Neurotropin reverses paclitaxel-induced neuropathy without affecting anti-tumour efficacy

Paclitaxel is a commonly used anticancer drug, but it frequently causes peripheral neuropathy. Neurotropin, a non-protein extract from inflamed rabbit skin inoculated with vaccinia virus, has been used to treat various chronic painful conditions. In the present study, we investigated the effect of neurotropin on the paclitaxel-induced neuropathy in rats. Repeated administration of paclitaxel induced mechanical allodynia, cold hyperalgesia, and motor dysfunction. These neuropathies were mostly reversed by the repeated administration of neurotropin. Furthermore, neurotropin ameliorated the paclitaxel-induced axonal degeneration in cultured PC12 and rat dorsal root ganglion cells, and in rat sciatic nerve. In addition, neurotropin did not affect the microtubule aggregation or anti-tumour effect induced by paclitaxel in the tumour cell lines or tumour cells-implanted mice. These results suggest that neurotropin reverses the paclitaxel-induced neuropathy without affecting anti-tumour activity of paclitaxel, and therefore may be useful for the paclitaxel-induced neuropathy in clinical settings.     

An effective therapeutic approach for oxaliplatin-induced peripheral neuropathy using a combination therapy with goshajinkigan and bushi

Oxaliplatin-induced peripheral neuropathy (OIPN) occurs at extraordinarily high frequency, but no effective treatment for this disorder has been established. Goshajinkigan (GJG), a traditional Japanese medicine known as Kampo, is known to reduce OIPN in both basic and clinical studies. However, its molecular mechanisms remain largely unknown. Here, we elucidate the mechanisms underlying the therapeutic effects of GJG against OIPN and the therapeutic benefits of combining GJG with bushi, a herbal medicine derived from the processed Aconiti tuber. Oxaliplatin (4 mg/kg) was injected into mice twice a week for up to 4 and 3 weeks, respectively. OIPN was assessed using pain behavioral tests, such as those testing cold hypersensitivity, thermal hyperalgesia, and mechanical allodynia, as well as a reduction of the current perception threshold (CPT). GJG (0.3 or 1 g/kg) and bushi (0.1 or 0.3 g/kg) were orally administered 5 times a week for 4 weeks. Behavioral analysis was performed 24 h after the final dose.

Oxaliplatin induced cold hypersensitivity and mechanical allodynia but not thermal hyperalgesia and reduced CPT of Aδ- and Aβ-fibers but not C-fibers. All these effects were counteracted by GJG. Bushi, an ingredient of GJG that shows analgesic effect, reduced oxaliplatin-induced cold hypersensitivity but had no effect on oxaliplatin-induced mechanical allodynia. However, bushi significantly accentuated the effects of GJG when co-administered with GJG. GJG reduces OIPN by counteracting the sensitization of Aδ- and Aβ-fibers and shows analgesic effects against cold hypersensitivity and mechanical allodynia. These effects are potentiated by bushi. The combination of GJG with bushi has high potential for preventing OIPN.     

Pain in oxaliplatin-induced neuropathy--sensitisation in the peripheral and central nociceptive system

BackgroundThis study aimed to determine the somatosensory characteristics and pain types in patients with acute oxaliplatin-induced neuropathy and to relate this profile to the hereby detected underlying pathophysiological mechanisms.Patients and methodsSixteen patients treated with oxaliplatin for cancer were characterised with neurological assessment and a standardised and validated set for quantitative sensory testing (QST). Patients were allocated to two groups depending on the presence or absence of pain symptoms of acute neuropathy.ResultsComparison with normative data revealed in patients with pain symptoms a characteristic somatosensory profile of cold and mechanical hyperalgesia. Group-to-group analysis revealed additional heat hyperalgesia and warm hypoesthesia.ConclusionPain symptoms of acute oxaliplatin-induced neuropathy are related to signs of sensitisation within the peripheral (cold and heat hyperalgesia) and central nervous nociceptive system (mechanical hyperalgesia). This strengthens the rationale for treatment with anticonvulsants and antidepressants and fosters research on ion channel and receptor related mechanisms.     

Analgesic effects of clinically used compounds in novel mouse models of polyneuropathy induced by oxaliplatin and cisplatin

Background

Peripheral neuropathy is the major dose-limiting side effect of cisplatin and oxaliplatin, and there are currently no effective treatments available. The aim of this study was to assess the pharmacological mechanisms underlying chemotherapy-induced neuropathy in novel animal models based on intraplantar administration of cisplatin and oxaliplatin and to systematically evaluate the analgesic efficacy of a range of therapeutics.

Methods

Neuropathy was induced by a single intraplantar injection of cisplatin or oxaliplatin in C57BL/6J mice and assessed by quantification of mechanical and thermal allodynia. The pharmacological basis of cisplatin-induced neuropathy was characterized using a range of selective pharmacological inhibitors. The analgesic effects of phenytoin, amitriptyline, oxcarbazepine, mexiletine, topiramate, retigabine, gabapentin, fentanyl, and Ca^2+/Mg²⁺ were assessed 24 hours after induction of neuropathy.

Results

Intraplantar administration of cisplatin led to the development of mechanical allodynia, mediated through Na_v1.6-expressing sensory neurons. Unlike intraplantar injection of oxaliplatin, cold allodynia was not observed with cisplatin, consistent with clinical observations. Surprisingly, only fentanyl was effective at alleviating cisplatin-induced mechanical allodynia despite a lack of efficacy in oxaliplatin-induced cold allodynia. Conversely, lamotrigine, phenytoin, retigabine, and gabapentin were effective at reversing oxaliplatin-induced cold allodynia but had no effect on cisplatin-induced mechanical allodynia. Oxcarbazepine, amitriptyline, mexiletine, and topiramate lacked efficacy in both models of acute chemotherapy-induced neuropathy.

Conclusion

This study established a novel animal model of cisplatin-induced mechanical allodynia consistent with the A-fiber neuropathy seen clinically. Systematic assessment of a range of therapeutics identified several candidates that warrant further clinical investigation.     

New pharmacological effect of fulvestrant to prevent oxaliplatin-induced neurodegeneration and mechanical allodynia in rats

Oxaliplatin, which is widely used as chemotherapy for certain solid cancers, frequently causes peripheral neuropathy. Commonly described neuropathic symptoms include aberrant sensations such as mechanical allodynia (hypersensitivity to normally innocuous stimuli). Although oxaliplatin neuropathy is a dose-limiting toxicity, there are no established preventive strategies available at present. By screening several sets of small-molecule chemical libraries (more than 3,000 compounds in total) using a newly established in vitro high-throughput phenotypic assay, we identified fulvestrant, a clinically approved drug for the treatment of breast cancer in postmenopausal women, as having a protective effect on oxaliplatin-induced neuronal damage. Furthermore, histological and behavioural analyses using a rat model of oxaliplatin neuropathy demonstrated the in vivo efficacy of fulvestrant to prevent oxaliplatin-induced axonal degeneration of the sciatic nerve and mechanical allodynia. Furthermore, fulvestrant did not interfere with oxaliplatin-induced cytotoxicity against cancer cells. Thus, our findings reveal a previously unrecognised pharmacological effect of fulvestrant to prevent oxaliplatin-induced painful peripheral neuropathy without impairing its cytotoxicity against cancer cells and may represent a novel prophylactic option for patients receiving oxaliplatin chemotherapy.     

普瑞巴林对泰素诱导大鼠神经病理性疼痛治疗作用的研究

目的：研究普瑞巴林在泰素化疗所致大鼠神经病理性疼痛方面的治疗作用。方法：40只SD雄性大鼠随机分为正常对照组、普瑞巴林治疗组（30mg／kg,共16d,口服）、泰素治疗组（2mg／kg,隔日1次,共4次,腹腔给药）、低剂量普瑞巴林治疗组和高剂量普瑞巴林治疗组（泰素大鼠模型给予普瑞巴林10和30mg／kg,共16d,口服）共5组。给药第16天检测所有大鼠的机械性痛阈、热痛阂和冷痛阈,电镜检测大鼠坐骨神经。结果：与正常对照组相比,泰素能够产生机械性异常疼痛[（32．5±3．7）％vs（7．5±3．1）％,P〈0．01]、机械性痛觉过敏[（52．5±7．5）％VS（12．5±3．7）％,P〈0．01]、冷异常性疼痛[（2．9±0．5）Svs（0．5±0．3）S,P〈0．01]以及坐骨神经损伤,不伴有热痛觉过敏[（9．1±0．6）s vs（11．0±0．8）S,P〉0．053。而口服普瑞巴林（30mg／kg）连续16d能有效的降低泰素导致的神经病理性疼痛,与泰素组相比,它能减轻机械性痛觉异常[（12．5±3．7）％us（32．5±3．7）％,P〈0．013、机械性痛觉过敏[（30．0±3．8）％vs（52．5±7．5）％,P〈0．053、冷异常性疼痛[（1．4±0．3）Svs（2．9±0．5）S,P〈0．05]以及部分减轻坐骨神经损伤。结论：普瑞巴林能有效的减轻泰素化疗所致的神经病理性疼痛,可能是一种潜在有效的治疗化疗药物神经毒性的药物。     

Oxaliplatin-induced neuropathic pain involves HOXA6 via a TET1-dependent demethylation of the SOX10 promoter

Chemotherapy-induced neuropathic pain is a common dose-limiting side effect of cancer treatment but the underlying mechanisms are largely unknown. Here, we used a whole-genome expression microarray and gene ontology analysis to identify the upregulation of a sequence-specific DNA-binding protein, HOXA6, in the spinal dorsal horn on Day 10 after injection of rats with oxaliplatin. Genetic disruption of HOXA6 with siRNAs alleviated mechanical allodynia after oxaliplatin administration. Reduced representation bisulfite sequencing assays indicated that oxaliplatin decreased the methylation levels of the SOX10 promoter but not of HOXA6. TET1 was also upregulated by oxaliplatin. Genetic disruption of TET1 with siRNA blocked the promoter demethylation of SOX10 and the upregulation of HOXA6 and SOX10. Importantly, inhibition of SOX10 by intrathecal application of SOX10 siRNA ameliorated the mechanical allodynia induced by oxaliplatin and downregulated the expression of HOXA6. Consistently, overexpression of SOX10 through intraspinal injection of AAV-SOX10-EGFP produced mechanical allodynia and upregulated the expression of spinal dorsal horn HOXA6. Moreover, chromatin immunoprecipitation assays demonstrated that oxaliplatin increased the binding of SOX10 to the promoter region of HOXA6. Taken together, our data suggest that HOXA6 upregulation through the TET1-mediated promoter demethylation of SOX10 may contribute to oxaliplatin-induced neuropathic pain.     

Clonidine,an alpha‐2 adrenoceptor agonist relieves mechanical allodynia in oxaliplatin‐induced neuropathic mice; potentiation by spinal p38 MAPK inhibition without motor dysfunction and hypotension

Cancer chemotherapy with platinum‐based antineoplastic agents including oxaliplatin frequently results in a debilitating and painful peripheral neuropathy. We evaluated the antinociceptive effects of the alpha‐2 adrenoceptor agonist, clonidine on oxaliplatin‐induced neuropathic pain. Specifically, we determined if (i) the intraperitoneal (i.p.) injection of clonidine reduces mechanical allodynia in mice with an oxaliplatin‐induced neuropathy and (ii) concurrent inhibition of p38 mitogen‐activated protein kinase (MAPK) activity by the p38 MAPK inhibitor SB203580 enhances clonidine's antiallodynic effect. Clonidine (0.01–0.1 mg kg^?1, i.p.), with or without SB203580(1‐10 nmol, intrathecal) was administered two weeks after oxaliplatin injection(10 mg kg^?1, i.p.) to mice. Mechanical withdrawal threshold, motor coordination and blood pressure were measured. Postmortem expression of p38 MAPK and ERK as well as their phosphorylated forms(p‐p38 and p‐ERK) were quantified 30 min or 4 hr after drug injection in the spinal cord dorsal horn of treated and control mice. Clonidine dose‐dependently reduced oxaliplatin‐induced mechanical allodynia and spinal p‐p38 MAPK expression, but not p‐ERK. At 0.1 mg  kg^?1, clonidine also impaired motor coordination and decreased blood pressure. A 10 nmol dose of SB203580 alone significantly reduced mechanical allodynia and p‐p38 MAPK expression, while a subeffective dose(3 nmol) potentiated the antiallodynic effect of 0.03 mg kg^?1 clonidine and reduced the increased p‐p38 MAPK. Coadministration of SB203580 and 0.03 mg kg^?1 clonidine decreased allodynia similar to that of 0.10 mg kg^?1 clonidine, but without significant motor or vascular effects. These findings demonstrate that clonidine treatment reduces oxaliplatin‐induced mechanical allodynia. The concurrent administration of SB203580 reduces the dosage requirements for clonidine, thereby alleviating allodynia without producing undesirable motor or cardiovascular effects.     

奥沙利铂神经毒性机制及预测

 作为大肠癌的主要化疗药物之一,奥沙利铂的应用正逐步扩展到其他肿瘤的治疗中,然而奥沙利铂相关外周神经病变却限制了其临床应用。奥沙利铂神经毒性的机制尚未明确,最新研究认为急性神经毒性是通过改变Na+短暂电导介导的;体外实验证实了丝裂原活化蛋白激酶(MAPK)在奥沙利铂慢性神经病变中的作用。多种指标可用于预测奥沙利铂相关的外周神经病变,为实现个体化药物治疗、提高化疗的连续性带来了希望。     

丹参酮ⅡA抑制奥沙利铂诱发周围神经病变大鼠神经生长因子的表达

目的 观察丹参酮ⅡA对奥沙利铂诱发周围神经毒性大鼠的神经生长因子的抑制作用。方法 30只健康Wistar大鼠随机分成3组,对照组、模型组、丹参酮防治组。除对照组外,其余各组均予以腹腔注射奥沙利铂（20 mg/kg）造模。防治组在造模前3天至造模后第7天持续给药;并利用神经电生理仪检测大鼠机械性痛阈和冷刺激性疼痛,Western blot检测脊髓背角神经中神经生长因子（nerve growth factor,NGF）的表达。结果 造模后6 h大鼠机械性痛阈较对照组降低,冷刺激缩足时间缩短（P<0.05）,并随着观察时间的延长,痛阈值明显下降,在72 h达到最低并一直持续1周;第7天检测各组大鼠脊髓背角神经元中NGF表达情况,模型组较对照组明显降低;应用丹参酮ⅡA干预后,与模型组相比,大鼠机械性痛阈明显回升,对冷刺激耐受时间延长,NGF表达量明显增高（P<0.05）。结论 丹参酮ⅡA可能是通过提高NGF的表达,发挥防治奥沙利铂诱导的周围神经病变的作用。     

The Kampo medicine,Goshajinkigan, prevents neuropathy in patients treated by FOLFOX regimen

Background  

Oxaliplatin is now considered a standard treatment for advanced or unresectable colorectal cancer, but its main dose-limiting toxicity is sensory neuropathy. The OPTIMOX (stop and go) approach offers a reasonable strategy, but the preventive agent is not established. It is reported that the Kampo medicine, Goshajinkigan (GJG), has recently been considered an effective agent for the neuropathy of taxanes and for vibration sensation in patients with diabetic neuropathy. The aim of this study was to clarify the efficacy of GJG for peripheral neuropathy associated with oxaliplatin therapy.     

Clinical management of oxaliplatin-associated neurotoxicity

In recent years, oxaliplatin-based chemotherapy protocols, particularly oxaliplatin in combination with infusional 5-fluorouracil/leucovorin (FOLFOX or FUFOX), have emerged as the standard of care in first- and second-line therapy of advanced-stage colorectal cancer. Although oxaliplatin by itself has only mild hematologic and gastrointestinal side effects, its clinically dominating toxicity affects the peripheral sensory nervous system in the form of 2 distinct types of neurotoxicity: (1) a unique, frequent, acute sensory neuropathy that is triggered or aggravated by exposure to cold but at the same time is rapidly reversible without persistent impairment of sensory functions; (2) the dose-limiting toxicity of oxaliplatin, a cumulative, chronic sensory neurotoxicity that resembles that of cisplatin with the important difference of its being more rapidly and completely reversible. This chronic sensory neurotoxicity is highly predictable, being closely associated with the cumulative dose of oxaliplatin that is administered. Various strategies have been proposed to prevent or treat oxaliplatin-induced neurotoxicity. The stop-and-go concept uses the predictability and reversibility of neurologic symptoms to allow patients to stay on an oxaliplatin-containing first-line therapy for a prolonged period. Several neuromodulatory agents such as calcium-magnesium infusions; antiepileptic drugs like carbamazepine, gabapentin, and venlafaxine; amifostine; a-lipoic acid; and glutathione have demonstrated some activity in the prophylaxis and treatment of oxaliplatin-induced acute neuropathy. However, randomized trials demonstrating a prophylactic or therapeutic effect on oxaliplatin's cumulative neurotoxicity are still lacking. The predictability of neurotoxicity associated with oxaliplatin-based therapy should allow patients and doctors to develop strategies to manage this side effect in view of the individual patient's clinical situation. This is of increasing importance, because the addition of bevacizumab to FOLFOX will conceivably further prolong the progression-free survival achieved with FOLFOX so that neurotoxicity and not tumor progression could become the dominating treatment-limiting issue in the first-line therapy of advanced colorectal cancer.     

Transient receptor potential ankyrin 1 (TRPA1) plays a critical role in a mouse model of cancer pain

There is a major, unmet need for the treatment of cancer pain, and new targets and medicines are required. The transient receptor potential ankyrin 1 (TRPA1), a cation channel expressed by nociceptors, is activated by oxidizing substances to mediate pain-like responses in models of inflammatory and neuropathic pain. As cancer is known to increase oxidative stress, the role of TRPA1 was evaluated in a mouse model of cancer pain. Fourteen days after injection of B16-F10 murine melanoma cells into the plantar region of the right hind paw, C57BL/6 mice exhibited mechanical and thermal allodynia and thigmotaxis behavior. While heat allodynia was partially reduced in TRP vanilloid 1 (TRPV1)-deficient mice, thigmotaxis behavior and mechanical and cold allodynia were absent in TRPA1-deficient mice. Deletion of TRPA1 or TRPV1 did not affect cancer growth. Intrathecal TRPA1 antisense oligonucleotides and two different TRPA1 antagonists (HC-030031 or A967079) transiently attenuated thigmotaxis behavior and mechanical and cold allodynia. A TRPV1 antagonist (capsazepine) attenuated solely heat allodynia. NADPH oxidase activity and hydrogen peroxide levels were increased in hind paw skin 14 days after cancer cell inoculation. The antioxidant, α-lipoic acid, attenuated mechanical and cold allodynia and thigmotaxis behavior, but not heat allodynia. Whereas TRPV1, via an oxidative stress-independent pathway, contributes partially to heat hypersensitivity, oxidative stress-dependent activation of TRPA1 plays a key role in mediating thigmotaxis behavior and mechanical and cold allodynia in a cancer pain model. TRPA1 antagonists might be beneficial in the treatment of cancer pain.     

Oxaliplatin and axonal Na+ channel function in vivo.

PURPOSE: The aim of the study was to investigate the pathophysiology of oxaliplatin-induced neurotoxicity using clinical nerve excitability techniques that provide information about axonal ion channel function. EXPERIMENTAL DESIGN: Excitability studies were combined with standard nerve conduction studies and clinical assessment in 22 patients undergoing treatment with oxaliplatin. RESULTS: Excitability studies recorded before and immediately after oxaliplatin infusion for 89 treatment cycles revealed significant increases in refractoriness and relative refractory period postinfusion in all patients, consistent with an effect of oxaliplatin on axonal Na(+) channels. However, those patients that developed chronic neuropathy had significantly greater changes. Following cessation of oxaliplatin treatment, 41% of patients had persistent symptoms and nerve conduction abnormalities consistent with the development of chronic neuropathy. CONCLUSION: The present study provides evidence that oxaliplatin-induced neurotoxicity is mediated through an effect on axonal Na(+) channels. Clinical nerve excitability techniques may prove beneficial in monitoring for early signs of neurotoxicity and in the assessment of future prophylactic therapies.     

High-dose 8% capsaicin patch in treatment of chemotherapy-induced peripheral neuropathy: single-center experience

High-dose capsaicin patch is effective in treatment of neuropathic pain in HIV-associated neuropathy and diabetic neuropathy. There are no studies assessing effectiveness of high-dose capsaicin patch in treatment of chemotherapy-induced peripheral neuropathy. We sought to determine the effectiveness of treatment of pain associated with chemotherapy-induced peripheral neuropathy with high-dose capsaicin patch. Our study group consisted of 18 patients with clinically confirmed oxaliplatin-induced neuropathy. Baseline characteristic including underling disease, received cumulative dose of neurotoxic agent, neuropathic symptoms, prior treatment and initial pain level were recorded. Pain was evaluated with Numeric Rating Scale prior to treatment with high-dose capsaicin and after 1.8 day and after 8 and 12 weeks after introducing treatment. Patients were divided into two groups accordingly to the amount of neurotoxic agent that caused neuropathy (high sensitivity and low sensitivity group). Most frequent symptoms of chemotherapy-induced neuropathy were: pain (88.89%), paresthesis (100%), sock and gloves sensation (100%) and hypoesthesis (100%). Initial pain level was 7.45 ± 1.14. Mean cumulative dose of oxaliplatin after which patients developed symptoms was 648.07 mg/m². Mean pain level after 12 weeks of treatment was 0.20 ± 0.41. When examined according to high and low sensitivity to neurotoxic agent patients with low sensitivity had higher pain reduction, especially after 8 days after introducing treatment (69.55 ± 12.09 vs. 49.40 ± 20.34%; p = 0.02) and after 12 weeks (96.96 ± 5.56 vs. 83.93 ± 18.59%; p = 0.04). High-dose capsaicin patch is an effective treatment for pain associated with chemotherapy-induced neuropathy in patients treated with oxaliplatin. Patients with lower sensitivity to neurotoxic agents have better response to treatment and pain reduction.     

外周神经组织中Nav1.7的表达在奥沙利铂诱发神经病理性疼痛中的作用

目的 探讨电压门控性钠离子通道（voltage-gated sodium channel,VGSC）Na_v1.7在奥沙利铂诱发神经病理性疼痛中的作用。方法 96只雄性Sprague-Dawley(SD)大鼠随机分为2组：奥沙利铂诱发神经病理性疼痛（oxaliplatin-induced neuropathic pain,OINP）组及介质葡萄糖注射组（Vehicle组）。前者一次性腹腔注射给予奥沙利铂6 mg/kg;后者一次性腹腔注射给予相应体积5%葡萄糖注射液。von Frey纤维丝测定大鼠50%缩足阈值( paw withdrawal threshold, PWT)作为神经病理性疼痛大鼠痛觉反应指标;分别于第3、7、10 d取大鼠L3~5背根神经节（dorsal root ganglions,DRG）,通过免疫组织化学(immunohistochemistry, IHC)、RT-PCR、Western blot法测定DRG Nav1.7及其mRNA表达情况。结果 IHC结果显示Na_v1.7在OINP组与Vehicle组DRG神经元均有阳性表达,定位于胞质,呈棕黄色颗粒状染色;Na_v1.7在OINP组较Vehicle组染色深,差异有统计学意义（P<0.05）。RT-PCR结果显示Nav1.7 mRNA在OINP组与Vehicle组DRG均有表达,但在OINP组与Vehicle组表达差异无统计学意义。Western blot结果显示Nav1.7在OINP组与Vehicle组DRG均有表达,且在OINP组中相对表达量高于Vehicle组,两组间的表达差异有统计学意义（P<0.05）。结论 奥沙利铂通过上调外周神经Na_v1.7的表达,参与神经病理性疼痛的发生与维持。     

奥沙利铂周围神经系统毒性的预防与治疗

周围神经毒性是奥沙利铂的临床剂量限制性毒性,随着对其机制的认识,临床上已有一些预防和治疗其毒性的药物,目前报道有预防和治疗作用的药物有镁盐、钙盐、卡马西平、阿米硫定、谷胱甘肽和加巴喷丁等。现就奥沙利铂神经毒性临床预防和治疗药物的进展做一综述。     

大鼠骨癌痛模型的建立及组织学研究

目的建立一个有用的癌痛动物模型.方法将MRMT-1大鼠乳腺癌细胞接种到SD大鼠胫骨上段骨髓腔内,造成骨癌痛动物模型.用von Frey细丝刺激足底和后肢负重测量仪分别测量机械性痛觉超敏和痛觉过敏,放射学方法评估骨破坏,同时,组织切片镜下观察肿瘤和骨结构的破坏情况.结果造模动物在14天左右开始出现机械性痛觉超敏和痛觉过敏,胫骨X线摄片显示明显的骨破坏,组织学研究显示骨髓腔内肿瘤生长,向外侵蚀破坏骨皮质,同时伴有新生的编织骨形成.结论从疼痛行为学、放射学、组织学多方面研究的结果,表明大鼠骨癌痛模型已复制成功.该癌痛模型的建立,将为我国癌痛新药的评价,尤其是研究治疗癌痛中药的疗效及作用机制提供一个有用的工具.     

Oxaliplatin causes selective atrophy of a subpopulation of dorsal root ganglion neurons without inducing cell loss

Peripheral neuropathy is induced by multiple doses of oxaliplatin and interferes with the clinical utility of the drug in patients with colorectal cancer. In this study, we sought to determine whether cell loss or selective neuronal damage was the basis for the peripheral neuropathy caused by oxaliplatin. Adult female rats were given 1.85 mg/kg oxaliplatin twice per week for 8 weeks. Nerve conduction and L5 dorsal root ganglia (DRG) were studied 1 week after the completion of all treatment. No mortality occurred during oxaliplatin treatment, but the rate of body weight gain was reduced compared to age-matched vehicle-treated controls. Oxaliplatin slowed conduction velocity and delayed conduction times in peripheral sensory nerves, without affecting central or motor nerve conduction. In L5 DRG, total numbers of neurons were unchanged by oxaliplatin, but there were significant reductions in neuronal size distribution, ganglion volume, average cell size and the relative frequency of large cells. In addition, the relative frequency of small DRG cells was increased by oxaliplatin. Oxaliplatin significantly altered the size distribution and average cell body area of the predominantly large parvalbumin-immunoreactive DRG neurons without affecting the frequency of parvalbumin staining. On the contrary, neither the staining frequency nor the size distribution of the predominantly small substance P-immunoreactive DRG neurons was changed by oxaliplatin. In conclusion, oxaliplatin causes selective atrophy of a subpopulation of DRG neurons with predominantly large parvalbumin-expressing cells without inducing neuronal loss. Because DRG cell body size and axonal conduction velocity are positively correlated, neuronal atrophy may be the morphological basis for the development of decreased sensory nerve conduction velocity that characterizes oxaliplatin-induced peripheral neuropathy.     

文拉法辛对奥沙利铂诱发神经病理性疼痛的抑制作用及机制

目的观察文拉法辛对抗奥沙利铂诱发神经病理性疼痛效果并探索其可能机制,进而为化疗相关神经病理性疼痛的治疗及预防提供实验数据和理论基础。方法Sprague–Dawley大鼠经侧尾静脉给予奥沙利铂4 mg/kg,每周2次,连续4周,共给药8次,建立奥沙利铂诱发神经病理性疼痛大鼠模型;von Frey纤维丝测定大鼠的机械刺激缩足反射阈值（mechanical withdrawal threshold,MWT）作为神经病理性疼痛大鼠模型痛觉反应指标;观察分别给予0.9%氯化钠溶液、文拉法辛7.5 mg/kg、文拉法辛15 mg/kg连续4周,每天一次灌胃后测MWT动态变化,并通过免疫组织化学法测定第五腰椎背根神经节μ、κ、δ阿片受体表达差异。结果文拉法辛明显升高神经病理性疼痛模型大鼠的MWT值,文拉法辛7.5及15 mg/kg组较0.9%氯化钠溶液组μ、κ、δ阿片受体高表达（P＜0.05）。结论文拉法辛可有效抑制奥沙利铂诱发神经病理性疼痛,其作用机制可能与诱导μ、κ、δ阿片受体表达升高有关。