Spermidine reduced neuropathic pain in chronic constriction injury-induced peripheral neuropathy in rats

Neuropathic pain is one of the most critical types of chronic pain despite the increasing advances in medical science. Spermidine (SPD) is a natural polyamine that has wide roles in several cellular processes inducing autophagy and reducing oxidative stress. This study aimed to investigate the effects of SPD on oxidative stress markers and pain threshold in the neuropathic rat model of chronic constriction injury (CCI) model. Eighteen adult male rats were divided into three groups: sham, CCI and CCI+SPD. After induction of neuropathy via CCI model in the CCI and CCI+SPD groups, SPD (1 mg/kg/day, orally) was administered to the CCI+SPD group for 3 weeks. The behavioral tests (von Frey, hot plate) were done four times during the experiment. At the end of the study, electrophysiological tests, the H & E staining, and oxidative stress assay of the prefrontal cortex (PFC), spinal cord, and sciatic nerve were performed. The threshold of pain in hot plate and von Frey tests was significantly lower in the CCI group than in the sham group, which was reversed by SPD treatment in the CCI+ SPD group. In addition, nerve conduction was considerably lower in the CCI group than in the sham and CCI+SPD groups (P < 0.01, P < 0.05, respectively). The CCI group showed neuronal degeneration and fibrosis in the different tissues in the H & E assay; elevated tissues level of nitrite, decreased levels of superoxide dismutase (SOD), glutathione (GPx), and catalase were also observed. However, SPD treatment modulated the pathological changes and oxidative stress biomarkers. In conclusion, SPD showed beneficial effects in decreasing neuropathic pains. SPD treatment reduced oxidative stress and improved histopathological changes and behavioral tests in the CCI-induced neuropathic pain in in vivo model.     

Glial cell line-derived neurotrophic factor gene transfer exerts protective effect on axons in sciatic nerve following constriction-induced peripheral nerve injury

Damage to peripheral nerves following trauma or neurodegenerative diseases often results in various sensory and motor abnormalities and chronic neuropathic pain. The loss of neurotrophic factor support has been proposed to contribute to the development of peripheral neuropathy. The main objective of this study was to investigate the protective effect of glial cell line-derived neurotrophic factor (GDNF) using peripheral gene delivery in a rat model of constriction-induced peripheral nerve injury. In this study, it was shown that mechanical and thermal hypersensitivity increased on the injured limb at day 7 after chronic constrictive injury (CCI) was induced. The neurological changes were correlated with the structural changes and loss of GDNF/Akt signaling, particularly in the distal stump of the injured sciatic nerve. Subsequently, recombinant adenovirus was employed to evaluate the potential of intramuscular GDNF gene delivery to alleviate the CCI-induced nerve degeneration ad neuropathic pain. After CCI for 3 days, intramuscular injection of adenovirus encoding GDNF (Ad-GDNF) restored the protein level and activity of GDNF/Akt signaling pathway in the sciatic nerve. This was associated with an improved myelination profile and behavioral outcomes in animals with CCI. In conclusion, the present study demonstrates the involvement of GDNF loss in the pathogenesis of CCI-induced neuropathic pain and the therapeutic potential of intramuscular GDNF gene delivery for the treatment of peripheral nerve degeneration.     

Higher pain perception and lack of recovery from neuropathic pain in females: A behavioural,immunohistochemical, and proteomic investigation on sex-related differences in mice

In experimental and clinical pain studies, the sex of subjects was rarely taken into account, even if nociceptive inputs appear to be processed and modulated by partially distinct neural mechanisms in each sex. In this study we analysed, in male and female mice, behavioural and neuronal responses in developing, maintaining, and recovering from neuropathic pain. Experiments were carried out in adult CD1 mice by using Chronic Constriction Injury (CCI) as neuropathic pain model. We investigated the temporal trend of mechanical nociceptive threshold together with functional recovery of the injured paw, and the immunofluorescence staining of proteins associated with nerve injury and repair and with spinal gliosis, 7 and 121 days after CCI. A proteomic analysis on proteins extracted from sciatic nerves was also performed. Male mice showed a gradual decrease of CCI-induced allodynia, the complete recovery occurring 81 days after the sciatic nerve ligation. On the contrary, in female mice, allodynia was still present 121 days after CCI. Sex-dependent differences also resulted from immunofluorescence experiments: in sciatic nerve, the expression of P0 and Neu200 is greater in neuropathic males than in neuropathic females, suggesting faster nerve regeneration. Proteomic analysis confirmed sex-related differences of proteins associated with nerve regenerative processes. In addition, the reactive gliosis induced by CCI at day 7, as revealed by colocalization of glial fibrillary acidic protein (astrocytes) and CD11b (microglia) with phosphorylated p38, disappeared 121 days after CCI in male but not in female mice. These results may have important therapeutic implications for the treatment of neuropathic pain.     

术前给予巴氯酚延迟坐骨神经松结扎神经病理痛的形成

目的研究术前鞘内注射GABAB受体激动剂巴氯酚(Bac)对慢性神经病理痛大鼠痛阈的影响,探讨脊髓GABA能系统在神经病理痛调节中的作用。方法建立慢性坐骨神经结扎损伤模型(CCI),SD大鼠32只随机分成4组:假手术组,大鼠左侧坐骨神经分离,但不结扎,术前鞘内注射生理盐水10μL;神经结扎组,大鼠左侧坐骨神经松结扎,术前鞘内注射生理盐水10μL;Bac 1组,大鼠左侧坐骨神经松结扎前10 min,鞘内注射Bac 0.03μg;Bac 2组,大鼠左侧坐骨神经松结扎前10min,鞘内注射Bac 0.3μg。术后第1、3、5、7、10、14天测大鼠机械刺激缩足反射阈值(MWT)和热刺激缩足反射潜伏期(TWL)以及运动功能。结果术后第1~14天神经结扎组大鼠MWT和TWL较假手术组大鼠明显降低(P<0.05);术前给Bac 0.3μg的坐骨神经结扎大鼠与术前给生理盐水的坐骨神经结扎大鼠比较,术后第1~5天MWT和TWL明显升高(P<0.05)。结论坐骨神经结扎前鞘内注射Bac 0.3μg可延缓大鼠神经病理性疼痛的形成。     

TGF-β1 Attenuates Spinal Neuroinflammation and the Excitatory Amino Acid System in Rats With Neuropathic Pain

Previous studies have reported that the intrathecal (i.t.) administration of transforming growth factor β1 (TGF-β1) prevents and reverses neuropathic pain. However, only limited information is available regarding the possible role and effects of spinal TGF-β1 in neuropathic pain. We aimed to investigate the antinociceptive effects of exogenous TGF-β1 on chronic constriction injury (CCI)-induced neuropathic pain in rats. We demonstrated that sciatic nerve injury caused a downregulation of endogenous TGF-β1 levels on the ipsilateral side of the lumbar spinal dorsal gray matter, and that the i.t. administration of TGF-β1 (.01–10 ng) significantly attenuated CCI-induced thermal hyperalgesia in neuropathic rats. TGF-β1 significantly inhibited CCI-induced spinal neuroinflammation, microglial and astrocytic activation, and upregulation of tumor necrosis factor-α. Moreover, i.t. TGF-β1 significantly attenuated the CCI-induced downregulation of glutamate transporter 1, the glutamate aspartate transporter, and the excitatory amino acid carrier 1 on the ipsilateral side. Furthermore, i.t. TGF-β1 significantly decreased the concentrations of 2 excitatory amino acids, aspartate and glutamate, in the spinal dialysates in CCI rats. In summary, we conclude that the mechanisms of the antinociceptive effects of i.t. TGF-β1 in neuropathy may include attenuation of spinal neuroinflammation, attenuation, or upregulation of glutamate transporter downregulation, and a decrease of spinal extracellular excitatory amino acids.     

Upregulation of spinal cannabinoid-1-receptors following nerve injury enhances the effects of Win 55,212-2 on neuropathic pain behaviors in rats

Exogenous cannabinoids are effective in attenuating neuropathic pain behaviors induced by peripheral nerve injury, but the mechanisms of their effectiveness remain unclear. Here we examined the expression of spinal cannabinoid-1-receptors (CB1Rs) following chronic constriction sciatic nerve injury (CCI) and its relation to the effects of a CBR agonist (Win 55,212-2) on neuropathic pain in rats. CCI induced a time-dependent upregulation of spinal CB1Rs primarily within the ipsilateral superficial spinal cord dorsal horn as revealed by both Western blot and immunohistochemistry. This CCI-induced CB1R upregulation was at least in part mediated through tyrosine kinase receptors (Trk), because intrathecal treatment with the Trk inhibitor K252a (1 microg) for postoperative days 1-6 significantly reduced the CB1R upregulation in CCI rats. At the intracellular level, the mitogen-activated protein kinase (ERK-MAPK) inhibitor PD98059 (1 microg) prevented, while the protein kinase C inhibitor chelerythrine (10 microg) partially reduced, the CCI-induced CB1R upregulation when each agent was administered intrathecally for postoperative days 1-6. Importantly, the CCI-induced upregulation of spinal CB1Rs enhanced the effects of Win 55,212-2 on both thermal hyperalgesia and mechanical allodynia, since inhibition of the CB1R upregulation by PD98059 resulted in a significant reduction of the effects of Win 55,212-2 in CCI rats. These results indicate that upregulation of spinal CB1Rs following peripheral nerve injury may contribute to the therapeutic effects of exogenous cannabinoids on neuropathic pain.     

Spinal leptin contributes to the pathogenesis of neuropathic pain in rodents

Pain after nerve injury, a phenomenon referred to as neuropathic pain, is a debilitating clinical condition, but the underlying mechanisms remain unclear. As leptin, an adipocytokine produced mainly by nonneuronal tissue, has been implicated in the regulation of neuronal functions, we examined the role of leptin in neuropathic pain using a rat model of the condition chronic constriction sciatic nerve injury (CCI). We report that leptin critically contributed to pain behaviors following CCI. Specifically, spinal administration of a leptin antagonist prevented and reversed neuropathic pain behaviors in rats. Further examination revealed that levels of both leptin and the long form of the leptin receptor (Ob-Rb) were substantially increased within the ipsilateral spinal cord dorsal horn after peripheral nerve injury. Mechanistic studies showed that leptin upregulated the expression of both the spinal NMDA receptor and IL-1β through the JAK/STAT pathway. Furthermore, these CCI-induced behavioral and cellular responses were diminished in leptin-deficient mice and mimicked by spinal administration of exogenous leptin in naive rats. Our findings reveal a critical role for spinal leptin in the pathogenesis of neuropathic pain and suggest what we believe to be a novel form of nonneuronal and neuronal interactions in the mechanisms of pathological pain.     

神经性疼痛对老龄大鼠学习记忆功能和海马超微结构的影响

目的:观察神经性疼痛对老龄大鼠学习记忆功能及脑脊液S100B蛋白表达、海马CA1区突触超微结构的影响。方法:18月龄雄性Wistar大鼠60只,随机分为3组:正常组(N组),假手术组(S组),坐骨神经结扎组(C组),松扎左侧坐骨神经。各组按术后第1、7、14、21天再随机分为4个亚组,每组5只。测大鼠热刺激回缩潜伏期(PWTL),用Morris水迷宫测大鼠学习记忆功能,并记录基础值,麻醉后抽取脑脊液ELISA法检测S100B蛋白浓度,透射电镜观察大鼠海马CA1区GrayI型突触结构的变化。结果:①与基础值比较,C组PWTL缩短显著(P0.01)。②与基础值比较,C组大鼠潜伏期显著延长(P0.01)和穿越平台次数显著减少(P0.01);与N组和S组比较,差异有显著性(P0.01)。③与N组和S组比较,C组脑脊液S100B蛋白浓度显著升高(P0.01)。④透射电镜观察,C组大鼠海马突触间隙的增宽,突触囊泡减少。结论:神经性疼痛可致老龄大鼠的空间学习记忆能力下降,脑脊液S100B蛋白表达上调和突触可塑性改变可能是其机制。     

慢性坐骨神经缩窄损伤导致大鼠背根神经节内质网应激反应

目的:研究坐骨神经慢性缩窄(chronic constriction injury,CCI)引起大鼠背根神经节内质网应激反应。方法:56只SD雄性大鼠随机分为两组:假手术组(sham组)和手术组(CCI组)(n=28)。手术前、术后1天、4天、7天、14天、21天和28天测定动物机械痛敏和热痛敏,背根神经节GRP78葡萄糖调节蛋白78(glucose-regulated protein 78,GRP78,内质网应激反应的标志蛋白)的含量。结果:与假手术组相比,CCI组的机械痛阈和热痛阈在术后明显下降,背根神经节GRP78蛋白表达在第1天开始升高,第7天达到高峰。结论:坐骨神经慢性缩窄模型可以激活大鼠背根神经节GRP78蛋白表达和内质网应激反应,可能与神经病理性疼痛的形成有关。     

Antinociceptive effect of peripheral serotonin 5-HT2B receptor activation on neuropathic pain

Serotonin is critically involved in neuropathic pain. However, its role is far from being understood owing to the number of cellular targets and receptor subtypes involved. In a rat model of neuropathic pain evoked by chronic constriction injury (CCI) of the sciatic nerve, we studied the role of 5-HT(2B) receptor in dorsal root ganglia (DRG) and the sciatic nerve. We showed that 5-HT(2B) receptor activation both prevents and reduces CCI-induced allodynia. Intrathecal administration of 5-HT(2B) receptor agonist BW723C86 significantly attenuated established mechanical and cold allodynia; this effect was prevented by co-injection of RS127445, a selective 5-HT(2B) receptor antagonist. A single application of BW723C86 on the sciatic nerve concomitantly to CCI dose-dependently prevented mechanical allodynia and significantly reduced cold allodynia 17 days after CCI. This behavioral effect was accompanied with a marked decrease in macrophage infiltration into the sciatic nerve and, in the DRG, with an attenuated abnormal expression of several markers associated with local neuroinflammation and neuropathic pain. CCI resulted in a marked upregulation of 5-HT(2B) receptor expression in sciatic nerve and DRG. In the latter structure, it was biphasic, consisting of a transient early increase (23-fold), 2 days after the surgery and before the neuropathic pain emergence, followed by a steady (5-fold) increase, that remained constant until pain disappeared. In DRG and sciatic nerve, 5-HT(2B) receptors were immunolocalized on sensory neurons and infiltrating macrophages. Our data reveal a relationship between serotonin, immunocytes, and neuropathic pain development, and demonstrate a critical role of 5-HT(2B) receptors in blood-derived macrophages.     

Effects of insulin treatment on endoneurial and systemic oxidative stress in relation to nerve conduction in streptozotocin-diabetic rats

As increased oxidative stress is probably a pathogenetic factor in the development of diabetic complications, we studied nerve function and endogenous antioxidants in plasma, erythrocytes and sciatic nerve of untreated and insulin-treated streptozotocin-diabetic rats. After 18 weeks, the diabetes-induced sciatic nerve conduction velocity deficits were approximately 65% improved by insulin ( P <0.001). Plasma superoxide dismutase was significantly reduced in diabetes ( P <0.01); smaller decreases in plasma catalase and glutathione levels were observed. These changes were corrected by insulin treatment. In erythrocytes, decreased superoxide dismutase ( P <0.05) and increased total glutathione levels ( P <0.05) were found. All effects of diabetes, including a rise in plasma malonyldialdehyde ( P <0.05), were partially reversed by insulin treatment. In nervous tissue, diabetes caused increased catalase activity, uninfluenced by insulin ( P <0.05). Nerve superoxide dismutase and glutathione did not change. The data suggest that, in diabetes, changes in systemic rather than endoneurial oxidative stress lead to nerve dysfunction.     

Effect of ursolic acid in attenuating chronic constriction injury‐induced neuropathic pain in rats

Ursolic acid (UA; 3b‐hydroxy‐12‐urs‐12‐en‐28‐oic acid), a natural pentacyclic triterpenoid carboxylic acid, has been known to possess potent anti‐inflammatory, antioxidant, and antinociceptive effects in various animal models. Therefore, this study was designed to investigate the antihyperalgesic, anti‐inflammatory, and antioxidant effects of UA at 5, 10, and 20 mg/kg of doses via per os (p.o.) route for 14 days in chronic constriction injury (CCI)‐induced neuropathic pain in rats. Pain behavior in rats was evaluated before and after UA administration via mechanical and heat hyperalgesia. CCI caused significant increase in levels of pro‐inflammatory cytokines and oxido‐nitrosative stress. In addition, significant increase in myeloperoxidase, malondialdehyde, protein carbonyl, nitric oxide (NO), and total oxidant status (TOS) levels in sciatic nerve and spinal cord concomitant with mechanical and heat hyperalgesia is also noted for CCI‐induced neuropathic pain. Administration of UA significantly reduced the increased levels of pro‐inflammatory cytokines and TOS. Further, reduced glutathione is also restored by UA. UA also showed in vitro NO and superoxide radical scavenging activity. UA has a potential in attenuating neuropathic pain behavior in CCI model which may possibly be attributed to its anti‐inflammatory and antioxidant properties.     

Strain-dependent modification of neuropathic pain behaviour in the rat hindpaw by a priming painful trigeminal nerve injury

The aim of the present study was to test the behavioural effect of infraorbital (IO) chronic constriction injury (CCI) on the development of neuropathic pain in the rat hindpaw following sciatic nerve CCI performed 7 days later. Control groups consisted of rats that underwent sham infraorbital surgery followed by sciatic CCI at identical time points. Sensory testing of the rat's face and hindpaw was performed at baseline and at 4, 11, 14, 17 and 21 days postoperative (dpo) relative to the IOCCI, at which time all rats were euthanized. To test for strain differences the experiment was performed on Sprague-Dawley, Sabra and Lewis rats. In Lewis rats the trigeminal nerve injury significantly accelerated the development of hindpaw mechanoallodynia (11th, 14th and 17th dpo, unpaired t-test, P<0.05) and mechanohyperalgesia (14th and 17th dpo, unpaired t-test, P<0.05), following a second sciatic nerve CCI relative to the control group. This effect was not observed in Sprague-Dawley or Sabra rats.     

Ameliorative effect of combined administration of inducible nitric oxide synthase inhibitor with cyclooxygenase-2 inhibitors in neuropathic pain in rats.

OBJECTIVES: The objective of this study was to examine the effects of rofecoxib, meloxicam, both cyclooxygenase-2 (COX-2) inhibitors and aminoguanidine hydrochloride, an inducible nitric oxide synthase (iNOS) inhibitor and their combinations in neuropathic pain in rats. METHODS: Neuropathy was induced by chronic constriction injury (CCI) of right sciatic nerve under ketamine anesthesia in rats. Effect of ED(50) of aminoguanidine hydrochloride, rofecoxib and meloxicam administered orally was investigated using behavioral tests. Effect of combinations of aminoguanidine hydrochloride with rofecoxib and meloxicam was also investigated in neuropathic pain employing behavioral tests. RESULTS: Behavioral tests, mechanical, thermal and cold stimuli confirmed the development of neuropathic pain after CCI. Aminoguanidine hydrochloride, rofecoxib and meloxicam when administered alone, produced significant increase in paw withdrawal threshold to mechanical stimuli at 6 h in ipsilateral hind paw after CCI. Co-administration of aminoguanidine hydrochloride (30 mg/kg) with rofecoxib (1.31 mg/kg) and meloxicam (1.34 mg/kg) was also found to produce significant increase in paw withdrawal latencies to mechanical stimuli at 6 h. Combined administration of aminoguanidine hydrochloride with meloxicam and rofecoxib produced significant rise in pain threshold for mechanical hyperalgesia in ipsilateral hind paw when compared with the groups treated with aminoguanidine hydrochloride, meloxicam and rofecoxib alone. CONCLUSION: Co-administration of meloxicam and rofecoxib with aminoguanidine hydrochloride may be an alternative approach for the treatment of neuropathic pain.     

Gabapentin suppresses ectopic nerve discharges and reverses allodynia in neuropathic rats

Repetitive ectopic discharges from injured afferent nerves play an important role in initiation and maintenance of neuropathic pain. Gabapentin is effective for treatment of neuropathic pain but the sites and mechanisms of its antinociceptive actions remain uncertain. In the present study, we tested a hypothesis that therapeutic doses of gabapentin suppress ectopic afferent discharge activity generated from injured peripheral nerves. Mechanical allodynia, induced by partial ligation of the sciatic nerve in rats, was determined by application of von Frey filaments to the hindpaw. Single-unit afferent nerve activity was recorded proximal to the ligated sciatic nerve site. Intravenous gabapentin, in a range of 30 to 90 mg/kg, significantly attenuated allodynia in nerve-injured rats. Furthermore, gabapentin, in the same therapeutic dose range, dose-dependently inhibited the ectopic discharge activity of 15 injured sciatic afferent nerve fibers through an action on impulse generation. However, the conduction velocity and responses of 12 normal afferent fibers to mechanical stimulation were not affected by gabapentin. Therefore, this study provides electrophysiological evidence that gabapentin is capable of suppressing the ectopic discharge activity from injured peripheral nerves. This action may contribute, at least in part, to the antiallodynic effect of gabapentin on neuropathic pain.     

An Improved Rodent Model of Trigeminal Neuropathic Pain by Unilateral Chronic Constriction Injury of Distal Infraorbital Nerve

The number of studies on trigeminal nerve injury using animal models remains limited. A rodent model of trigeminal neuropathic pain was first developed in 1994, in which chronic constriction injury (CCI) is induced by ligation of the infraorbital nerve (IoN). This animal model has served as a major tool to study trigeminal neuropathic pain. Unfortunately, the surgical procedure in this model is complicated and far more difficult than ligation of peripheral nerves (eg, sciatic nerve). The aim of this study was to improve on the current surgical procedure of IoN ligation to induce trigeminal neuropathic pain in rats. We show that the IoN can be readily accessed through a small facial incision. CCI can be induced by ligation of a segment at the distal IoN (dIoN). This dIoN-CCI procedure is simple, minimally invasive, and time-saving. Our data show that the dIoN-CCI procedure consistently induced acute as well as chronic nociceptive behaviors in rats. Daily gabapentin treatment attenuated mechanical allodynia and reduced face-grooming episodes in dIoN-CCI rats.

Acupoint stimulation with diluted bee venom (apipuncture) alleviates thermal hyperalgesia in a rodent neuropathic pain model: involvement of spinal alpha 2-adrenoceptors.

Chemical acupuncture with diluted bee venom (DBV), termed apipuncture, has been traditionally used in oriental medicine to treat several inflammatory diseases and chronic pain conditions. In the present study we investigated the potential antihyperalgesic and antiallodynic effects of apipuncture in a rat neuropathic pain model. DBV (0.25 mg/kg, subcutaneous) was injected into the Zusanli acupoint 2 weeks after chronic constrictive injury (CCI) of the sciatic nerve. Between 5 and 45 minutes after DBV injection, we observed a significant reduction in the thermal hyperalgesia induced by CCI, but apipuncture failed to reduce CCI-induced mechanical allodynia. We subsequently examined whether this antihyperalgesic effect of apipuncture was related to the activation of spinal opioid receptors and/or alpha2-adrenoceptors. Intrathecal pretreatment with naloxone (10 microg/rat), an opioid receptor antagonist, did not reverse the antihyperalgesic effect of apipuncture, whereas pretreatment with idazoxan (40 microg/rat), an alpha2-adrenoceptor antagonist, completely blocked the effect of apipuncture. These results indicate that DBV-induced apipuncture significantly reduces the thermal hyperalgesia generated by CCI and also suggest that this antihyperalgesic effect is dependent on the activation of alpha2-adrenoceptors, but not opioid receptors, in the spinal cord. PERSPECTIVE: The antinociceptive effect of apipuncture was evaluated in a rodent neuropathic pain model. The relieving effect of apipuncture on thermal hyperalgesia was found to be mediated by spinal alpha2-adrenoceptors, but not opioid receptors. These data suggest that apipuncture might be an effective alternative therapy for patients with painful peripheral neuropathy, especially for those who are poorly responsive to opioid analgesics.     

Tocotrienol ameliorates behavioral and biochemical alterations in the rat model of alcoholic neuropathy

Chronic alcohol consumption produces a painful peripheral neuropathy for which there is no reliable successful therapy, which is mainly due to lack of understanding of its pathobiology. Alcoholic neuropathy is characterized by spontaneous burning pain, hyperalgesia (an exaggerated pain in response to painful stimuli) and allodynia (a pain evoked by normally innocuous stimuli). Chronic alcohol intake is known to decrease the nociceptive threshold with increased oxidative–nitrosative stress and release of proinflammatory cytokines coupled with activation of protein kinase C. The aim of the present study is to investigate the effect of both isoforms of vitamin E, α-tocopherol (100 mg/kg; oral gavage) and tocotrienol (50, 100 and 200 mg/kg; oral gavage) against alcohol-induced neuropathic pain in rats. Male Wistar rats, were administered 35% v/v ethanol (10 g/kg; oral gavage) for 10 weeks, and were treated with α-tocopherol and tocotrienol for the same duration. Ethanol-treated animals showed a significant decrease in nociceptive threshold as evident from decreased tail flick latency (thermal hyperalgesia) and decreased paw-withdrawal threshold in Randall–Sellito test (mechanical hyperalgesia) and von-Frey hair test (mechanical allodynia) along with the reduction in nerve glutathione and superoxide dismutase levels. TNF-α and IL-1β levels were also significantly increased in both serum and sciatic nerve of ethanol-treated rats. Treatment with α-tocopherol and tocotrienol for 10 weeks significantly improved all the above-stated functional and biochemical deficits in a dose-dependent manner with more potent effects observed with tocotrienol. The study demonstrates the effectiveness of tocotrienol in attenuation of alcoholic neuropathy.     

Tramadol relieves thermal hyperalgesia in rats with chronic constriction injury of the sciatic nerve

The present study was designed to test whether tramadol is effective in the control of neuropathic pain in rats. Chronic constriction injury (CCI) of the sciatic nerve was induced over the left hind limb in male Sprague-Dawley rats. Identical surgery was performed on the opposite side except that the sciatic nerve was not ligated (sham surgery). Paw withdrawal latency (PWL) to heat was tested for each hind paw 1 day before surgery and on the 4th day after surgery to ensure the development of thermal hyperalgesia. In the acute treatment groups, saline or tramadol was administered subcutaneously at doses of 10, 20 or 30 mg/kg, and PWLs were measured 30, 60, 90, 120, 150 and 180 min after treatment. In the semi-chronic treatment groups, continuous systemic administration of tramadol 40 mg/kg/day or saline for 7 days was provided at a uniform rate via osmotic mini pumps. Tramadol reversed PWL in a dose-dependent manner in the acute treatment groups. PWLs were significantly reversed at 2 days after tramadol infusion, and this effect was sustained throughout the remainder of the treatment period in comparison with the saline group. Tramadol also resulted in a decreased sensitivity to thermal stimulus on the sham limb both in acute and semi-chronic administration. We conclude that both acute and semi-chronic tramadol treatment relieves thermal hyperalgesia effectively in rats with CCI of the sciatic nerve. This indicates that tramadol shows promise as a potential treatment for relief of neuropathic pain in humans.