Changes in cardiovascular parameters and plasma norepinephrine level in rats after chronic constriction injury on the sciatic nerve

To evaluate whether neuropathic pain affects autonomic nervous activities, we investigated daily change in cardiovascular parameters and plasma norepinephrine (NE) in free-moving rats after chronic constriction injury (CCI) on the sciatic nerve. Arterial blood pressure (BP), heart rate (HR), and the power spectrum of pulse interval variability were analyzed. Daily change in motor activity and nociceptive behavior was also measured from some CCI rats. In others, NE from daily blood samples was quantified and spontaneous pain was evaluated by daily monitoring of foot guarding behavior. We identified three stages in the daily change of cardiovascular parameters and plasma NE level over 3 weeks following CCI. The first stage (up to 3 days after the surgery) was characterized by increased MAP and HR, especially in the daytime, even though plasma NE was unchanged and motor activity decreased. The second stage (mid first to mid second postoperative weeks) was characterized by increased daytime MAP and HR, and the animals developed punctate hyperalgesia in the affected hindpaw. An NE surge that may have been related to spontaneous pain was present 3-5 days after CCI. The third stage, which appeared after the second postoperative week, was characterized by normalized MAP and decreased HR, and increased high-frequency (0.8-3.0Hz) power in pulse interval variability, which is an index of cardiac parasympathetic tone. These results demonstrated that cardiovascular function was kept high through sympathetic and non-sympathetic activity for 2 weeks after CCI, followed by a predominance of parasympathetic tone.     

The tibial neuroma transposition (TNT) model of neuroma pain and hyperalgesia

Peripheral nerve injury may lead to the formation of a painful neuroma. In patients, palpating the tissue overlying a neuroma evokes paraesthesias/dysaesthesias in the distribution of the injured nerve. Previous animal models of neuropathic pain have focused on the mechanical hyperalgesia and allodynia that develops at a location distant from the site of injury and not on the pain from direct stimulation of the neuroma. We describe a new animal model of neuroma pain in which the neuroma was located in a position that is accessible to mechanical testing and outside of the innervation territory of the injured nerve. This allowed testing of pain in response to mechanical stimulation of the neuroma (which we call neuroma tenderness) independent of pain due to mechanical hyperalgesia. In the tibial neuroma transposition (TNT) model, the posterior tibial nerve was ligated and transected in the foot just proximal to the plantar bifurcation. Using a subcutaneous tunnel, the end of the ligated nerve was positioned just superior to the lateral malleolus. Mechanical stimulation of the neuroma produced a profound withdrawal behavior that could be distinguished from the hyperalgesia that developed on the hind paw. The neuroma tenderness (but not the hyperalgesia) was reversed by local lidocaine injection and by proximal transection of the tibial nerve. Afferents originating from the neuroma exhibited spontaneous activity and responses to mechanical stimulation of the neuroma. The TNT model provides a useful tool to investigate the differential mechanisms underlying the neuroma tenderness and mechanical hyperalgesia associated with neuropathic pain.     

Low frequencies, but not high frequencies of bi-polar spinal cord stimulation reduce cutaneous and muscle hyperalgesia induced by nerve injury

Spinal cord stimulation (SCS) is an established treatment for neuropathic pain. However, SCS is not effective for all the patients and the mechanisms underlying the reduction in pain by SCS are not clearly understood. To elucidate the mechanisms of pain relief by SCS, we utilized the spared nerve injury model. Sprague–Dawley rats were anesthetized, the tibial and common peroneal nerves were tightly ligated, and an epidural SCS lead implanted in the upper lumbar spinal cord. SCS was delivered daily at one of 4 different frequencies (4 Hz, 60 Hz, 100 Hz, and 250 Hz) at approximately 85% of motor threshold 2 weeks after nerve injury for 4 days. Mechanical withdrawal threshold of the paw and compression withdrawal threshold of the hamstring muscles were measured before and after SCS on each day. All rats showed a decrease in withdrawal threshold of the paw and the muscle 2 weeks after nerve injury. Treatment with either 4 Hz or 60 Hz SCS significantly reversed the decreased withdrawal threshold of the paw and muscle. The effect was cumulative with a greater reversal by the fourth treatment when compared to the first treatment. Treatment with 100 Hz, 250 Hz or sham SCS had no significant effect on the decreased withdrawal threshold of the paw or muscle that normally occurs after nerve injury. In conclusion, SCS at 4 Hz and 60 Hz was more effective in reducing hyperalgesia than higher frequencies of SCS (100 Hz and 250 Hz); and repeated treatments result in a cumulative reduction in hyperalgesia.     

Somatosensory function in patients with and without pain after traumatic peripheral nerve injury

Why traumatic injuries to the peripheral nervous system infrequently result in neuropathic pain is still unknown. The aim of this study was to examine the somatosensory system in patients with traumatic peripheral nerve injury with and without pain to try to unravel possible links to mechanisms underlying development and maintenance of pain. Eighteen patients with spontaneous ongoing pain and 16 patients without pain after unilateral partial peripheral traumatic nerve injury were studied. In the area of partial denervation and in the corresponding contralateral area perception thresholds to warmth, cold, light touch, pressure pain, cold‐ and heat pain were assessed as were pain intensities at suprathreshold heat pain stimulation. Comparing sides patients with pain reported allodynia to cold (p = 0.03) and pressure (p = 0.016) in conjunction with an increase in the perception threshold to non‐painful warmth (p = 0.024) on the injured side. Pain‐free patients reported hypoesthesia to light touch (p = 0.002), cold (p = 0.039) and warmth (p = 0.001) on the injured side. There were no side differences in stimulus–response functions using painful heat stimuli in any of the groups. In addition, no significant difference could be demonstrated in any sensory modality comparing side‐to‐side differences between the two groups. In conclusion, increased pain sensitivity to cold and pressure was found on the injured side in pain patients, pointing to hyperexcitability in the pain system, a finding not verified by a more challenging analysis of side‐to‐side differences between patients with and without pain.     

Lack of interleukin-17 leads to a modulated micro-environment and amelioration of mechanical hypersensitivity after peripheral nerve injury in mice

Interleukin-17 (IL-17) is involved in a wide range of inflammatory disorders and in recruitment of inflammatory cells to injury sites. A recent study of IL-17 knock-out mice revealed that IL-17 contributes to neuroinflammation and neuropathic pain after peripheral nerve injury. Surprisingly, little is known of micro-environment modulation by IL-17 in injured sites and in pathologically related neuroinflammation and chronic neuropathic pain. Therefore, we investigated nociceptive sensitization, immune cell infiltration, myeloperoxidase (MPO) activity, and expression of multiple cytokines and opioid peptides in damaged nerves of wild-type (IL-17^+/+) and IL-17 knock-out (IL-17−/−) mice after partial sciatic nerve ligation. Our results demonstrated that the IL-17−/− mice had less behavioral hypersensitivity after partial sciatic nerve ligation, and inflammatory cell infiltration and pro-inflammatory cytokine (tumor necrosis factor–α, IL-6, and interferon-γ) levels in damaged nerves were significantly decreased, with the levels of anti-inflammatory cytokines IL-10 and IL-13, and expressions of enkephalin, β-endorphin, and dynorphin were also decreased compared to those in wild-type control mice. In conclusion, we provided evidence that IL-17 modulates the micro-environment at the level of the peripheral injured nerve site and regulates progression of behavioral hypersensitivity in a murine chronic neuropathic pain model. The attenuated behavioral hypersensitivity in IL-17−/− mice could be a result of decreased inflammatory cell infiltration to the injured site, resulting in modulation of the pro- and anti-inflammatory cytokine milieu within the injured nerve. Therefore, IL-17 may be a critical component for neuropathic pain pathogenesis and a novel target for therapeutic intervention for this and other chronic pain states.     

P-selectin is required for neutrophils and macrophage infiltration into injured site and contributes to generation of behavioral hypersensitivity following peripheral nerve injury in mice

Growing evidence suggests that leukocyte extravasation is initiated by the interaction of selectins with their ligands; as well as an essential role for P-selectin in the initial recruitment of inflammatory cells to sites of inflammation. In this study, P-selectin-deficient (P-sel−/−) mice were used to test the hypothesis that lack of P-selectin would attenuate the recruitment of inflammatory cells to the site of inflammation, thereby modulating pain in a murine chronic neuropathic pain model. Nociceptive sensitization and the microenvironment of the peripheral injury site were studied in wild-type (P-sel+/+) and P-selectin-deficient (P-sel−/−) mice after partial sciatic nerve ligation (PSNL). Variables measured included myeloperoxidase (MPO) activity, several inflammatory cell infiltration profiles, cytokines, and endogenous opioid peptide expression in damaged nerves. Results indicate that behavioral hypersensitivity, MPO activity, and infiltration of neutrophils and macrophages were attenuated in P-sel−/− mice after PSNL. Proinflammatory cytokines, tumor necrosis factor α, and interleukin (IL)-6, were reduced in damaged nerves following PSNL; however, several antiinflammatory cytokines – IL-1Ra, IL-4, and IL-10 – were significantly increased in P-sel−/− mice. In addition, endogenous opioid peptides mRNA was significantly lower in P-sel−/− mice compared with P-sel +/+ mice. The current results demonstrated that the absence of P-selectin in mice leads to an altered microenvironment that attenuated behavioral hypersensitivity. The specific role of P-selectin could have been a result of decreased neutrophils, as well as the accumulation of macrophages at the site of injury, which may subsequently modulate the inflammatory cytokine expression and impact behavioral hypersensitivity within the injured nerve.     

Fast-conducting mechanoreceptors contribute to withdrawal behavior in normal and nerve injured rats

Fast-conducting myelinated high-threshold mechanoreceptors (AHTMR) are largely thought to transmit acute nociception from the periphery. However, their roles in normal withdrawal and in nerve injury–induced hyperalgesia are less well accepted. Modulation of this subpopulation of peripheral neurons would help define their roles in withdrawal behaviors. The optically active proton pump, ArchT, was placed in an adeno-associated virus-type 8 viral vector with the CAG promoter and was administered by intrathecal injection resulting in expression in myelinated neurons. Optical inhibition of peripheral neurons at the soma and transcutaneously was possible in the neurons expressing ArchT, but not in neurons from control animals. Receptive field characteristics and electrophysiology determined that inhibition was neuronal subtype–specific with only AHTMR neurons being inhibited. One week after nerve injury the AHTMR are hyperexcitable, but can still be inhibited at the soma and transcutaneously. Withdrawal thresholds to mechanical stimuli in normal and in hyperalgesic nerve-injured animals also were increased by transcutaneous light to the affected hindpaw. This suggests that AHTMR neurons play a role not only in threshold-related withdrawal behavior in the normal animal, but also in sensitized states after nerve injury. This is the first time this subpopulation of neurons has been reversibly modulated to test their contribution to withdrawal-related behaviors before and after nerve injury. This technique may prove useful to define the role of selective neuronal populations in different pain states.     

Effects of intrathecal lidocaine on hyperalgesia and allodynia following chronic constriction injury in rats

The present study investigated the effects of different doses of intrathecal lidocaine on established thermal hyperalgesia and tactile allodynia in the chronic constriction injury model of neuropathic pain, defined the effective drug dose range, the duration of pain‐relief effects, and the influence of this treatment on the body and tissues. Male Sprague–Dawley rats were divided into five groups and received intrathecal saline or lidocaine (2, 6.5, 15, and 35mg/kg) 7 days after loose sciatic ligation. Respiratory depression and hemodynamic instability were found to become more severe as doses of lidocaine increased during intrathecal therapy. Two animals in the group receiving 35mg/kg lidocaine developed pulmonary oedema and died. Behavioral tests indicated that 6.5, 15, and 35mg/kg intrathecal lidocaine showed different degrees of reversal of thermal hyperalgesia, and lasted for 2–8 days, while 2mg/kg lidocaine did not. The inhibition of tactile allodynia was only observed in rats receiving 15 and 35mg/kg lidocaine, and the anti‐allodynic effects were identical in these two groups. Histopathologic examinations on the spinal cords revealed mild changes in rats receiving 2–15mg/kg lidocaine. However, lesions were severe after administration of 35mg/kg lidocaine. These findings indicate that intrathecal lidocaine has prolonged therapeutic effects on established neuropathic pain. The balance between sympathetic and parasympathetic nervous activities could be well preserved in most cases, except for 35mg/kg. Considering the ratio between useful effects and side effects, doses of 15mg/kg are suitable for intrathecal injection for relief of neuropathic pain.     

Induction of high mobility group box-1 in dorsal root ganglion contributes to pain hypersensitivity after peripheral nerve injury

Pro-inflammatory cytokine high mobility group box-1 (HMGB-1) is involved in inflammation in the central nervous system, but less is known about its biological effects in the peripheral nervous system. In the present study, the role of HMGB-1 in the primary afferent nerve was investigated in the context of the pathophysiology of peripheral nerve injury-induced pain hypersensitivity. Real-time PCR confirmed an increase in HMGB-1 mRNA expression in the dorsal root ganglion (DRG) and spinal nerve at 1 day after spinal nerve ligation (SNL). Induction of HMGB-1 mRNA was observed in both injured L5 and uninjured L4. Immunohistochemistry for HMGB-1 revealed that SNL-induced HMGB-1 expression in the primary afferent neurons and satellite glial cells (SGCs) in the DRG, and in Schwann cells in the spinal nerve. Up-regulation of HMGB-1 was associated with translocation of its signal from the nucleus to the cytoplasm. Injection of HMGB-1 into the sciatic nerve produces transient behavioural hyperalgesia. Neutralizing antibody against HMGB-1 successfully alleviated the mechanical allodynia observed after SNL treatment. Receptor for advanced glycation end products (RAGE), one of the major receptors for HMGB-1, was expressed in the primary afferent neurons and SGCs in the DRG, as well as in Schwann cells in the spinal nerve. These results indicate that HMGB-1 is synthesized and secreted into the DRG and spinal nerve, and contributes to the development of neuropathic pain after nerve injury. Blocking HMGB-1/RAGE signalling might thus be a promising therapeutic strategy for the management of neuropathic pain.     

Mechanical allodynia but not thermal hyperalgesia is impaired in mice deficient for ERK2 in the central nervous system

Extracellular signal-regulated kinase (ERK) plays critical roles in pain plasticity. However, the specific contribution of ERK2 isoforms to pain plasticity is not necessarily elucidated. Here we investigate the function of ERK2 in mouse pain models. We used the Cre-loxP system to cause a conditional, region-specific, genetic deletion of Erk2. To induce recombination in the central nervous system, Erk2-floxed mice were crossed with nestin promoter-driven cre transgenic mice. In the spinal cord of resultant Erk2 conditional knockout (CKO) mice, ERK2 expression was abrogated in neurons and astrocytes, but indistinguishable in microglia compared to controls. Although Erk2 CKO mice showed a normal baseline paw withdrawal threshold to mechanical stimuli, these mice had a reduced nociceptive response following a formalin injection to the hind paw. In a partial sciatic nerve ligation model, Erk2 CKO mice showed partially restored mechanical allodynia compared to control mice. Interestingly, thermal hyperalgesia was indistinguishable between Erk2 CKO and control mice in this model. In contrast to Erk2 CKO mice, mice with a targeted deletion of ERK1 did not exhibit prominent anomalies in these pain models. In Erk2 CKO mice, compensatory hyperphosphorylation of ERK1 was detected in the spinal cord. However, ERK1 did not appear to influence nociceptive processing because the additional inhibition of ERK1 phosphorylation using MEK (MAPK/ERK kinase) inhibitor SL327 did not produce additional changes in formalin-induced spontaneous behaviors in Erk2 CKO mice. Together, these results indicate that ERK2 plays a predominant and/or specific role in pain plasticity, while the contribution of ERK1 is limited.     

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.     

Post-operative pain behavior in rats is reduced after single high-concentration capsaicin application

Surgical procedures associated with tissue injury are often followed by increased sensitivity to innocuous and noxious stimuli in the vicinity of the surgical wound. The aim of this study was to evaluate the role of transient receptor potential vanilloid 1 receptor (TRPV1) containing nociceptors in this process, by their functional inactivation using a high-concentration intradermal injection of capsaicin in a rat plantar incision model. Paw withdrawal responses to mechanical stimuli (von Frey filaments 10-367mN) and to radiant heat applied on plantar skin were tested in animals treated with capsaicin or the vehicle 6 days and 24h before or 2h after the incision was made. In the vehicle-treated animals, mechanical and thermal sensitivity increased significantly 1-96h following the incision. Capsaicin applied 24h before the surgery was most effective and significantly diminished the development of post-incisional mechanical allodynia and hyperalgesia. Thermal hypoalgesia was present in the incised paw after the capsaicin treatment. Capsaicin application 6 days before the incision induced thermal hypoalgesia before the incision but did not prevent completely the thermal hyperalgesia after the incision, while there was also a reduction of mechanical hypersensitivity. Application of the capsaicin injection after the incision showed its first effect at 2h after the injection and at 24h the effect was comparable with the 6 days pretreatment. Our results show an important role of TRPV1-containing nociceptors in the development of post-surgical hypersensitivity and suggest that local, high-concentration capsaicin treatment could be used to reduce it.     

Methylprednisolone prevents nerve injury-induced hyperalgesia in neprilysin knockout mice

The pathophysiology of the complex regional pain syndrome involves enhanced neurogenic inflammation mediated by neuropeptides. Neutral endopeptidase (neprilysin, NEP) is a key enzyme in neuropeptide catabolism. Our previous work revealed that NEP knock out (ko) mice develop more severe hypersensitivity to thermal and mechanical stimuli after chronic constriction injury (CCI) of the sciatic nerve than wild-type (wt) mice. Because treatment with glucocorticoids is effective in early complex regional pain syndrome, we investigated whether methylprednisolone (MP) reduces pain and sciatic nerve neuropeptide content in NEP ko and wt mice with nerve injury. After CCI, NEP ko mice developed more severe thermal and mechanical hypersensitivity and hind paw edema than wt mice, confirming previous findings. Hypersensitivity was prevented by MP treatment in NEP ko but not in wt mice. MP treatment had no effect on protein levels of calcitonin-gene related peptide, substance P, and bradykinin in sciatic nerves of NEP ko mice. Endothelin-1 (ET-1) levels were higher in naïve and nerve-injured NEP ko than in wt mice, without an effect of MP treatment. Gene expression of the ET-1 receptors ET_AR and ET_BR was not different between genotypes and was not altered after CCI, but was increased after additional MP treatment. The ET_BR agonist IRL-1620 was analgesic in NEP ko mice after CCI, and the ET_BR antagonist BQ-788 showed a trend to reduce the analgesic effect of MP. The results provide evidence that MP reduces CCI-induced hyperalgesia in NEP ko mice, and that this may be related to ET-1 via analgesic actions of ET_BR.     

Spinal administration of a delta opioid receptor agonist attenuates hyperalgesia and allodynia in a rat model of neuropathic pain.

Neuropathic (NP) pain is a debilitating chronic pain disorder considered by some to be inherently resistant to therapy with traditional analgesics. Indeed, micro opioid receptor (OR) agonists show reduced therapeutic benefit and their long term use is hindered by the high incidence of adverse effects. However, pharmacological and physiological evidence increasingly suggests a role for deltaOR agonists in modulating NP pain symptoms. In this study, we examined the antihyperalgesic and antiallodynic effects of the spinally administered deltaOR agonist, d-[Ala(2), Glu(4)]deltorphin II (deltorphin II), as well as the changes in deltaOR expression, in rats following chronic constriction injury (CCI) of the sciatic nerve. Rats with CCI exhibited cold hyperalgesia and mechanical allodynia over a 14-day testing period. Intrathecal administration of deltorphin II reversed cold hyperalgesia on day 14 and dose-dependently attenuated mechanical allodynia. The effects of deltorphin II were mediated via activation of the deltaOR as the effect was antagonized by co-treatment with the delta-selective antagonist, naltrindole. Western blotting experiments revealed no changes in deltaOR protein in the dorsal spinal cord following CCI. Taken together, these data demonstrate the antihyperalgesic and antiallodynic effectiveness of a spinally administered deltaOR agonist following peripheral nerve injury and support further investigation of deltaORs as potential therapeutic targets in the treatment of NP pain.     

Prevention of NKCC1 phosphorylation avoids downregulation of KCC2 in central sensory pathways and reduces neuropathic pain after peripheral nerve injury

Neuropathic pain after peripheral nerve injury is characterized by loss of inhibition in both peripheral and central pain pathways. In the adult nervous system, the Na⁺–K⁺–2Cl⁻ (NKCC1) and neuron-specific K⁺–Cl⁻ (KCC2) cotransporters are involved in setting the strength and polarity of GABAergic/glycinergic transmission. After nerve injury, the balance between these cotransporters changes, leading to a decrease in the inhibitory tone. However, the role that NKCC1 and KCC2 play in pain-processing brain areas is unknown. Our goal was to study the effects of peripheral nerve injury on NKCC1 and KCC2 expression in dorsal root ganglia (DRG), spinal cord, ventral posterolateral (VPL) nucleus of the thalamus, and primary somatosensory (S1) cortex. After sciatic nerve section and suture in adult rats, assessment of mechanical and thermal pain thresholds showed evidence of hyperalgesia during the following 2 months. We also found an increase in NKCC1 expression in the DRG and a downregulation of KCC2 in spinal cord after injury, accompanied by later decrease of KCC2 levels in higher projection areas (VPL and S1) from 2 weeks postinjury, correlating with neuropathic pain signs. Administration of bumetanide (30 mg/kg) during 2 weeks following sciatic nerve lesion prevented the previously observed changes in the spinothalamic tract projecting areas and the appearance of hyperalgesia. In conclusion, the present results indicate that changes in NKCC1 and KCC2 in DRG, spinal cord, and central pain areas may contribute to development of neuropathic pain.     

针刺激对大鼠坐骨神经损伤后神经生长因子mRNA表达的影响

目的:探讨针刺对神经生长因子信使RNA(NGF mRNA)表达的影响,并且从这一角度分析评价电针频率的不同,及电针与手针对神经生长的影响。方法:78只雄性SD大鼠随机分为5组,治疗1组(n=18),疏波,电压2V,频率:F1:5Hz。治疗2组(n=18):疏波,电压2V,频率:F1:100Hz。治疗3组(n=18):手针。模型组(n=18):行坐骨神经损伤手术造模,不行治疗。对照组(n=6),正常成年大鼠。治疗组与模型组均行坐骨神经损伤手术造模,术后第2天开始给予电针及针刺治疗,电针正极接在近心端,负极接在远心端。分别夹在"环跳"、"足三里"处的针柄上,每次30min,每日2次。手针针刺相同穴位,每次30min,每日2次。术后1、2、6周取治疗组大鼠神经损伤部位远侧坐骨神经干0.6cm,应用原位杂交的方法和图像分析处理系统定量测定坐骨神经组织中NGF mRNA水平。结果:治疗组NGF mRNA表达明显增加,均高于模型组(均P<0.01);治疗1组NGF mRNA表达始终处于高水平,明显高于模型组(P<0.01)。结论:针刺激是促进周围神经损伤再生的重要手段,其中5Hz低频电针效果最佳。     

Sigma-1 receptors regulate activity-induced spinal sensitization and neuropathic pain after peripheral nerve injury

Sigma-1 receptor (σ₁R) is expressed in key CNS areas involved in nociceptive processing but only limited information is available about its functional role. In the present study we investigated the relevance of σ₁R in modulating nerve injury-evoked pain. For this purpose, wild-type mice and mice lacking the σ₁R gene were exposed to partial sciatic nerve ligation and neuropathic pain-related behaviors were investigated. To explore underlying mechanisms, spinal processing of repetitive nociceptive stimulation and expression of extracellular signal-regulated kinase (ERK) were also investigated. Sensitivity to noxious heat of homozygous σ₁R knockout mice did not differ from wild-type mice. Baseline values obtained in σ₁R knockout mice before nerve injury in the plantar, cold-plate and von Frey tests were also indistinguishable from those obtained in wild-type mice. However, cold and mechanical allodynia did not develop in σ₁R null mice exposed to partial sciatic nerve injury. Using isolated spinal cords we found that mice lacking σ₁R showed reduced wind-up responses respect to wild-type mice, as evidenced by a reduced number of action potentials induced by trains of C-fiber intensity stimuli. In addition, in contrast to wild-type mice, σ₁R knockout mice did not show increased phosphorylation of ERK in the spinal cord after sciatic nerve injury. Both wind-up and ERK activation have been related to mechanisms of spinal cord sensitization. Our findings identify σ₁R as a constituent of the mechanisms modulating activity-induced sensitization in pain pathways and point to σ₁R as a new potential target for drugs designed to alleviate neuropathic pain.     

Chronic blockade of interleukin‐1 (IL‐1) prevents and attenuates neuropathic pain behavior and spontaneous ectopic neuronal activity following nerve injury

Neuropathic pain is a chronic pain state resulting from peripheral nerve injury, characterized by hyperalgesia and allodynia. We have reported that mice with genetic impairment of IL‐1 signaling display attenuated neuropathic pain behavior and ectopic neuronal activity. In order to substantiate the role of IL‐1 in neuropathic pain, WT mice were implanted subcutaneously with osmotic micropumps containing either IL‐1ra or vehicle. Two days following the implantation, two models of neuropathic pain were used; partial nerve injury (spinal nerve transection, SNT), or complete nerve cut (spinal neuroma model). Mechanosensitivity was assessed seven consecutive days following SNT, and on day 7 recordings of spontaneous ectopic activity were performed. In the spinal nerve neuroma model, autotomy scores were recorded up to 35 days. Vehicle‐treated mice developed significant allodynia and autotomy, and clear ectopic activity (4.1±1.1% of the axons); whereas IL‐1ra‐treated mice did not display allodynic response, displayed delayed onset of autotomy and markedly reduced severity of autotomy scores, and displayed reduced spontaneous activity (0.8±0.4% of the axons). To test whether IL‐1 is involved in maintenance of mechanical allodynia, a separate group of WT mice was treated with a single injection of either saline or IL‐1ra four days following SNT, after the allodynic response was already manifested. Whereas saline‐treated mice displayed robust allodynia, acute IL‐1ra treatment induced long‐lasting attenuation of the allodynic response. The results support our hypothesis that IL‐1 signaling plays an important role in neuropathic pain and in the ectopic neuronal activity that underling its development.     

低频电针对选择性神经损伤大鼠神经痛维持期脊髓背角PKA-TRPV1通路及痛敏递质的干预作用

目的 探讨低频电针干预神经病理痛维持期脊髓背角（SCDH）蛋白激酶A（PKA）、辣椒素受体（TRPV1）通路的调控机制。 方法 将大鼠随机分为空白对照组、假手术组、模型对照组、电针干预组4组。采用坐骨神经分支选择性神经损伤（SNI）方法建立神经病理痛模型。电针干预取术侧足三里、昆仑穴,频率2Hz,每日1次,连续干预14d。检测大鼠术侧后足缩足阈值（PWT）、SCDH PKA和TRPV1以及降钙素基因相关肽（CGRP）和P物质（SP）水平。 结果 SNI模型大鼠术侧PWT下降（P<0.01）,术侧SCDH PKA、TRPV1、CGRP、SP水平均上调（P<0.05）;2Hz电针可提高SNI模型大鼠PWT（P<0.01）,降低术侧SCDH PKA、TRPV1、CGRP、SP水平（P<0.05）。 结论 低频电针能改善神经病理痛,可能与其下调SCDH PKA-TRPV1通路以及CGRP、SP痛敏递质水平有关。     

Brain derived nerve growth factor induces spinal noradrenergic fiber sprouting and enhances clonidine analgesia following nerve injury in rats

Many treatments for neuropathic pain activate or augment norepinephrine release in the spinal cord, yet these treatments are less effective against acute nociceptive stimuli. We previously showed in mice that peripheral nerve injury results in sprouting of spinal noradrenergic fibers, possibly reflecting the substrate for this shift in drug efficacy. Here, we tested whether such sprouting also occurs in rats after nerve injury and examined one signal for such sprouting. Ligation of L5 and L6 spinal nerves unilaterally in rats resulted in hypersensitivity to tactile stimulation of the ipsilateral paw, and sprouting of noradrenergic fibers in the dorsal horn of the lumbar spinal cord. Brain derived nerve growth factor (BDNF) content increased in L4-L6 dorsal root ganglia ipsilateral to injury and in lumbar spinal cord following nerve injury, and intrathecal infusion of BDNF antiserum prevented spinal noradrenergic sprouting. This treatment also prevented the increased analgesic efficacy of intrathecal clonidine observed after nerve injury. Intraspinal injection of BDNF in non-injured rats mimicked the sprouting of spinal noradrenergic fibers seen after nerve injury. These results suggest that increased BDNF synthesis and release drives spinal noradrenergic sprouting following nerve injury, and that this sprouting may paradoxically increase the capacity for analgesia in the setting of neuropathic pain from drugs which utilize or mimic the noradrenergic pathway.