Descending Modulation of Nerve Injury and Injury-Evoked Pain

神经损伤和损伤引起的疼痛的降序调节

基本信息

批准号：
7593308
负责人：
Toni Shippenberg
金额：
$ 44.6万
依托单位：
NATIONAL INSTITUTE ON DRUG ABUSE
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7593308
关键词：
Absence of pain sensation Acute Adverse effects Affect Agonist Amino Acid Transporter Analgesics Animal Model Animals Attenuated Bilateral Brain region Cells Chemosensitization Condition Constipation Data Detection Development Dicarboxylic Acids Dose Enkephalin, Ala(2)-MePhe(4)-Gly(5)-Excitatory Amino Acid Receptors Excitatory Amino Acids Freund&apos s Adjuvant GABA Antagonists GABA-A Receptor Glutamates Hindlimb Hyperalgesia Hypersensitivity Inflammation Infusion procedures Injection of therapeutic agent Injury Masks Mechanics Mediating Microdialysis Modality Morphine Neurons Neurosciences Neurotransmitters Nociception Opiates Opioid Opioid Receptor Pain Pain management Perfusion Peripheral Nervous System Diseases Persistent pain Pharmaceutical Preparations Process Production Protein Family Proteins Pyrrolidines Rattus Receptor Activation Regulation Relative (related person)Role Signal Transduction Slice Spinal Cord Stimulus Synapses System Tactile Tactile Hyperalgesias Testing Therapeutic Therapeutic Effect Thermal Hyperalgesias Ventilatory Depression Week Withdrawal Work allodynia behavior test compliance behavior delta opioid receptor diabetic dysphoria endogenous opioids gamma-Aminobutyric Acid in vivo inhibitor/antagonist kappa opioid receptors mu opioid receptors nerve injury novel novel therapeutics painful neuropathy patch clamp prevent pyrrolidine pyrrolidine-2,4-dicarboxylic acid relating to nervous system response transmission process uptake

项目摘要

The rostral ventral medulla (RVM) has been implicated in the descending modulation of pain. The RVM is enriched in mu-, delta- and kappa opioid receptors. Systemic opioid agonist administration of infusion of these agents directly into the RVM produces antinociception. The selective blockade of opioid receptors in the RVM attenuates the analgesic effect of systemically administered opiates indicating that activation of opioid receptors in this brain region is both sufficient and necessary for the production of antinociception. Previous work has shown that the analgesic effects produced by supraspinal infusion of mu and delta opioid receptor agonists are potentiated during persistent inflammation. Whether this potentiation extends to other stimulus modalities or to kappa opioid receptor agonists is unknown. To examine these issues, rats received a unilateral intraplantar injection of complete Freund's adjuvant. Antinociception produced by RVM infusion of the kappa opioid receptor agonist, U69593, and the mu opioid receptor agonist, DAMGO, was tested 4h-2 weeks thereafter by assessing thermal paw withdrawal latencies and mechanical thresholds of the inflammed and non-inflammed hindlimb. Withdrawal latencies and mechanical thresholds of the inflamed paw were reduced for at least 2 weeks after the induction of inflammation. Infusion of either U69593 or DAMGO increased withdrawal latencies of the inflammed and non-inflammed hindlimb. A bilateral enhancement of the response to both agonists was observed 2 weeks relative to 4h post-CFA injection. Agonist infusion also elevated mechanical thresholds of the inflamed and non-inflamed paws. The magnitude of the DAMGO effect was greater 2 weeks after the induction of inflammation whereas the effects of U69593 increased progressively as a function of the duration of inflammation. These data demonstrate that RVM infusion of mu- or kappa agonists attenuates thermal and tactile allodynia and that these effects increase during prolonged inflammation. The augmented response of the non-inflamed paw to agonists suggests that inflammation induces centrally-mediated neuroplastic changes which enhances antinociception. GABAergic and glutamatergic signaling has been implicated in mediating RVM-mediated opiate antinociception. Infusion of GABA receptor antagonists into the RVM produces analgesia. Infusion of glutamate into this region produces simlar effects. Analgesia produced by systemic morphine administration can be prevented by RVM administration of GABA-A receptor agonists or non-selective excitatory amino acid receptor antagonists Whole cell patch clamp recordings in RVM slices have provided functional evidence that mu-opioid receptor activation modulate the release of inhibitory and excitatory neurotransmitters onto spinally projecting neurons Although these data suggest that GABAergic signaling is altered in the RVM during mu-opioid receptor mediated analgesia, studies directly assessing mu-opioid receptor agonist evoked changes in glutamate and GABA release in the behaving animal are lacking. We used in vivo microdialysis to investigate this issue. Local perfusion of the selective mu-opioid receptor agonist, DAMGO, produced a concentration-dependent decrease of GABA release in the RVM. Behavioral testing revealed that only concentrations of DAMGO that decreased GABA levels increased thermal withdrawal thresholds. DAMGO did not alter glutamate concentrations in microdialysates. Addition of KCl (60 mM) was also without effect. Since rapid, transporter-mediated uptake may mask detection of changes in glutamate release, the selective excitatory amino acid transporter inhibitor pyrrolidine-2,4-dicarboxylic acid (tPDC) was added to the perfusion medium for subsequent studies. tPDC increased glutamate concentrations, confirming transport inhibition. KCl increased microdialysate levels of gluatame in the presence of tPDC demonstratting that transport inhibition permits detection of depolarization-evoked glutamate release. In the presence of tPDC, DAMGO increased glutamate levels in a concentration-dependent manner. These data provide the first direct demonstration that mu opioid receptor activation decreases GABA and increases glutamate release in the RVM. We hypothesize that the opposing effects of mu-opioid receptor activation on glutamate and GABA transmission contribute to opiate antinociception. In view of the role of glutamate transmission in nociceptive processing and opiate antinociception, we have initiated studies to determine whether a novel family of proteins that involved in the post-synaptic regulation of glutamate function are altered in response to nerve injury and inflammation and whether manipulations that affect their activity can modulate the thermal and mechanical hypersensitivity. hyperalgesia. Using animal models of peripheral neuropathy, we have found that manipulations that decrease protein activity significantly attenuate the development and expression of nerve-injury evoked mechanical hyperalgesia and allodynia. These manipulations are also effective in modulating the hyperalgesia and tactile allodynia that occur following persistent inflammation. On-going studies are examining whether targeting these proteins can attenuate diabetic and retroviral therapy-associated peripheral neuropathy.

延髓头侧腹侧（RVM）与疼痛的下行调节有关。 RVM 富含 mu、delta 和 kappa 阿片受体。将这些药物直接输注到 RVM 中进行全身阿片受体激动剂给药可产生镇痛作用。选择性阻断 RVM 中的阿片受体会减弱全身阿片类药物的镇痛效果，表明该大脑区域阿片受体的激活对于产生抗伤害作用是充分且必要的。先前的研究表明，在持续性炎症期间，脊髓上输注 mu 和 delta 阿片受体激动剂产生的镇痛作用会增强。这种增强作用是否延伸到其他刺激方式或κ阿片受体激动剂尚不清楚。为了研究这些问题，大鼠接受了完全弗氏佐剂的单侧足底注射。 4小时至2周后，通过评估发炎和非发炎后肢的热缩爪潜伏期和机械阈值，测试RVM输注kappa阿片受体激动剂U69593和mu阿片受体激动剂DAMGO产生的镇痛作用。在引发炎症后至少两周内，发炎爪子的缩回潜伏期和机械阈值降低。输注 U69593 或 DAMGO 会增加发炎和非发炎后肢的撤药潜伏期。相对于 CFA 注射后 4 小时，观察到 2 周后双侧对两种激动剂的反应均增强。激动剂输注还提高了发炎和非发炎爪子的机械阈值。 DAMGO 效应的强度在炎症诱导后 2 周更大，而 U69593 的效应随着炎症持续时间的变化而逐渐增强。这些数据表明，RVM 输注 mu 或 kappa 激动剂可减轻热和触觉异常性疼痛，并且这些效应在长期炎症过程中会增强。未发炎的爪子对激动剂的增强反应表明炎症诱导中枢介导的神经塑性变化，从而增强抗伤害作用。 GABA 能和谷氨酸能信号传导参与介导 RVM 介导的阿片类镇痛作用。将 GABA 受体拮抗剂输注到 RVM 中可产生镇痛作用。将谷氨酸注入该区域会产生类似的效果。 RVM 施用 GABA-A 受体激动剂或非选择性兴奋性氨基酸受体拮抗剂可以预防全身吗啡施用产生的镇痛。RVM 切片中的全细胞膜片钳记录提供了功能性证据，表明 mu-阿片受体激活调节抑制性药物的释放。尽管这些数据表明，在 mu-阿片受体介导的镇痛过程中，RVM 中的 GABA 信号发生了改变，但研究直接目前还缺乏对 mu-阿片受体激动剂引起行为动物谷氨酸和 GABA 释放变化的评估。我们使用体内微透析来研究这个问题。局部灌注选择性 mu-阿片受体激动剂 DAMGO，导致 RVM 中 GABA 释放呈浓度依赖性减少。行为测试表明，只有降低 GABA 水平的 DAMGO 浓度才能提高热退缩阈值。 DAMGO 不会改变微透析液中谷氨酸的浓度。添加 KCl (60 mM) 也没有效果。由于转运蛋白介导的快速摄取可能会掩盖谷氨酸释放变化的检测，因此将选择性兴奋性氨基酸转运蛋白抑制剂吡咯烷-2,4-二甲酸（tPDC）添加到灌注介质中以进行后续研究。 tPDC 增加了谷氨酸浓度，证实了转运抑制。在 tPDC 存在的情况下，KCl 增加了微透析液中谷氨酸的水平，这表明转运抑制允许检测去极化引起的谷氨酸释放。在 tPDC 存在下，DAMGO 以浓度依赖性方式增加谷氨酸水平。这些数据首次直接证明 mu 阿片受体激活会减少 RVM 中的 GABA 并增加谷氨酸释放。我们假设 mu-阿片受体激活对谷氨酸和 GABA 传输的相反作用有助于阿片类药物的镇痛作用。鉴于谷氨酸传输在伤害性加工和阿片类镇痛中的作用，我们已经启动了研究，以确定参与突触后谷氨酸功能调节的新型蛋白质家族是否会因神经损伤和炎症而改变，以及操作是否会改变。影响其活动的物质可以调节热和机械超敏反应。痛觉过敏。使用周围神经病变的动物模型，我们发现降低蛋白质活性的操作可显着减弱神经损伤引起的机械性痛觉过敏和异常性疼痛的发展和表达。这些操作还可有效调节持续炎症后发生的痛觉过敏和触觉异常性疼痛。正在进行的研究正在研究针对这些蛋白质是否可以减轻糖尿病和逆转录病毒治疗相关的周围神经病变。