional recovery following brain, spinal cord and peripheral nerve lesions. We have recently shown MSC selective migration to the ipsilateral lumbar (L3-6) dorsal root ganglia (DRGs) after a sciatic nerve SLNC. In this study, we have analyzed the thermal and mechanical sensitivities of animals subjected to a SLNC of the sciatic nerve and an ipsilateral intraganglionic MSC injection, using the von Frey and Choi tests. Control animals were subjected to the nerve lesion either alone or followed by the administration of phosphate-buffered saline (PBS) or bone marrow non-adherent mononuclear cells (BNMCs). All the animals were tested both before surgery and after 1, 3, 7, 14, 21, 28 and 56 days. Animals subjected to the sciatic nerve constriction developed ipsilateral mechanical and thermal allodynia already 3 days after the lesion. The allodynic responses were maintained even after 56 days. MSC administration prevented the generation of mechanical allodynia and reduced the number of allodynic responses to cold stimuli. On the contrary, the injection of either PBS or BNMCs could not counteract allodynia. These results suggest that MSCs may modulate pain generation after sciatic nerve constriction. The underlying mechanisms by which MSCs exert their actions on pain behavior need to be clarified.     

Exaggeration of tissue trauma induces signs and symptoms of acute CRPS I, however displays distinct differences to experimental CRPS II

As CRPS I frequently develops after tissue trauma, we proposed that an exaggerated inflammatory response to tissue trauma may underlie CRPS I. Therefore, we studied the vascular inflammatory, nociceptive and apoptotic sequelae of (i) soft tissue trauma and (ii) exaggerated soft tissue trauma in comparison to those of (iii) sciatic nerve chronic constriction injury, modeling CRPS II. Standardized soft tissue trauma (TR) was induced by means of a controlled impact injury technique in the hind limb of pentobarbital-anesthetized rats. Additional animals received soft tissue trauma and femoral arterial infusion of mediator-enriched supernatant achieved by homogenization and centrifugation of traumatized muscle tissue in order to provoke an exaggerated trauma response (ETR). Infusion of supernatant of non-traumatized muscle served as control intervention (STR, sham trauma response). Neuropathy was induced by chronic constriction injury of the sciatic nerve (CCI). Untreated animals served as controls (CO). Detailed nociceptive testing showed temporarily decreased mechanical pain thresholds in ETR animals that resolved within 14 days, while TR and STR animals, i.e. those with singular limb trauma, and controls remained free of pain. Neither cold- nor heat-evoked allodynia developed in post-traumatic animals, whereas CCI animals presented the well-known pattern of ongoing neuropathic pain. Using high-resolution in vivo multifluorescence microscopy, muscle tissue of traumatized animals revealed an enhanced inflammatory response that was found most pronounced in ETR animals. CCI of the sciatic nerve was not accompanied by tissue inflammation; however, induced myocyte apoptosis. Collectively, these data indicate that exaggeration of trauma response induces signs and symptoms of acute CRPS I. Pain perception displays differences to that in CRPS II. Apoptosis turns out to be a distinctive marker for CRPS, warranting further evaluation in clinical studies.     

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.