趋化因子CXCL13及其受体CXCR5在1型糖尿病DPNP中的作用机制

目的 探讨趋化因子CXCL13及其受体CXCR5在1型糖尿病引发的糖尿病性周围神经病理性疼痛（DPNP）中的作用机制。方法 将36只C57BL/6小鼠随机分为C57BL/6空白对照组和C57BL/6模型组（每组18只）。C57BL/6模型组采用腹腔注射链脲佐菌素（60 mg/kg）构建1型糖尿病模型。每周观测小鼠的体质量、血糖、机械痛和热痛阈值。于第15周检测2组脊髓中趋化因子、趋化因子受体和促炎因子水平的变化以及血清中炎症因子的变化。在上述试验基础上,再分别取12只C57BL/6小鼠和12只CXCR5^-/-小鼠按前述方法分别设立对照组和模型组（每组6只）,于第4周检测各组机械痛敏、第6周检测热痛敏。结果 C57BL/6模型组小鼠的脊髓中CXCL13和CXCR5等趋化因子及其受体的mRNA明显上调（P均<0.05）。C57BL/6模型组小鼠血糖升高、体质量减少,第4周的机械痛阈值降低、第6周的热痛阈值降低（P均<0.05）,但CXCR5^-/-模型组小鼠机械痛和热痛阈值无变化。与C57BL/6空白对照组比较,C57BL/6模型组小鼠的星形胶质细胞标志物胶质纤维酸性蛋白、小型胶质细胞标志物离子钙结合衔接分子1以及炎症因子标志物环氧化酶-2、IL-1β以及磷酸化的丝裂原活化蛋白激酶（ERK）和信号转导和转录激活因子3（STAT3）的水平升高（P均<0.05）;血清中炎症因子IL-6、TNF-α和IL-1β蛋白水平升高（P均<0.01）。结论 趋化因子CXCL13及其受体CXCR5的激活或可促使1型糖尿病DPNP的发生,相关机制可能是通过激活胶质细胞与磷酸化的ERK、STAT3和炎症因子表达实现的。     

CXCL13通过CXCR5激活星形胶质细胞中JNK参与痛觉过敏

目的:探讨CXCL13及其受体CXCR5参与痛觉过敏的机制.方法:细胞培养和免疫荧光染色检测脊髓背角神经元中CXCL13的表达;通过转染CXCL13和CXCR5过表达质粒研究CXCL13和CXCR5的相互作用;Western Blot方法检测CXCL13重组因子刺激原代星形胶质细胞后JNK磷酸化水平变化和鞘内注射CXC...     

Chemokine contribution to neuropathic pain: Respective induction of CXCL1 and CXCR2 in spinal cord astrocytes and neurons

Recent studies have indicated an important role of chemokines such as CCL2 in the development of chronic pain. However, the distinct roles of different chemokines in the development and maintenance of neuropathic pain and in their interactions with neurons have not been clearly elucidated. We found that spinal nerve ligation (SNL) not only induced persistent neuropathic pain symptoms, including mechanical allodynia and heat hyperalgesia, but also produced sustained CXCL1 upregulation in the spinal cord. Double staining of immunofluorescence and in situ hybridization revealed that CXCL1 was primarily induced in spinal astrocytes. In cultured astrocytes, tumor necrosis factor-α induced robust CXCL1 expression via the activation of the c-jun N-terminal kinase. Intrathecal administration of CXCL1 neutralizing antibody transiently reduced SNL-induced pain hypersensitivity, suggesting an essential role of CXCL1 in neuropathic pain sensitization. In particular, intraspinal delivery of CXCL1 shRNA lentiviral vectors, either before or after SNL, persistently attenuated SNL-induced pain hypersensitivity. Spinal application of CXCL1 not only elicited pain hypersensitivity but also induced rapid neuronal activation, as indicated by the expression of phosphorylated extracellular signal-regulated kinase and cAMP response element binding protein, and c-Fos in spinal cord neurons. Interestingly, CXCR2, the primary receptor of CXCL1, was upregulated in dorsal horn neurons after SNL, and the CXCR2 antagonist SB225002 completely blocked the CXCL1-induced heat hyperalgesia. SB225002 also attenuated SNL-induced pain hypersensitivity. Collectively, our results have demonstrated a novel form of chemokine-mediated glial-neuronal interaction in the spinal cord that can drive neuropathic pain. Inhibition of the CXCL1-CXCR2 signaling may offer a new therapy for neuropathic pain management.     

系统性红斑狼疮患者外周血滤泡辅助性T细胞与CXCR5及其配体CXCL13基因表达水平的研究

目的检测滤泡辅助性T细胞(Tfh)的CXCR5、CXCL13在系统性红斑狼疮(SLE)患者外周血中的表达,探讨其与SLE的发生及病情活动性的关系。方法 90例SLE患者和60例健康对照者,采用流式细胞术检测外周血单个核细胞(PBMC)中CXCR5+PD-1+/CD4+T细胞(Tfh)比例,酶联免疫吸附试验(ELISA)法检测血清中CXCR5、CXCL13浓度,实时荧光定量RT-PCR检测PBMC中CXCR5 mRNA、CXCL13 mRNA的表达。结果活动组SLE患者外周血Tfh比例(11.01%±1.31%)、血清中CXCR5、CXCL13浓度[分别为(368.21±171.56)pg/ml、(387.59±213.54)pg/ml]和CXCR5 mRNA、CXCL13 mRNA(分别为2.15±0.63、1.71±0.37)的表达均高于健康对照组[分别为1.78%±0.11%,(210.6±100.17)pg/ml,(149.45±104.52)pg/ml,0.53±0.22,0.46±0.13;均P<0.05];SLE患者外周血Tfh比例与CXCR5 mRNA的表达水平呈正相关(r=0.68,P<0.01),与SLEDAI亦呈正相关(r=0.67,P<0.01),其中CXCR5 mRNA的表达水平与SLEDAI呈高度正相关(r=0.82,P<0.01)。SLE患者外周血Tfh比例与CXCL13 mRNA的表达水平呈正相关(r=0.73,P<0.01),与SLEDAI亦呈正相关(r=0.87,P<0.01)。结论 SLE患者外周血中Tfh细胞比例、CXCR5、CXCL13明显升高,可能在其发病过程中起了一定的作用。     

Low-dose methotrexate reduces peripheral nerve injury-evoked spinal microglial activation and neuropathic pain behavior in rats

Peripheral nerve injuries that provoke neuropathic pain are associated with microglial activation in the spinal cord. We have investigated the characteristics of spinal microglial activation in three distinct models of peripheral neuropathic pain in the rat: spared nerve injury (SNI), chronic constriction injury, and spinal nerve ligation. In all models, dense clusters of cells immunoreactive for the microglial marker CD11b formed in the ipsilateral dorsal horn 7 days after injury. Microglial expression of ionised calcium binding adapter molecule 1 (Iba1) increased by up to 40% and phosphorylation of p38 mitogen-activated protein kinase, a marker of microglial activity, by 45%. Expression of the lysosomal ED1-antigen indicated phagocytic activity of the cells. Unlike the peripheral nerve lesions, rhizotomy produced only a weak microglial reaction within the spinal gray matter but a strong activation of microglia and phagocytes in the dorsal funiculus at lumbar and thoracic spinal cord levels. This suggests that although degeneration of central terminals is sufficient to elicit microglial activation, it does not account for the inflammatory response in the dorsal horn after peripheral nerve injury. Early intrathecal treatment with low-dose methotrexate, beginning at the time of injury, decreased microglial activation, reduced p38 phosphorylation, and attenuated pain-like behavior after SNI. In contrast, systemic or intrathecal delivery of the glucocorticoid dexamethasone did not inhibit the activation of microglia or reduce pain-like behavior. We confirm that microglial activation is crucial for the development of pain after nerve injury, and demonstrates that suppression of this cellular immune response is a promising approach for preventing neuropathic pain.     

Differential activation of spinal cord glial cells in murine models of neuropathic and cancer pain

Activation of spinal cord microglia and astrocytes is a common phenomenon in nerve injury pain models and is thought to exacerbate pain perception. Following a nerve injury, a transient increase in the presence of microglia takes place while the increased numbers of astrocytes stay elevated for an extended period of time. It has been proposed that activated microglia are crucial for the development of neuropathic pain and that they lead to activation of astrocytes which then play a role in maintaining the long term pathological pain sensation. In the present report, we examined the time course of spinal cord glial activation in three different murine pain models to investigate if microglial activation is a general prerequisite for astrocyte activation in pain models. We found that two different types of cancer induced pain resulted in severe spinal astrogliosis without activation of microglia. In contrast, sciatic nerve injury led to a transient activation of microglia and sustained astrogliosis. These results show that development of hypersensitivity and astrocyte activation in pain models can take place independent of microglial activation.     

Referred sensations and neuropathic pain following spinal cord injury

It has been proposed that painful and non-painful referred sensations (RSs) are associated with reorganization of sensory pathways in patients with complete spinal cord injury (SCI). In order to investigate the referred sensation (RS) phenomenon and its correlation with neuropathic pain (NP) 48 patients with complete SCI, 24 with chronic NP and 24 without pain or paraesthesias were studied using clinical examination and neurophysiological tests. Patients reporting RSs were re-examined at 2 and 10 weeks after the first examination. We defined the presence of RS as sensations perceived below the injury level in response to touch and pinprick stimuli in various body points above the injury level. The examination was carried out by one researcher applying the stimuli to the patient under two visual conditions (open and closed eyes), and then asking the patient to make tactile self-stimulation. Seven patients with SCI and NP (29%) reported RS below the injury level. RS were well located and consistently evoked at repeated examinations. Touch and pinprick stimulation elicited similar RS that were non-painful in six patients and painful in one. Visual feedback did not change RS perception and characteristics. None of the patients in the SCI group without NP presented RS. In conclusion, our results indicate that RS is relatively frequent in patients with complete SCI and NP. The common occurrence of RS in patients with NP and the location of the sensations in the same area as NP suggest that pain and RS share common pathophysiological mechanisms.     

趋化因子CXCL10作为神经病理性疼痛生物标记物的研究

目的:目前临床上缺乏神经病理性疼痛诊断和预后判断的客观指标,本研究旨在检测神经病理性疼痛小鼠和人的脑脊液(cerebrospinal fluid,CSF)和血清中趋化因子CXCL10的表达情况。方法:结扎ICR小鼠L5脊神经(spinal nerve ligation,SNL)构建神经病理性疼痛(neuropathic pain,NP)模型,足底注射福尔马林或完全弗氏佐剂(complete Freund's adjuvant,CFA)建立炎症性疼痛模型;收集捐献者的脑脊液和血液,采用Real-time PCR、半定量PCR、Western Blot、免疫荧光和ELISA方法,分别检测CXCL10和CXCR3的mRNA和蛋白表达、CSF和血清中CXCL10的表达。结果:①Cxcl10在正常ICR小鼠的脾脏、淋巴结、背根神经节(dorsal root ganglion,DRG)、脊髓和脑中有不同程度的基础表达;②Cxcr3在正常ICR小鼠的脾脏、淋巴结、DRG、脊髓和脑中也有不同程度的基础表达;③与假手术组相比,SNL模型小鼠CSF与血清中CXCL10含量显著增加(P<0.05,P<0.01);急性炎症性疼痛小鼠CSF和血清中CXCL10与对照组相比无显著变化;慢性炎症性疼痛小鼠CSF中CXCL10与对照组相比无显著变化;血清中CXCL10显著增加(P<0.05);④健康人类受试者的脊髓、DRG和淋巴结中有CXCL10和CXCR3表达;⑤疱疹后神经痛病人CSF与血清中CXCL10与对照组相比显著增加(P<0.05),骨性关节炎病人CSF和血清中CXCL10无显著增加。结论:神经病理性小鼠CSF和血清以及疱疹后神经痛病人CSF和血清中CXCL10表达显著增加,CXCL10可能作为神经病理性疼痛的生物标志物。     

Reactive oxygen species contribute to neuropathic pain and locomotor dysfunction via activation of CamKII in remote segments following spinal cord contusion injury in rats

In this study, we examined whether blocking spinal cord injury (SCI)-induced increases in reactive oxygen species (ROS) by a ROS scavenger would attenuate below-level central neuropathic pain and promote recovery of locomotion. Rats with T10 SCI developed mechanical allodynia in both hind paws and overproduction of ROS, as assayed by Dhet intensity, in neurons in the lumbar 4/5 dorsal horn (^∗P < 0.05). To scavenge ROS, phenyl-N-tert-butylnitrone (PBN, a ROS scavenger) was administered immediately after SCI and for 7 consecutive days (early treatment) by either intrathecal (it; 1 and 3 mg) or systemic (ip; 10, 50 and 100 mg) injections. In addition, the high doses of it (3 mg) or ip (100 mg) injections were performed at 35 days (delayed treatment) after SCI. High doses of PBN (ip, 100 mg, and it, 3 mg) significantly attenuated mechanical allodynia in both hind paws at both early and delayed treatments, respectively (^∗P < 0.05). The abnormal hyperexcitability of wide dynamic range neurons after SCI was significantly attenuated by both early and delayed PBN treatment (^∗P < 0.05). Early PBN treatment (100 mg, ip, and 3 mg, it) attenuated overproduction of ROS in neurons in the lumbar 4/5 dorsal horn. In addition, it and ip t-BOOH (ROS donor) treatment dose-dependently produced mechanical allodynia in both hind paws (^∗P < 0.05). Both SCI and t-BOOH treatment groups showed significantly increased phospho-CamKII (pCamKII) expression in neurons and KN-93 (an inhibitor of pCamKII) significantly attenuated mechanical allodynia (^∗P < 0.05). In addition, high doses of PBN significantly promoted the recovery of locomotion (^∗P < 0.05). In conclusion, the present data suggest that overproduction of ROS contribute to sensory and motor abnormalities in remote segments below the lesion after thoracic SCI.     

Complement activation in the peripheral nervous system following the spinal nerve ligation model of neuropathic pain

Neuroinflammatory and neuroimmune mechanisms, as exemplified by infiltrating immune cells and activation of resident endothelial/glial cells, respectively, are known to be involved in the establishment and maintenance of chronic pain. An immune system pathway that may be involved in the activation of both immune and glial cells is complement. The complement pathway is made up of a large number of distinct plasma proteins which react with one another to opsonize pathogens and induce a series of inflammatory responses to help fight infection. Cleaved products and complexes produced by complement activation are responsible for a range of effects including mediation of immune infiltration, activation of phagocytes, opsonization/lysis of pathogens and injured cells, and production of vasoactive amines such as histamine and serotonin. Gene-expression microarray-analysis performed on the rat spinal nerve ligation (SNL) model of neuropathic pain revealed that multiple complement components including the C1 inhibitor, C1q alpha, beta, and gamma, C1r, C1s, C2, C3, C4, C7, and factors B, D, H, and P, were up-regulated while DAF was down-regulated. Regulation of C3 and DAF was confirmed by real-time RT-PCR and in situ hybridization. To test the hypothesis that complement plays a role in neuropathic pain, SNL rats were treated with cobra venom factor (CVF) to deplete plasma of complement component C3. Pain behavior was significantly attenuated in SNL rats treated with CVF as was complement activity at the ipsilateral dorsal root ganglia. Our results suggest the complement pathway might be a novel target for the development of neuropathic pain therapeutics.     

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.     

脊髓活性氧激活自噬参与调节2型糖尿病神经病理性疼痛

目的:探讨脊髓中活性氧(reactive oxygen species, ROS)是否通过激活自噬参与大鼠2型糖尿病神经病理性疼痛(diabetic neuropathic pain, DNP)的形成和发展。方法:清洁级雄性SD大鼠高脂高糖喂养8周,后链脲佐菌素(streptozocin, STZ)单次小剂量(35 mg/kg)腹腔注射,注射后3 d血糖≥16.7 mmol/L为成功诱导2型糖尿病发生;注射后14 d行为学测定痛阈下降至基础值的85%以下,即为成功制备出大鼠2型DNP模型,否则为2型糖尿病不痛组(PL组)。将造模成功的2型DNP大鼠随机分为3组,每组10只:DNP组、DNP+ROS清除剂组(DNP+PBN组)和溶剂对照组(SC组)。另取10只正常SD大鼠为对照组(C组),普通饲料喂养,给予PBN后3 d、7 d、14 d时测定所有组别大鼠的机械缩足反应阈值(mechanical withdrawal threshold, MWT)和热缩足潜伏期(thermal withdrawal latency, TWL),随后处死大鼠,取脊髓腰膨大L4-L6,用免疫印迹法测定脊髓中Beclin 1、LC3II/LC3I和p62的表达水平;用流式细胞仪测定脊髓组织中活性氧(ROS)的含量。结果:与C组和PL组比较,DNP组和SC组于模型制备成功后3 d、7 d和14 d时MWT下降,TWL缩短,脊髓ROS、Beclin 1和LC3II/LC3I表达上调(P <0.05),而p62表达下降(P <0.05);与DNP组比较,DNP+PBN组在3 d、7 d和14 d时MWT升高、TWL延长,脊髓Beclin 1和LC3II/LC3I表达下降(P <0.05),而p62表达上调(P <0.05);DNP组与SC组各指标比较差异均无统计学意义。结论:脊髓ROS通过激活自噬参与调节2型糖尿病神经病理性疼痛的产生和维持。     

Cell therapy for neuropathic pain in spinal cord injuries

Cell therapy to treat neuropathic pain after spinal cord injury (SCI) is in its infancy. However, the development of cellular strategies that would replace or be used as an adjunct to existing pharmacological treatments for neuropathic pain have progressed tremendously over the past 20 years. The earliest cell therapy studies for pain relief tested adrenal chromaffin cells from rat or bovine sources, placed in the subarachnoid space, near the spinal cord pain- processing pathways. These grafts functioned as cellular minipumps, secreting a cocktail of antinociceptive agents around the spinal cord for peripheral nerve injury, inflammatory or arthritic pain. These initial animal, and later clinical, studies suggested that the spinal intrathecal space was a safe and accessible location for the placement of cell grafts. However, one major problem was the lack of a homogeneous, expandable cell source to supply the antinociceptive agents. Cell lines that can be reversibly immortalised are the next phase for the development of a practical, homogenous cell source. These technologies have been modelled with a variety of murine cell lines, derived from embryonic adrenal medulla or CNS brainstem, in which cells are transplanted, which downregulate their proliferative, oncogenic phenotype either before or after transplant. An alternative approach for existing human cell lines is the use of neural or adrenal precursors, in which the antinociceptive properties are induced by in vitro treatment with molecules that move the cells to an irreversible neural or chromaffin, and non-oncogenic, phenotype. Although such human cell lines are at an early stage of investigation, their clinical antinociceptive potential is significant given the daunting problem of difficult-to-treat neuropathic SCI pain.     

Cell therapy for neuropathic pain in spinal cord injuries

Cell therapy to treat neuropathic pain after spinal cord injury (SCI) is in its infancy. However, the development of cellular strategies that would replace or be used as an adjunct to existing pharmacological treatments for neuropathic pain have progressed tremendously over the past 20 years. The earliest cell therapy studies for pain relief tested adrenal chromaffin cells from rat or bovine sources, placed in the subarachnoid space, near the spinal cord pain- processing pathways. These grafts functioned as cellular minipumps, secreting a cocktail of antinociceptive agents around the spinal cord for peripheral nerve injury, inflammatory or arthritic pain. These initial animal, and later clinical, studies suggested that the spinal intrathecal space was a safe and accessible location for the placement of cell grafts. However, one major problem was the lack of a homogeneous, expandable cell source to supply the antinociceptive agents. Cell lines that can be reversibly immortalised are the next phase for the development of a practical, homogenous cell source. These technologies have been modelled with a variety of murine cell lines, derived from embryonic adrenal medulla or CNS brainstem, in which cells are transplanted, which downregulate their proliferative, oncogenic phenotype either before or after transplant. An alternative approach for existing human cell lines is the use of neural or adrenal precursors, in which the antinociceptive properties are induced by in vitro treatment with molecules that move the cells to an irreversible neural or chromaffin, and non-oncogenic, phenotype. Although such human cell lines are at an early stage of investigation, their clinical antinociceptive potential is significant given the daunting problem of difficult-to-treat neuropathic SCI pain.     

Chronic neuropathic pain in spinal cord injury: Efficiency of deep brain and motor cortex stimulation therapies for neuropathic pain in spinal cord injury patients

ObjectivesIn spite of all the scientific advances in pharmacological research, a great number of patients cannot efficiently manage their chronic pain with conventional pharmacological treatments. Brain stimulation techniques have considerably improved these last 10 years. These techniques could be an interesting option after a rigorous selection of patients. We aim to evaluate the efficacy of brain stimulation (deep brain stimulation [DBS] and motor cortex stimulation [MCS]) within the framework of neuropathic pain management in spinal cord injury (SCI) patients and elaborate some recommendations.Material and methodThe methodology used, proposed by the French Society of Physical Medicine and Rehabilitation (SOFMER), includes a systematic review of the literature, the gathering of information regarding current clinical practices and a validation by a multidisciplinary panel of experts.ResultsDBS is more effective on nociceptive pain than deafferentation pain. For the central pain of SCI patients, the long-term efficacy of DBS is quite low (three patients out of 19, amounting to 16%). MCS seems to have an interesting potential with a long-term efficacy of 57% (four patients out of seven), with less complications than DBS.ConclusionFor central pain in SCI patients, there is no sufficient level of evidence to validate the use of DBS. There is however a low level of evidence for MCS. These results must be validated by larger comparative or controlled versus placebo clinical studies.     

Peripherally acting mu-opioid receptor agonist attenuates neuropathic pain in rats after L5 spinal nerve injury

Studies in experimental models and controlled patient trials indicate that opioids are effective in managing neuropathic pain. However, side effects secondary to their central nervous system actions present barriers to their clinical use. Therefore, we examined whether activation of the peripheral mu-opioid receptors (MORs) could effectively alleviate neuropathic pain in rats after L5 spinal nerve ligation (SNL). Systemic loperamide hydrochloride (0.3–10 mg/kg, s.c.), a peripherally acting MOR-preferring agonist, dose-dependently reversed the mechanical allodynia at day 7 post-SNL. This anti-allodynic effect produced by systemic loperamide (1.5 mg/kg, s.c.) was blocked by systemic pretreatment with either naloxone hydrochloride (10 mg/kg, i.p.) or methyl-naltrexone (5 mg/kg, i.p.), a peripherally acting MOR-preferring antagonist. It was also blocked by ipsilateral intraplantar pretreatment with methyl-naltrexone (43.5 μg/50 μl) and the highly selective MOR antagonist CTAP (5.5 μg/50 μl). However, this anti-allodynic effect of systemic loperamide was not blocked by intraplantar pretreatment with the delta-opioid receptor antagonist naltrindole hydrochloride (45.1 μg/50 μl). The anti-allodynic potency of systemic loperamide varied with time after nerve injury, with similar potency at days 7, 28, and 42 post-SNL, but reduced potency at day 14 post-SNL. Ipsilateral intraplantar injection of loperamide also dose-dependently (10–100 μg/50 μl) reversed mechanical allodynia on day 7 post-SNL. We suggest that loperamide can effectively attenuate neuropathic pain, primarily through activation of peripheral MORs in local tissue. Therefore, peripherally acting MOR agonists may represent a promising therapeutic approach for alleviating neuropathic pain.