NMDA受体甘氨酸位点拮抗剂Lacosamide

综合临床特征和异常脑电图分析可见，癫痫患者易反复无因性发作。癫痫是最常见的神经系统疾病之一，由多因素引起。应根据患者个体确切的癫痫类别和发作类型给予适当治疗，从而降低癫痫发作的强度和频率及缩短发作时间。已有强有力的证据表明，癫痫患者脑内NMDA（N-甲基D天门冬氨酸）谷氨酸受体发生了变化。谷氨酸是中枢神经系统（CNS）中主要的兴奋性氨基酸，大多数兴奋性突触传导以及疼痛信号传导都通过谷氨酸受体途径，这就解释了许多抗癫痫药对神经性疼痛同样有效。神经性疼痛是影响外周神经系统和CNS正常功能的一组异质性疾病所表现的一种慢性疼痛，其特征为神经元过度兴奋，且传统镇痛药对其治疗效果差，而NMDA受体靶向药物的使用也因疗效差或不能耐受的副作用而受到限制。     

硫酸镁用于PCA镇痛作用和疗效的观察

手术后的疼痛是引起患者对手术恐惧的一个重要原因,阿片类药物是缓解疼痛的基本用药。但是所有的阿片类药物都会产生副作用,如恶心、呕吐、瘙痒、呼吸抑制、便秘、耐药性和依赖性等情况,这就使患者担心出现这些副作用尤其是耐药性和依赖性而宁愿忍受痛苦也不愿意使用阿片类药物进行术后的疼痛治疗,如何有效地降低阿片药物的剂量是我们应该考虑的问题。镁作为一种天然生理性钙通道阻滞药和非竞争性的N-甲基-D-天冬氨酸(NMDA)谷氨酸受体拮抗剂,在疼痛和术后疼痛的调节中可能发挥重要作用。镁可以对NMDA受体及与其相关的离子通道发挥拮抗剂…     

神经病理性疼痛的受体机制研究进展

神经病理性疼痛是一类治疗难度非常大的慢性疼痛,由于其发病机制尚未完全阐明,目前尚缺乏理想的治疗药物。以往研究显示,神经病理性疼痛与阿片受体、NMDA受体等有关,现阶段又发现多种受体参与了神经病理性疼痛的病理生理过程。该文综述了嘌呤与嘧啶受体、GABA受体、PAF受体等在神经病理性疼痛发病机制中的作用。     

侧脑室微量注射NMDA受体拮抗剂对神经病理疼痛的作用

目的:观察大鼠侧脑室微量注射N-甲基-D-天冬门氨酸(N-methyl-D-aspartate,NMDA)受体拮抗剂对神经病理性疼痛的影响,探讨脊髓上水平镇痛的机制,为临床上开发新的镇痛药物提供实验依据.方法:建立大鼠坐骨神经结扎(partial scicticnerve ligature,PSL)神经病理性疼痛模型,采用压爪-缩腿法和辐射热缩腿法测定大鼠的机械痛阈和热痛阈,观测侧脑室微量注射MK-801(NMDA受体非竞争性拮抗剂)与APV(NMDA受体竞争性拮抗剂)对神经病理性疼痛模型大鼠痛阈的影响.结果:PSL模型大鼠术后数小时痛阈即明显降低(P＜0.05),出现机械痛敏和热痛敏.侧脑室微量注射MK-801(5 nmol)、APV(2 nmol)后,大鼠机械痛阈和热痛阈明显升高,痛敏现象明显减轻(P＜0.05).结论:NMDA受体在中枢脊髓上水平与痛觉的形成和维持过程中可能起重要的作用.     

脊髓背角PKC在慢性炎性疼痛中的作用及其机制

目的探讨蛋白激酶C(protein kinase C,PKC)的抑制剂和激动剂对痛觉超敏的影响及其分子机制。方法小鼠后趾皮下注射完全弗氏佐剂(complete Freund's adjuvant,CFA)建立炎性疼痛模型;鞘内给予PKC抑制剂白屈菜赤碱(chelerythrine,CHE)或激动剂Phorbol 12-myristate 13-acetate(PMA)前后,测定小鼠缩足阈值;随后立即分离脊髓背角,免疫印迹法检测NMDA(N-methyl-D-aspartate)型谷氨酸受体的突触表达。结果 PKC抑制剂CHE在缓解炎性痛觉超敏的同时,明显翻转脊髓NMDA受体NR2B亚基的突触表达亢进;而正常小鼠鞘内给予PKC激动剂PMA,可模拟CFA的效应,即:诱发痛觉超敏,并特异性增加NR2B亚基的突触含量。结论 PKC通过调节脊髓NMDA受体NR2B亚基的突触表达,参与炎性疼痛的形成。     

阿片和非阿片镇痛药在慢性疼痛中的药理作用

慢性疼痛是一种混合的病理生理学机制，是自发和诱发疼痛的复杂状态，对镇痛药的反应差别很大。尽管没有系统的实验依据。但阿片类镇痛药始终是治疗严重慢性疼痛的首选药物，环氧合酶抑制剂量治疗中的首选辅助药物，对急性疼痛几乎无效的抗抑郁药，抗癫痫药和静注局麻药，在一些慢性疼痛病例中显示出明显的长期疗效，NMDA受体拮抗剂盐酸氯胺酮和α2受体激动剂可乐定对急性和慢性疼痛都有效，并可减少阿片类药物的用量，但常伴有严重的副作用，辣椒素等局部用药和阿片类等鞘内给药对某些病人也有效，模拟人类慢性疼痛状态建立了一些实验动物模型，但至今这些模型的药理学特点还没有很好地确定。     

海马内注射MK-801对甲醛炎性痛大鼠海马NO含量的影响

目的观察海马内给予N-甲基-D-天门冬氨酸(NMDA)受体拮抗剂MK-801对足底注射甲醛诱导的海马一氧化氮生成增加的影响。方法采用硝酸还原酶法测定海马组织NO含量。结果足底注射甲醛后大鼠即出现舔、咬注射侧脚掌等疼痛相关表现,注射甲醛后12h时,海马组织NO含量显著增加;预先海马内注射MK-801,可使甲醛炎性痛大鼠海马组织NO含量明显降低。结论海马内注射MK-801可逆转甲醛炎性痛诱导的海马NO产生的增加,海马内NO生成增加可能与NMDA受体的活动有关。     

NMDA受体数量在吗啡增敏、耐受和依赖形成过程中的重要性

阿片受体激动剂可使阿片受体下调,而其拮抗剂则可使阿片受体上调,此上调与阿片药物作用增敏有关,因此阿片受体拮抗剂可用于防治阿片类药物所致耐受。近年来还发现NMDA受体拮抗剂可减轻或逆转耐受及依赖程度;相反,预先用NMDA受体拮抗剂则可加重耐受,表明NMDA受体在阿片类药物耐受形成过程中有作用。本文旨在研究纳曲酮和NMDA受体拮抗剂地佐环平(dizocilpine,MK801)在吗啡所致耐受和依赖过程中的作用以及对脑NMDA受体动力学(Kd,Bmax)的影响。方法　将大鼠随机分为6组:盐水-盐水组、盐水-吗啡组、纳曲酮-盐水组、纳曲酮-吗啡组、地佐…     

神经病理性疼痛与电压门控性钠离子通道机制研究的新进展

神经病理性疼痛是一种主要由外周或中枢神经感染、创伤、压迫、代谢障碍引起的难治性疼痛[1]。近来诸多学者研究发现在神经病理性疼痛的病理状态下,可能与钠离子、钙离子、钾离子等电压门控离子通道、受体、各种神经肽、酶、神经递质和细胞表面分子都有不同程度的上调或下调有     

FDA批准治疗便秘药物Naloxegol上市

美国FDA于2014年9月16日批准阿斯利康(Astrazeneca)公司的Naloxegol(商品名:Movantik)片剂上市,用于慢性非癌性疼痛成年患者治疗阿片类药物引起的便秘。Naloxegol为阿片受体拮抗药,可与μ-阿片受体结合。在推荐剂量下,Naloxegol可选择性作用于外周μ-阿片受体(如胃肠道组织中的μ-阿片受体),继而降低阿片类药物引起的便秘。Naloxegol为纳洛酮(通用名:Naloxone)的聚乙二醇衍生物,同时也是P-糖蛋白底物。与纳洛酮相比,Naloxe-     

Transient allodynia pain models in mice for early assessment of analgesic activity

BACKGROUND AND PURPOSE: The most common preclinical models of neuropathic pain involve surgical ligation of sensory nerves, which is especially difficult in mice. Transient models of chemically sensitized allodynia are potentially useful for rapidly characterizing the analgesic profile of compounds and conducting mechanistic studies.EXPERIMENTAL APPROACH: Increasing doses of NMDA, sulprostone (an EP1/EP3 prostaglandin receptor agonist) or phenylephrine (an alpha (1) adrenoceptor agonist) were injected intrathecally (i.t.) or i.p., and animals were subsequently assessed for allodynia. The effects of receptor antagonists and analgesic compounds on allodynia were also assessed.KEY RESULTS: A comparison of total body doses that cause allodynia following spinal or systemic administration indicated that NMDA induces allodynia in the spinal cord while sulprostone and phenylephrine act through a peripheral mechanism. Inhibition of the allodynia with receptor antagonists indicated that each agent induces allodynia by a distinct mechanism. The three models were benchmarked using compounds known to be active in neuropathic pain patients and nerve injury animal models, including gabapentin, amitriptyline and clonidine.CONCLUSIONS AND IMPLICATIONS: These transient allodynia models are a useful addition to the toolbox of preclinical pain models. They are simple, rapid and reproducible, and will be especially useful for characterizing the pain phenotype of knockout mice.     

雌激素对慢性内脏痛雌鼠的敏化作用及其机制

目的探讨雌激素对慢性内脏痛雌鼠痛反应的影响及其与脊髓NMDA受体的关系。方法在♀大鼠新生期给予数次结直肠扩张刺激,成年后分为高、低雌激素组,用腹外斜肌放电水平来评价成鼠内脏痛觉敏感性,用NMDA受体拮抗剂D(-)-2-amino-5-phosphonopentanoic acid(AP-5)鞘内给药比较两组大鼠脊髓NMDA受体的功能。结果 (1)模型鼠高雌激素组的内脏痛反应比低雌激素组的反应强。(2)AP-5鞘内给药对内脏痛反应的抑制作用在模型鼠两组中的差异无统计学意义。结论高雌激素可加重模型雌鼠的内脏痛反应,雌激素不能使模型雌鼠脊髓背角的NMDA受体功能上调。     

Activation of the spinal sigma-1 receptor enhances NMDA-induced pain via PKC- and PKA-dependent phosphorylation of the NR1 subunit in mice

BACKGROUND AND PURPOSE: Previously we demonstrated that the spinal sigma-1 receptor (Sig-1 R) plays an important role in pain transmission, although the exact mechanism is still unclear. It has been suggested that Sig-1 R agonists increase glutamate-induced calcium influx through N-methyl-D-aspartate (NMDA) receptors. Despite data suggesting a link between Sig-1 Rs and NMDA receptors, there are no studies addressing whether Sig-1 R activation directly affects NMDA receptor sensitivity. EXPERIMENTAL APPROACH: We studied the effect of intrathecal (i.t.) administration of Sig-1 R agonists on protein kinase C (PKC) and protein kinase A (PKA) dependent phosphorylation of the NMDA receptor subunit NR1 (pNR1) as a marker of NMDA receptor sensitization. In addition, we examined whether this Sig-1 R mediated phosphorylation of NR1 plays an important role in sensory function using a model of NMDA-induced pain. KEY RESULTS: Both Western blot assays and image analysis of pNR1 immunohistochemical staining in the spinal cord indicated that i.t. injection of the Sig-1 R agonists, PRE-084 or carbetapentane dose dependently enhanced pNR1 expression in the murine dorsal horn. This increased pNR1 expression was significantly reduced by pretreatment with the specific Sig-1 R antagonist, BD-1047. In another set of experiments Sig-1 R agonists further potentiated NMDA-induced pain behaviour and pNR1 immunoreactivity and this was also reversed with BD-1047. CONCLUSIONS AND IMPLICATIONS: The results of this study suggest that the activation of spinal Sig-1 R enhances NMDA-induced pain via PKC- and PKA-dependent phosphorylation of the NMDA receptor NR 1 subunit.     

Analgesic effects of morphine and loperamide in the rat formalin test: interactions with NMDA receptor antagonists

To reveal peripheral components of opiate analgesia, effects of loperamide, opioid agonist which does not penetrate the blood-brain barrier, were examined in formalin and acute thermal pain tests in comparison with morphine. Formalin administration induces pain behaviour such licking/biting of injected paw expressed as two phases. The first phase is caused by C-fibre activation due to peripheral stimulation, the second phase attributed to ongoing input from peripheral site, leading to spinal hyperexcitability, which is dependent on N-methyl-D-aspartate (NMDA) receptor activation. Loperamide (3-10 mg/kg) and morphine (6 mg/kg) reduced formalin-induced nociceptive behaviours and these effects were reversed by naloxone methiodide (0.03-10 mg/kg), opioid receptor antagonist which poorly penetrates the blood-brain barrier. Loperamide action was enhanced only by centrally active NMDA receptor antagonists memantine (3 mg/kg) and CGP 37849 (3 mg/kg), but not by NMDA/glycineB receptor antagonists showing weak or no central nervous system (CNS) activity. Present results suggest that central NMDA receptor blockade may be necessary to enhance analgesia induced through peripheral opioid mechanisms in formalin-evoked nociception.     

Contributions of peripheral and central opioid receptors to antinociception in rat muscle pain models

Administration of hypertonic saline (HS) is an accepted model to study muscular pain. HS-induced nociceptive responses were tested in masseter, already described, and in two new pain models of spinally innervated muscles (gastrocnemius and triceps) developed in rats at our laboratory. HS administration in the masseter induced vigorous hindpaw shaking and in the gastrocnemius or triceps, paw withdrawal or flexing. Participation of the central and peripheral opioid receptors in HS-induced pain is compared in these muscles: masseter, innervated by trigeminal nerve, and gastrocnemius and triceps by spinal nerves. Morphine and loperamide were used to reveal peripheral and central components of opioid analgesia. Both agonists reduced HS-induced nociceptive behaviours in the masseter and were antagonised by the opioid antagonist naloxone and by naloxone methiodide, an opioid receptor antagonist that poorly penetrates the blood-brain barrier. Unexpectedly, in the gastrocnemius and triceps, morphine, but not loperamide, decreased the nociceptive behaviour and this effect was only reversed by naloxone. So, peripheral opioid receptors seem to participate in HS-induced masseter pain, whereas only central opioid receptors reduced the nociception in gastrocnemius and triceps. Our results suggest that the use of peripheral opioids can be more advantageous than central opioids for treatment of orofacial muscular pain.     

NMDA receptors as targets for drug action in neuropathic pain.

Hyperalgesia and allodynia following peripheral tissue or nerve injury are not only due to an increase in the sensitivity of primary afferent nociceptors at the site of injury but also depend on NMDA receptor-mediated central changes in synaptic excitability. Functional inhibition of NMDA receptors can be achieved through actions at different recognition sites such as the primary transmitter site (competitive), strychnine-insensitive glycine site (glycine(B)), polyamine site (NR2B selective) and phencyclidine site located inside the cationic channel. Unfortunately, most agents which completely block NMDA receptors cause numerous side effects such as memory impairment, psychotomimetic effects, ataxia and motor incoordination. There is now, however, considerable evidence that moderate affinity channel blockers, glycine(B) and NR2B selective antagonists show a much better profile in animal models than high affinity channel blockers and competitive NMDA receptor antagonists. These "therapeutically" safe NMDA receptor antagonists are also able to slow or prevent the development of opioid tolerance, indicating the utility of their combination with opioids in the treatment of chronic pain. The antinociceptive effects of NMDA receptor antagonists and opioids could be predicted to be synergistic and the presence of an NMDA receptor antagonist should block both the development of chronic pain states and inhibit the development of tolerance to the analgesic effects of morphine. Peripheral NMDA receptors offer a very attractive target for NMDA receptor antagonists that do not cross the blood brain barrier in inflammatory and visceral pain. Such agents might be predicted to be devoid of CNS side effects at doses producing powerful antinociception at peripheral NMDA receptors.     

Effects of (S)-3,4-DCPG, an mGlu8 receptor agonist, on inflammatory and neuropathic pain in mice

In this study, the effect of (S)-3,4-dicarboxyphenylglycine (DCPG), a selective mGlu8 receptor agonist, has been investigated in inflammatory and neuropathic pain models in order to elucidate the role of mGlu8 receptor in modulating pain perception. Inflammatory pain was induced by the peripheral injection of formalin or carrageenan in awake mice. Systemic administration of (S)-3,4-DCPG, performed 15 min before formalin, decreased both early and delayed nociceptive responses of the formalin test. When this treatment was carried out 15 min after the peripheral injection of formalin it still reduced the late hyperalgesic phase. Similarly, systemic (S)-3,4-DCPG reduced carrageenan-induced thermal hyperalgesia and mechanical allodynia when administered 15 min before carrageenan, but no effect on pain behaviour was observed when (S)-3,4-DCPG was given after the development of carrageenan-induced inflammatory pain. When microinjected into the lateral PAG (RS)-alpha-methylserine-O-phoshate (MSOP), a group III receptor antagonist, antagonised the analgesic effect induced by systemic administration of (S)-3,4-DCPG in both of the inflammatory pain models. Intra-lateral PAG (S)-3,4-DCPG reduced pain behaviour when administered 10 min before formalin or carrageenan; both the effects were blocked by intra-lateral PAG MSOP. (S)-3,4-DCPG was ineffective in alleviating thermal hyperalgesia and mechanical allodynia 7 days after the chronic constriction injury of the sciatic nerve, whereas it proved effective 3 days after surgery. Taken together these results suggest that stimulation of mGlu8 receptors relieve formalin and carrageenan-induced hyperalgesia in inflammatory pain, whereas it would seem less effective in established inflammatory or neuropathic pain.     

The antiallodynic effect of NMDA antagonists in neuropathic pain outlasts the duration of the in vivo NMDA antagonism

Clinical reports have described a long-lasting relief in neuropathic pain patients treated with NMDA receptor antagonists; it is unclear, however, what mediates this effect. In this work, we have used two NMDA antagonists of different class to investigate if the antiallodynic effects in a rat neuropathy model can outlast their in vivo NMDA antagonism. Both the uncompetitive NMDA antagonist ketamine and the glycine(B) antagonist MRZ 2/576 inhibited neuronal responses to iontophoretic NMDA in anaesthetised rats with the time course consistent with their known pharmacokinetics (t(1/2) approximately 10-12min, similar in control and nerve-injured rats). Surprisingly, the antiallodynic effects of the same doses of the NMDA antagonists in the neuropathic pain model were long-lasting (>3h with ketamine, >24h with MRZ 2/576). The effect of ketamine was further prolonged (>24h) when combined with a short-acting opioid, fentanyl, which only produced a short effect ( approximately 40min) when given alone. The duration of centrally mediated side effects of ketamine and MRZ 2/576 was short, similar to the in vivo NMDA antagonism. We speculate that NMDA receptor blockade may down-regulate the central sensitisation triggered by nerve injury, resulting in a long-lasting antiallodynic effect. Development of short-acting NMDA antagonists could represent a strategy for improving their tolerability.     

Effects of low-affinity NMDA receptor channel blockers in two rat models of chronic pain

In contrast to conventional opioid analgesics, antagonists acting at the N-methyl-d-aspartate (NMDA) subtype of glutamate receptors are capable of suppressing pain-related phenomena in chronic pain models while having little or no effect on acute nociception. One of the few clinically used NMDA receptor antagonists, memantine, differs from prototypic antagonists with psychotomimetic activity such as phencyclidine and (+)MK-801, in showing lower receptor affinity, faster unblocking kinetics and stronger voltage-dependency. Recently, a series of novel amino-alkyl-cyclohexanes was reported to interact with NMDA receptors in a manner similar to that of memantine. The present study aimed to evaluate the effects of these compounds as well as (+)MK-801 and memantine in two rat models of chronic pain and the rotarod test. Unlike (+)MK-801 and memantine, most of the tested compounds were inactive against tactile allodynia induced by sciatic nerve ligation. On the other hand, all tested drugs were found to inhibit formalin-induced grooming behavior-a model of chronic pain induction. In agreement with previous reports on the effects of NMDA receptor antagonists in similar assays, the late phase seemed to be inhibited to a greater extent than the early phase. For all tested compounds, inhibition of formalin-induced behaviors occurred at dose levels that were also producing significant motor deficits (rotarod test). These results confirm low efficacy of acute administration of NMDA receptor antagonists in the models of established pain states. Thus, studies on the prevention and management of chronic pain should focus on preemptive or long-term administration of NMDA receptor antagonists.     

大鼠鞘内注射AP5的抗内脏伤害作用

目的观察鞘内注射竞争性N-甲基-D-天冬氨酸（NMDA）受体拮抗剂2-氨基-5-磷酰基戊酸酯（AP5）对大鼠结直肠扩张（CRD）诱发的内脏伤害性刺激的影响及剂量关系。方法利用大鼠CRD模型诱导的内脏伤害性刺激,经鞘内引入药物,观察对腹壁撤回反射（AWR）达到3级时痛阈的影响。结果AP5剂量依赖地抑制CRD诱导的内脏伤害性刺激,并有时间作用特点。结论竞争性NMDA受体拮抗剂AP5可以抑制CRD诱导的内脏伤害性刺激,NMDA受体在内脏伤害性刺激脊髓水平的传递中起重要作用。