BACKGROUND & AIMS: Tricyclic antidepressants have been shown to be useful for the treatment of pain of varying etiology. Monoaminergic systems seem to be implicated in this phenomenon. In this study, the influence of the selective beta 1- (CGP 20712A) and beta 2- (ICI 118551) adrenergic blockers on the antinociceptive effect of desipramine and nortriptyline was studied in mice using physical and chemical nociceptive tests that implicate different levels of sensory-motor integration in the central nervous system (CNS). An activity test was performed to detect "false positive" or "false negative" results. Results obtained show that both CGP 20712A and ICI 118551 are able to antagonize the antinociceptive effect of these antidepressants in physical tests (hot-plate and tail-flick). However, in chemical tests (acetic acid and formalin), the analgesic effect of the antidepressants used was only antagonized by CGP 20712A. These results suggest that the analgesic effect of desipramine and nortriptyline is mediated by beta-adrenoceptors. The beta-adrenoceptor involved depends on the type of nociceptive stimulusbeta 1 and beta 2 are both implicated when the stimulus is physical, but only beta 1 is involved when the stimulus is chemical.

背景与目标： 三环抗抑郁药已被证明可用于治疗不同病因的疼痛。单胺能系统似乎与这种现象有关。在这项研究中，使用物理和化学伤害性测试在小鼠中研究了选择性 β1- (CGP 20712A) 和 β2- (ICI 118551) 肾上腺素能阻滞剂对地昔帕明和去甲替林的抗伤害感受作用的影响，该测试涉及中枢神经系统 (CNS) 中不同水平的感觉-运动整合。进行活性测试以检测 “假阳性” 或 “假阴性” 结果。获得的结果表明，CGP 20712A和ICI 118551都能够在物理测试 (热板和甩尾) 中拮抗这些抗抑郁药的抗伤害感受作用。然而，在化学测试 (乙酸和福尔马林) 中，所使用的抗抑郁药的镇痛作用仅被CGP 20712A拮抗。这些结果表明，地昔帕明和去甲替林的镇痛作用是由 β-肾上腺素受体介导的。涉及的 β-肾上腺素能受体取决于伤害性刺激的类型，当刺激是物理刺激时，β1和 β2都涉及，但当刺激是化学刺激时，只有 β1涉及。

BACKGROUND & AIMS: :The post-ictal immobility syndrome is followed by a significant increase in the nociceptive thresholds in animals and men. In this interesting post-ictal behavioral response, endogenous opioid peptides-mediated mechanisms, as well as cholinergic-mediated antinociceptive processes, have been suggested. However, considering that many serotonergic descending pathways have been implicated in antinociceptive reactions, the aim of the present work is to investigate the involvement of 5-HT(2)-serotonergic receptor subfamily in the post-ictal antinociception. The analgesia was measured by the tail-flick test in seven or eight Wistar rats per group. Convulsions were followed by statistically significant increase in the tail-flick latencies (TFL), at least for 120 min of the post-ictal period. Male Wistar rats were submitted to stereotaxic surgery for introduction of a guide-cannula in the rhombencephalon, aiming either the nucleus raphe magnus (NRM) or the gigantocellularis complex. In independent groups of animals, these nuclei were neurochemically lesioned with a unilateral microinjection of ibotenic acid (1.0 microg/0.2 microL). The neuronal damage of either the NRM or nucleus reticularis gigantocellularis/paragigantocellularis complex decreased the post-ictal analgesia. Also, in other independent groups, central administration of ritanserin (5.0 microg/0.2 microL) or physiological saline into each of the reticular formation nuclei studied caused a statistically significant decrease in the TFL of seizing animals, as compared to controls, in all post-ictal periods studied. These results indicate that serotonin input-connected neurons of the pontine and medullarly reticular nuclei may be involved in the post-ictal analgesia.

背景与目标： : 发作期后不动综合症之后，动物和男性的伤害性阈值显着增加。在这种有趣的发作期后行为反应中，已经提出了内源性阿片肽介导的机制以及胆碱能介导的抗伤害感受过程。然而，考虑到许多血清素能下降途径与抗伤害感受反应有关，因此本工作的目的是研究5-HT(2)-血清素能受体亚家族在发作期抗伤害感受中的参与。每组7或8只Wistar大鼠通过甩尾试验测量镇痛效果。抽搐后，至少在发作后的120分钟内，甩尾潜伏期 (TFL) 具有统计学上的显着增加。雄性Wistar大鼠接受立体定向手术，以在菱形脑中引入引导套管，以瞄准中缝大核 (NRM) 或千兆体复合体。在独立的动物组中，这些核通过单侧微量注射ibotenic酸 (1.0 microg/0.2 microL) 被神经化学损伤。NRM或网状核巨囊细胞/旁囊细胞复合物的神经元损伤降低了发作后的镇痛作用。同样，在其他独立组中，在研究的所有发作期后，与对照组相比，将利坦色林 (5.0 microg/0.2 microL) 或生理盐水集中施用到每个研究的网状形成核中，引起抓住动物的TFL在统计学上显着降低。这些结果表明，脑桥和延髓网状核的5-羟色胺输入连接的神经元可能参与了发作期后的镇痛。

BACKGROUND & AIMS: :Several ginsenosides (Rb1, Rb2, Rc, Rd, Re, Rf, Rg1 and Rg3) are neuroprotective and antinociceptive agents. In this study, we assessed the effects of these ginsenosides following intracerebroventricular (i.c.v.) administration on the nociceptive behaviors induced by intrathecal injection of pro-inflammatory cytokines (tumor necrosis factor-a (TNF-alpha), interleukin-1 beta (IL-1 beta), and interferon-gamma (IFN-gamma)). The ginsenosides, Rb1, Rb2, Rc, Rd, Re, Rf and Rg1, significantly attenuated the nociceptive behavior induced by TNF-alpha, IL-1 beta, and IFN-gamma injection, but ginsenoside-Rg3 did not. These results suggest that several ginsenosides may regulate the nociceptive processing induced by pro-inflammatory cytokines.

背景与目标： : 几种人参皂甙 (Rb1、Rb2、Rc、Rd、Re、Rf、Rg1和Rg3) 是神经保护和抗伤害感受性药。在这项研究中，我们评估了这些人参皂甙在脑室内 (i.c.v.) 给药后对鞘内注射促炎性细胞因子 (肿瘤坏死因子-a (TNF-α)，interleukin-1 β (IL-1 β)，和干扰素-γ (IFN-γ)。人参皂苷Rb1，Rb2，Rc，Rd，Re，Rf和Rg1显着减弱了TNF-α，IL-1 β 和IFN-γ 注射引起的伤害性行为，但ginsenoside-Rg3没有。这些结果表明，几种人参皂甙可能调节促炎细胞因子诱导的伤害性过程。

BACKGROUND & AIMS: :Recently, it has been shown that intrathecal injection of norepinephrine and the mixed A1/A2 adenosine agonist 5'-N-ethylcarboxamide adenosine (NECA) interact in a supra-additive manner to produce antinociception. The present studies were designed to determine whether alpha 1 or alpha 2 noradrenergic receptors are involved in producing the antinociception induced by NECA and norepinephrine. The results indicated that intrathecal injection of NECA (0.97-4.9 nmol), the alpha 2 noradrenergic agonist clonidine (3.8-375 nmol), or the alpha 1 agonist phenylephrine (4.9-73.4 nmol) produced dose-dependent antinociception in rats. Furthermore, intrathecal injection of subeffective doses of NECA and clonidine interacted supra-additively to produce potent antinociception. In contrast, no supra-additive interaction was observed between NECA and phenylephrine. The supra-additive interaction of NECA and clonidine did not appear to result from alterations in cardiovascular tone because changes in blood pressure and nociceptive thresholds were not correlated in time. These results suggest that the noradrenergic component of the supra-additive interaction between adenosine A2 receptor agonists and noradrenergic agonists is mediated by alpha 2 noradrenergic receptors.

背景与目标： : 最近，已经显示鞘内注射去甲肾上腺素和混合的A1/A2腺苷激动剂5 '-N-乙基羧酰胺腺苷 (NECA) 以超加成方式相互作用以产生抗伤害感受。本研究旨在确定 α1或 α2去甲肾上腺素能受体是否参与产生NECA和去甲肾上腺素诱导的抗伤害感受。结果表明，鞘内注射NECA (0.97-4.9 nmol)，α2去甲肾上腺素能激动剂可乐定 (3.8-375 nmol) 或 α1激动剂去氧肾上腺素 (4.9-73.4 nmol) 在大鼠中产生剂量依赖性的抗伤害感受。此外，鞘内注射有效剂量的NECA和可乐定可相互作用，从而产生有效的抗伤害感受。相反，在NECA和去氧肾上腺素之间未观察到超加成相互作用。NECA和可乐定的超加性相互作用似乎不是由心血管张力的改变引起的，因为血压和伤害性阈值的变化与时间无关。这些结果表明，腺苷A2受体激动剂和去甲肾上腺素能激动剂之间的超加成相互作用的去甲肾上腺素能成分是由 α2去甲肾上腺素能受体介导的。

BACKGROUND & AIMS: :A series of 7-chloro-2,3-dihydro-2-[1-(pyridinyl)alkyl]-pyridazino[4,5-b]quinoline-1,4,10(5H)-triones were synthesized and found to have potent activity at the glycine site of the NMDA receptor. In some cases, these compounds possessed poor aqueous solubility that may have contributed to poor rat oral bioavailability. Subsequently, compounds have been identified with improved aqueous solubility and oral bioavailability. Several of these compounds were examined in a rat chronic constrictive injury (CCI) model of neuropathic pain and found to have potent activity when dosed orally.

背景与目标： : 合成了一系列7-氯-2,3-二氢-2-[1-(吡啶基) 烷基]-哒嗪基 [4,5-b] 喹啉-1,4，10(5H)-三酮，并发现在NMDA受体的甘氨酸位点具有有效的活性。在某些情况下，这些化合物具有较差的水溶性，这可能导致大鼠口服生物利用度较差。随后，已经鉴定出具有改善的水溶性和口服生物利用度的化合物。在大鼠慢性收缩损伤 (CCI) 神经性疼痛模型中检查了其中一些化合物，发现口服时具有有效的活性。

BACKGROUND & AIMS: :The endogenous fatty acid ethanolamide, palmitylethanolamide, alleviated, in a dose-dependent manner, pain behaviors elicited in mice by injections of formalin (5%, intraplantar), acetic acid (0.6%, 0.5 ml per animal, intraperitoneal, i.p.), kaolin (2.5 mg per animal, i.p.), and magnesium sulfate (120 mg per kg, i.p.). The antinociceptive effects of palmitylethanolamide were prevented by the cannabinoid CB2 receptor antagonist SR144528 [N-([1s]-endo-1.3.3-trimethylbicyclo[2.3.1]heptan-2-yl)-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide], not by the cannabinoid CB1 receptor antagonist SR141716A [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide x HCl]. By contrast, palmitylethanolamide had no effect on capsaicin-evoked pain behavior or thermal nociception. The endogenous cannabinoid, anandamide (arachidonylethanolamide), alleviated nociception in all tests (formalin, acetic acid, kaolin, magnesium sulfate, capsaicin and hot plate). These effects were prevented by the cannabinoid CB1 receptor antagonist SR141716A, not the cannabinoid CB2 receptor antagonist SR141716A. Additional fatty acid ethanolamides (oleylethanolamide, myristylethanolamide, palmitoleylethanolamide, palmitelaidylethanolamide) had little or no effect on formalin-evoked pain behavior, and were not investigated in other pain models. These results support the hypothesis that endogenous palmitylethanolamide participates in the intrinsic control of pain initiation. They also suggest that the putative receptor site activated by palmitylethanolamide may provide a novel target for peripherally acting analgesic drugs.

背景与目标： : 内源性脂肪酸乙醇酰胺 (palmitylethanolamide) 以剂量依赖性方式减轻了通过注射福尔马林 (5%，足底内)，乙酸 (0.6%，每只动物0.5毫升，腹膜内，腹腔内)，高岭土 (每只动物2.5 mg，i.p.) 和硫酸镁 (120 mg/kg，i.p.)。大麻素CB2受体拮抗剂SR144528 [N-([1s]-endo-1.3.3-trimethylbicyclo[2.3.1]heptan-2-yl)-5-(4-氯-3-甲基苯基)-1-(4-甲基苄基)-pyrazole-3-carboxamide]，非大麻素CB1受体拮抗剂SR141716A [N-(piperidin-1-yl)-5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1h-吡唑-3-甲酰胺xhcl]。相比之下，棕榈乙醇酰胺对辣椒素引起的疼痛行为或热伤害感受没有影响。在所有测试 (福尔马林，乙酸，高岭土，硫酸镁，辣椒素和热板) 中，内源性大麻素，anandamide (花生四烯乙醇酰胺) 减轻了伤害性。大麻素CB1受体拮抗剂SR141716A，而不是大麻素CB2受体拮抗剂SR141716A预防了这些作用。额外的脂肪酸乙醇酰胺 (油酰乙醇酰胺，肉豆蔻乙醇酰胺，棕榈油酰乙醇酰胺，棕榈油酰乙醇酰胺) 对福尔马林诱发的疼痛行为几乎没有影响，也没有在其他疼痛模型中进行研究。这些结果支持内源性棕榈酰乙醇酰胺参与疼痛起始的内在控制的假设。他们还表明，由棕榈酰乙醇酰胺激活的推定受体位点可能为外周镇痛药物提供了新的靶标。

BACKGROUND & AIMS: :Treatments for chronic pain are inadequate, and new options are needed. Nonpharmaceutical approaches are especially attractive with many potential advantages including safety. Light therapy has been suggested to be beneficial in certain medical conditions such as depression, but this approach remains to be explored for modulation of pain. We investigated the effects of light-emitting diodes (LEDs), in the visible spectrum, on acute sensory thresholds in naive rats as well as in experimental neuropathic pain. Rats receiving green LED light (wavelength 525 nm, 8 h/d) showed significantly increased paw withdrawal latency to a noxious thermal stimulus; this antinociceptive effect persisted for 4 days after termination of last exposure without development of tolerance. No apparent side effects were noted and motor performance was not impaired. Despite LED exposure, opaque contact lenses prevented antinociception. Rats fitted with green contact lenses exposed to room light exhibited antinociception arguing for a role of the visual system. Antinociception was not due to stress/anxiety but likely due to increased enkephalins expression in the spinal cord. Naloxone reversed the antinociception, suggesting involvement of central opioid circuits. Rostral ventromedial medulla inactivation prevented expression of light-induced antinociception suggesting engagement of descending inhibition. Green LED exposure also reversed thermal and mechanical hyperalgesia in rats with spinal nerve ligation. Pharmacological and proteomic profiling of dorsal root ganglion neurons from green LED-exposed rats identified changes in calcium channel activity, including a decrease in the N-type (CaV2.2) channel, a primary analgesic target. Thus, green LED therapy may represent a novel, nonpharmacological approach for managing pain.

背景与目标： : 慢性疼痛的治疗方法不足，需要新的选择。非药物方法特别有吸引力，具有许多潜在的优势，包括安全性。已建议在某些医学状况 (例如抑郁症) 中使用光疗法是有益的，但是这种方法仍有待探索以调节疼痛。我们研究了可见光谱中的发光二极管 (led) 对幼稚大鼠以及实验性神经性疼痛的急性感觉阈值的影响。接受绿色LED光 (波长525 nm，8 h/d) 的大鼠对有害的热刺激表现出明显增加的爪子退缩潜伏期; 这种抗伤害感受作用在最后一次暴露终止后持续了4天，而没有产生耐受性。没有发现明显的副作用，并且运动性能没有受到损害。尽管有LED暴露，但不透明的隐形眼镜可防止伤害。装有绿色隐形眼镜的大鼠暴露于室内光线下，表现出抗伤害感受，主张视觉系统的作用。抗伤害感受不是由于压力/焦虑，而是由于脊髓中脑啡肽的表达增加。纳洛酮逆转了抗伤害感受，表明中枢阿片样物质回路参与。延髓腹内侧髓质失活阻止了光诱导的抗伤害感受的表达，表明参与了下降抑制作用。绿色LED暴露还可以逆转脊髓神经结扎大鼠的热和机械痛觉过敏。来自绿色LED暴露大鼠的背根神经节神经元的药理和蛋白质组学分析确定了钙通道活性的变化，包括主要镇痛靶标N型 (CaV2.2) 通道的减少。因此，绿色LED疗法可能代表了一种新颖的非药物治疗疼痛的方法。

BACKGROUND & AIMS: :Peripheral neuropathic pain is one of the most common and debilitating complications of diabetes. Several genes have been shown to be effective in reducing neuropathic pain in animal models of diabetes after transfer to the dorsal root ganglion using replication-defective herpes simplex virus (HSV)1-based vectors, yet there has never been a comparative analysis of their efficacy. We compared four different HSV1-based vectors engineered to produce one of two opioid receptor agonists (enkephalin or endomorphin), or one of two isoforms of glutamic acid decarboxylase (GAD65 or GAD67), alone and in combination, in the streptozotocin-induced diabetic rat and mouse models. Our results indicate that a single subcutaneous hindpaw inoculation of vectors expressing GAD65 or GAD67 reduced diabetes-induced mechanical allodynia to a degree that was greater than daily injections of gabapentin in rats. Diabetic mice that developed thermal hyperalgesia also responded to GAD65 or endomorphin gene delivery. The results suggest that either GAD65 or GAD67 vectors are the most effective in the treatment of diabetic pain. The vector combinations, GAD67+endomorphin, GAD67+enkephalin or endomorphin+enkephalin also produced a significant antinociceptive effect but the combination did not appear to be superior to single gene treatment. These findings provide further justification for the clinical development of antinociceptive gene therapies for the treatment of diabetic peripheral neuropathies.

背景与目标： : 周围神经病理性疼痛是糖尿病最常见和使人衰弱的并发症之一。使用基于复制缺陷型单纯疱疹病毒 (HSV)1的载体转移到背根神经节后，几种基因已被证明可有效减轻糖尿病动物模型中的神经病理性疼痛，但从未对其功效进行比较分析。我们在链脲佐菌素诱导的糖尿病大鼠和小鼠模型中比较了四种不同的HSV1-based载体，这些载体单独或组合产生两种阿片受体激动剂 (脑啡肽或内啡肽) 之一，或谷氨酸脱羧酶 (GAD65或GAD67) 的两种同工型之一。我们的结果表明，单次皮下后爪接种表达GAD65或GAD67的载体可将糖尿病诱导的机械性异常性疼痛降低到比每天注射加巴喷丁更大的程度。发生热痛觉过敏的糖尿病小鼠也对GAD65或内吗啡基因递送有反应。结果表明，GAD65或GAD67载体在治疗糖尿病疼痛中最有效。载体组合GAD67内吗啡，GAD67脑啡肽或内吗啡脑啡肽也产生了显着的抗伤害感受作用，但该组合似乎并不优于单基因治疗。这些发现为抗伤害感受基因疗法治疗糖尿病周围神经病的临床发展提供了进一步的理由。

BACKGROUND & AIMS: :Copaiba oil resins are extensively commercialized in Brazil as capsules or crude oil and used as anti-inflammatory and anti-septic. Comparative pharmacological studies between different species of Copaiba oils are scarce. In the present work we compared the antinociceptive activity of two Amazonian Copaiba oils (Copaifera multijuga Hayne and Copaifera reticulata Ducke, Fabaceae) administered by oral route using peripheral (acetic acid-induced abdominal writhing and formalin), spinal (tail flick) and supra-spinal (hot plate) models. Results demonstrated that the Copaiba oils did not develop toxic effects. Doses ranging from 30 to 150 mg/kg were enough to significantly develop peripheral antinociceptive effect. All Copaiba oils demonstrate central activity but with less effect on supra-spinal regions of the brain. Administration of the opioid receptor antagonist, naloxone completely inhibited the antinociceptive effect induced by both Copaiba oils. Our results indicate that Copaiba oils demonstrate peripheral and central antinociceptive effect. This new comprobate effect may be useful in the treatment of algesic disorders.

背景与目标： : Copaiba油树脂在巴西作为胶囊或原油广泛商业化，并用作抗炎和防腐。缺乏不同种类的Copaiba油之间的比较药理学研究。在目前的工作中，我们比较了两种亚马逊Copaiba油 (Copaifera multijuga Hayne和Copaifera reticulata Ducke，Fabaceae) 的抗伤害感受活性，该方法通过口服途径使用外周 (乙酸诱导的腹部扭动和福尔马林)，脊柱 (甩尾) 和脊髓上 (热板) 模型。结果表明，Copaiba油不会产生毒性作用。30至150 mg/kg的剂量足以显着发展外周抗伤害感受作用。所有Copaiba油均表现出中枢活性，但对大脑脊髓上区域的影响较小。服用阿片受体拮抗剂，纳洛酮完全抑制了两种Copaiba油诱导的抗伤害感受作用。我们的结果表明，Copaiba油具有外围和中央抗伤害作用。这种新的药物作用可能有助于治疗痛觉障碍。

BACKGROUND & AIMS: :Mammalian zinc ectopeptidases play important roles in turning off neural and hormonal peptide signals at the cell surface, notably those processing sensory information. We report here the discovery of a previously uncharacterized physiological inhibitor of enkephalin-inactivating zinc ectopeptidases in humans, which we have named Opiorphin. It is a QRFSR peptide that inhibits two enkephalin-catabolizing ectoenzymes, human neutral ecto-endopeptidase, hNEP (EC 3.4.24.11), and human ecto-aminopeptidase, hAP-N (EC 3.4.11.2). Opiorphin displays potent analgesic activity in chemical and mechanical pain models by activating endogenous opioid-dependent transmission. Its function is closely related to the rat sialorphin peptide, which is an inhibitor of pain perception and acts by potentiating endogenous mu- and delta-opioid receptor-dependent enkephalinergic pathways. Here we demonstrate the functional specificity in vivo of human Opiorphin. The pain-suppressive potency of Opiorphin is as effective as morphine in the behavioral rat model of acute mechanical pain, the pin-pain test. Thus, our discovery of Opiorphin is extremely exciting from a physiological point of view in the context of endogenous opioidergic pathways, notably in modulating mood-related states and pain sensation. Furthermore, because of its in vivo properties, Opiorphin may have therapeutic implications.

背景与目标： : 哺乳动物锌外肽酶在关闭细胞表面的神经和激素肽信号中起重要作用，尤其是那些处理感觉信息的信号。我们在这里报告了在人类中发现了一种以前未表征的脑啡肽失活锌外肽酶的生理抑制剂，我们将其命名为Opiorphin。它是一种QRFSR肽，可抑制两种脑啡肽分解代谢的外胚酶，人中性外胚肽内肽酶hNEP (EC 3.4.24.11) 和人外胚肽氨基肽酶hAP-N (EC 3.4.11.2)。Opiorphin通过激活内源性阿片样物质依赖性传递在化学和机械疼痛模型中显示出有效的镇痛活性。其功能与大鼠唾液酸肽密切相关，唾液酸肽是一种疼痛感的抑制剂，可通过增强内源性mu和 δ 阿片受体依赖性脑啡肽途径发挥作用。在这里，我们证明了人Opiorphin在体内的功能特异性。在急性机械性疼痛的行为大鼠模型 (pin-pain测试) 中，Opiorphin的疼痛抑制作用与吗啡一样有效。因此，从生理学的角度来看，在内源性阿片样肽途径的背景下，特别是在调节情绪相关状态和疼痛感方面，我们对阿片样肽的发现非常令人兴奋。此外，由于其体内特性，Opiorphin可能具有治疗意义。

BACKGROUND & AIMS: :Cannabinoids are currently used for the treatment of excessive weight loss and nausea; however, there are very few studies that have examined cannabinoid effects in females of any species. A previous study has shown that there are sex differences in cannabinoid pharmacokinetics in rats, suggesting that there could be sex differences in cannabinoid-induced behaviors. To address this issue, Delta9-tetrahydrocannabinol, 11-hydroxy-Delta9-tetrahydrocannabinol (natural cannabinoids) or (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)-phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol) (CP55940, a synthetic cannabinoid) was administered i.p. to male and female Sprague-Dawley rats, who were tested on the 50 degrees C warm water tail withdrawal, paw pressure, catalepsy bar and spontaneous locomotor activity tests at various times post-injection. At the doses tested, all three cannabinoid agonists produced greater effects in females than males in two or more behavioral tests. This study demonstrates that there are sex differences in the behavioral effects of cannabinoids in the rat.

背景与目标： : 大麻素目前用于治疗过度减肥和恶心; 然而，很少有研究检查大麻素对任何物种的女性的影响。先前的研究表明，大鼠大麻素的药代动力学存在性别差异，这表明大麻素诱导的行为可能存在性别差异。为了解决这个问题，Delta9-tetrahydrocannabinol，11-hydroxy-Delta9-tetrahydrocannabinol (天然大麻素) 或 (-)-cis-3-[2-羟基-4-(1,1-二甲基庚基)-苯基]-trans-4-(3-羟丙基) 环己醇) (CP55940，合成大麻素) 被i.p.对于雄性和雌性Sprague-Dawley大鼠，在注射后的不同时间对50摄氏度的温水尾巴戒断，爪子压力，僵直性棒和自发运动能力测试进行了测试。在测试的剂量下，在两个或多个行为测试中，所有三种大麻素激动剂对女性的影响均大于男性。这项研究表明，大麻素对大鼠的行为影响存在性别差异。

BACKGROUND & AIMS: :The effect of drugs that influence the opioidergic and monoaminergic neuronal systems on the antinociceptive action of tizanidine [5-chloro-4-(2-imidazolin-2-yl-amino)-2,1, 3-benzothiodiazole] was compared with their effect on the action of clonidine. The potency of the clonidine-induced antinociceptive action was 1.83 and 7.75 times greater than that of tizanidine in the tail-flick and acetic acid-induced writhing tests, respectively. The action of tizanidine and clonidine was completely antagonized by pretreatment with yohimbine, an alpha 2-adrenoceptor blocker, but not by prazosin, an alpha 1-adrenoceptor blocker. Other alpha-adrenoceptor blockers, phenoxybenzamine and phentolamine, also attenuated the action of tizanidine and clonidine but the potency of these drugs was less than that of yohimbine. An opioid antagonist (naloxone), drugs influencing the serotonergic neuronal system (p-chlorophenylalanine, 5,6-dihydroxytryptamine, cyproheptadine), and drugs influencing the catecholaminergic system (alpha-methyl-p-tyrosine, diethyl-dithiocarbamate, 6-hydroxydopamine, haloperidol) showed no effect on the action of tizanidine and clonidine. From these results, it appears that alpha 2-adrenoceptors might be of importance in mediating the tizanidine and clonidine antinociceptive action in the tail-flick test.

背景与目标： : 比较了影响碘化和单胺能神经元系统的药物对替扎尼定 [5-氯-4-(2-咪唑啉-2-基-氨基)-2,1，3-苯并硫二唑] 的抗伤害作用的影响。对可乐定的作用。在甩尾和乙酸诱导的扭动试验中，可乐定诱导的抗伤害感受作用的效力分别是替扎尼定的1.83倍和7.75倍。tizanidine和可乐定的作用通过用 α2-肾上腺素受体阻滞剂育亨宾进行预处理而完全拮抗，而不用 α1-肾上腺素受体阻滞剂哌唑嗪。其他 α-肾上腺素受体阻滞剂苯氧基苯甲胺和酚妥拉明也减弱了替扎尼定和可乐定的作用，但这些药物的效力低于育亨宾。阿片类药物拮抗剂 (纳洛酮)，影响5-羟色胺能神经元系统的药物 (对氯苯丙氨酸，5,6-二羟色胺，赛庚啶) 和影响儿茶酚胺能系统的药物 (α-甲基-对-酪氨酸，二乙基-二硫代氨基甲酸，6-羟基多巴胺，氟哌啶醇) 对替扎尼定和可乐定的作用没有影响。从这些结果看来，在甩尾试验中，α2-肾上腺素受体在介导tizanidine和可乐定的抗伤害作用中可能很重要。

BACKGROUND & AIMS: :The presence of opioid receptors and enkephalin-releasing neurons in the spinal dorsal horn prompted us to examine whether an enkephalinase inhibitor, SCH32615, given intrathecally would alter the response of the rat on several nociceptive endpoints: 49 degrees C hot plate (HP), 52 degrees C HP; tail flick (TF) and the paw pressure (PP) test. SCH (16-320 nmol, i.t.) resulted in a submaximal dose-dependent increase in the 49 degrees C HP, 52 degrees C HP, TF, and PP measures with the respective ED50 values being 40, 74, 68 and 83 nmol, respectively. AT 320 nmol, no additional increment in effect was observed. Concurrent examination of the effects of 0.1-10 nmol morphine on the 49 degrees C HP, 52 degrees C HP, TF and PP measures revealed i.t. ED50 values of 0.2, 0.8, 0.9 and 0.6 nmol, respectively, with the maximum dose leading to a complete block on all measures. The effects of SCH were totally reversed by naloxone (1 mg/kg, i.p.), a dose which had no detectable effect upon baseline nociceptive response measures. The effects of SCH, even at the highest dose were not accompanied by motor dysfunction or catalepsy. These results are consistent with the hypothesis that high-threshold thermal and mechanical stimuli will evoke the release of an opioid in the spinal space, the metabolism of which is significantly influenced by enkephalinase inhibition.

背景与目标： : 脊髓背角阿片受体和脑啡肽释放神经元的存在促使我们检查鞘内给予的脑啡肽酶抑制剂SCH32615是否会改变大鼠在几个伤害性终点上的反应: 49 ℃ 热板 (HP)，52 ℃ HP; 甩尾 (TF) 和爪子压力 (PP) 测试。SCH (16-320 nmol，i.t.) 导致49摄氏度HP、52摄氏度HP、TF和PP量度的次最大剂量依赖性增加，各自的ED50值分别为40、74、68和83 nmol。在320 nmol时，没有观察到额外的效应增量。同时检查0.1-10 nmol吗啡对49 ℃ HP，52 ℃ HP，TF和PP措施的影响，揭示了i.t.ED50值分别为0.2，0.8，0.9和0.6 nmol，最大剂量导致所有措施的完全阻滞。SCH的作用被纳洛酮 (1 mg/kg，ip) 完全逆转，该剂量对基线伤害性反应措施没有可检测到的作用。即使在最高剂量下，SCH的作用也不伴有运动功能障碍或僵直。这些结果与以下假设一致: 高阈值的热刺激和机械刺激会引起阿片类物质在脊柱间隙中的释放，其代谢受到脑啡肽酶抑制的显着影响。

BACKGROUND & AIMS: :Our previous study has proven that hypothalamic paraventricular nucleus (PVN) stimulation increases pain threshold and PVN cauterization decreases pain threshold. The studied neuropeptides in PVN were investigated to involve to pain modulation in the rat. The results showed that (1) intraventricular injection (icv) of anti-arginine vasopressin (AVP) serum completely reversed pain threshold increase induced by l-glutamate sodium (Glu) injection into the PVN, and local administration (icv) of anti-leucine-enkephalin (L-Ek) serum or anti-beta-endorphin (beta-Ep) serum partly attenuated pain threshold increase induced by Glu injection into the PVN, but pre-treatment of anti-oxytocin (OXT), dynorphinA(1-13) (DynA(1-13)), cholecystokinin-like peptide (CCK), neurotensin (NT), corticotrophin-releasing hormone (CRH), adrenocorticotrophin (ACTH), somatostatin (SST), prolactin-releasing hormone (PRH), angiotensinII (AngII), vasoactive intestinal polypeptide (VIP), melanotropin-releasing hormone (MRH), thyrotropin-releasing hormone (TRH), substance P (SP) or growth hormone-releasing hormone (GHRH) serum (icv) did not influence the analgesic effect of PVN administration with Glu; (2) PVN stimulation with Glu elevated the concentrations of AVP, OXT, CCK, NT, CRH, SST, PRH and DynA(1-13) in PVN perfusion liquid, and could not change the concentrations of L-Ek, beta-Ep, AngII, ACTH, VIP, MRH, TRH, SP and GHRH in PVN perfusion liquid; (3) Pain stimulation increased the concentrations of AVP, L-Ek, beta-Ep, DynA(1-13), CRH and ACTH in PVN perfusion liquid, and did not alter the concentrations of OXT, CCK, NT, SST, PRH, AngII, VIP, MRH, TRH, SP and GHRH in PVN perfusion liquid. The data suggested that AVP played a more important role than the other studied peptides (OXT, L-Ek, beta-Ep, DynA(1-13), CCK, NT, CRH, ACTH, SST, PRH, AngII, VIP, MRH, TRH, SP and GHRH) in PVN antinociceptive progress.

背景与目标： : 我们先前的研究已经证明，下丘脑室旁核 (PVN) 刺激会增加疼痛阈值，而PVN烧灼会降低疼痛阈值。研究了PVN中研究的神经肽与大鼠疼痛调节有关。结果表明 :( 1) 脑室内注射 (icv) 抗精氨酸加压素 (AVP) 血清完全逆转左旋谷氨酸钠 (Glu) 注入PVN引起的痛阈升高，局部给药 (icv) 抗亮氨酸脑啡肽 (l-ek) 血清或抗 β-内啡肽 (beta-Ep) 血清部分减轻了Glu注射到PVN中引起的疼痛阈值增加，但预治疗抗-催产素 (OXT)，强啡肽 (1-13) (DynA(1-13))，胆囊收缩素样肽 (CCK)，神经降压素 (NT)，促肾上腺皮质激素释放激素 (CRH)，促肾上腺皮质激素 (ACTH)，生长抑素 (SST)，催乳素释放激素 (PRH)，血管紧张素 (AngII)，血管活性肠多肽 (VIP)，促甲状腺素释放激素 (MRH)，促甲状腺激素释放激素 (TRH)，p物质 (SP) 或生长激素释放激素 (GHRH) 血清 (icv) 不影响PVN与Glu的镇痛作用; (2) 用Glu刺激PVN可提高PVN灌注液中AVP，OXT，CCK，NT，CRH，SST，PRH和DynA(1-13) 的浓度，并且不能改变L-Ek，β-Ep，AngII，ACTH，VIP，MRH，PVN灌注液中的TRH，SP和GHRH; (3) 疼痛刺激增加了PVN灌注液中AVP，L-Ek，β-Ep，DynA(1-13)，CRH和ACTH的浓度，并且没有改变OXT，CCK，NT，SST，PVN灌注液中的PRH、AngII、VIP、MRH、TRH、SP和GHRH。数据表明，AVP比其他研究的肽 (OXT，l-ek，beta-Ep，DynA(1-13)，CCK，NT，CRH，ACTH，SST，PRH，AngII，VIP，MRH，TRH，SP和GHRH) 在PVN抗伤害感受方面的进展。

BACKGROUND & AIMS: :Docosahexaenoic acid (DHA), an omega-3 polyunsaturated fatty acid (n-3 PUFAs), is an essential polyunsaturated fatty acid in the central nervous system, and possesses many physiological functions in neurodegenerative diseases. Previously, there are some reports that n-3 PUFAs contribute to pain relief. As the antinociceptive effect of DHA alone has not been reported, this study examined the antinociceptive effect of DHA on various pain stimuli. To evaluate the antinociceptive effect of DHA on thermal and chemical nociception, we employed the tail flick test, acetic acid writhing test and formalin test in mice. DHA was orally administrated at 5, 15 and 25 mmol/kg at 30 min before measurement. DHA administration dose-dependently exerted an antinociceptive effect against thermal and chemical stimulation in comparison to the control olive oil administration. These effects of DHA were abolished when mice were pretreated with naloxone, an opioid receptor antagonist. These findings suggest that DHA has opiod receptor-mediated pain control activities, and may provide valuable information towards an advanced therapeutic approach for pain control.

背景与目标： 二十二碳六烯酸 (DHA) 是一种 ω-3多不饱和脂肪酸 (n-3 PUFAs)，是中枢神经系统中必需的多不饱和脂肪酸，在神经退行性疾病中具有许多生理功能。以前，有一些报道称n-3 PUFAs有助于缓解疼痛。由于尚未报道单独使用DHA的抗伤害感受作用，因此本研究检查了DHA对各种疼痛刺激的抗伤害感受作用。为了评估DHA对热和化学伤害感受的抗伤害作用，我们在小鼠中进行了甩尾试验，乙酸扭体试验和福尔马林试验。DHA在测量前30分钟以5、15和25 mmol/kg口服给药。与对照橄榄油相比，DHA给药对热和化学刺激具有剂量依赖性的抗伤害作用。当用阿片受体拮抗剂纳洛酮预处理小鼠时，DHA的这些作用被消除了。这些发现表明DHA具有阿片受体介导的疼痛控制活性，并可能为疼痛控制的先进治疗方法提供有价值的信息。