The Pharmacology of Spinal Analgesics

脊髓镇痛药的药理学

• 批准号: 6919004
• 负责人: TONY L. YAKSH
• 金额: $ 29.91万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 1983
• 资助国家: 美国
• 起止时间: 1983-07-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6919004
• 关键词: G protein; GABA receptor; NMDA receptors; adrenergic receptor; afferent nerve; analgesics; drug administration routes; drug tolerance; excitatory aminoacid; fos protein; inhibitor /antagonist; laboratory rat; microinjections; morphine; neuropeptide receptor; neuropharmacology; opioid receptor; pharmacokinetics; protein kinase C; protooncogene; purinergic receptor; receptor expression; receptor sensitivity; spinal cord; substance P

DESCRIPTION (provided by applicant): Intrathecal agonists for inhibitory G coupled receptors (e.g. mu and alpha2) produce analgesia. Based on receptor distribution and block of afferent release (substance P: SP), we think the analgesia reflects a joint pre- and post-synaptic action. Neurokinin 1 receptor (NK1) internalization and cFos/pCREB expression are robust tools to define in vivo the effect of acute and chronic interventions on small afferent release and post synaptic excitability and to explore several hypothesized ramifications of this action. 1) IT analgesic activity will co-vary with the inhibitory effects on small afferent terminal excitability (NK1 internalization). We will examine in rats the effects/pharmacology of IT agents acting on small afferent terminal receptors (mu, delta, alpha2, NPY, GABAB, and Adenosine A1) to block paw injury evoked NK1 internalization. 2) Spinal receptors located postsynaptic to the primary afferent will control excitatory outflow of spinal neurons driven by afferent input. Using cFos/pCREB expression, paw injury, IT-SP or IT-NMDA will be used to activate spinal neurons and indirectly supraspinal neurons (n. parabrachialis) in the presence of IT-analgesics. 3) Systemic morphine exerts its effect upon spinal function by concurrent spinal and supraspinal actions. We will examine the spinal effects of intracerebral and systemically administered morphine at analgesic doses on spinal NK1 internalization and activation of spinal/supraspinal cFos/pCREB by paw injury, IT SP or IT NMDA. 4) Given tolerance and dependence observed with chronic IT mu and alpha2 agonists and the proposed sensitization of spinal processing mediated though NMDA and PKC, we hypothesize that i) chronic IT mu or alpha2 agonist infusion will enhance injury evoked NK1 internalization and increased IT SP-evoked cFos activation at spinal and supraspinal levels; ii) increased NK1 internalization and cFos after naloxone; and iii) a reversal of mu tolerance with NMDA antagonism or PKC inhibition. In short, these studies seek to illuminate the complex pre- and postsynaptic mechanisms by which modulatory receptors regulate spinal nociceptive outflow.

描述（由申请人提供）：固定的激动剂用于抑制性G偶联受体（例如MU和Alpha2）产生镇痛。基于受体分布和传入释放的阻滞（物质P：SP），我们认为镇痛反映了关节前和突触后作用。 Neurokinin 1受体（NK1）内在化和CFOS/PCREB表达是在体内定义急性和慢性干预措施对小传入释放和突触后兴奋性的影响的强大工具，并探索了这种动作的几种假设的后果。 1）IT镇痛活性将与对小传入终端兴奋性（NK1内在化）的抑制作用共同变化。我们将在大鼠中检查作用于小传入末端受体（MU，Delta，Alpha2，NPY，Gabab和腺苷A1）的IT剂的作用/药理学，以阻止PAW损伤的NK1内在化。 2）位于主要传入的突触后的脊柱受体将控制由传入输入驱动的脊柱神经元的兴奋性流出。使用CFOS/PCREB表达，PAW损伤，IT-SP或IT-NMDA将在存在IT-甲状腺素的情况下激活脊柱神经元和间接上跨脊髓神经元（n。parabrachialis）。 3）系统性吗啡通过并发的脊柱和脊柱上部作用发挥其对脊柱功能的影响。我们将通过PAW损伤，IT SP或IT NMDA检查，以镇痛剂量的脊柱NK1内在化和脊柱/脊柱上CFOS/PCREB激活脊柱剂量的脊柱和系统给药的脊柱作用。 4) Given tolerance and dependence observed with chronic IT mu and alpha2 agonists and the proposed sensitization of spinal processing mediated though NMDA and PKC, we hypothesize that i) chronic IT mu or alpha2 agonist infusion will enhance injury evoked NK1 internalization and increased IT SP-evoked cFos activation at spinal and supraspinal levels; ii）纳洛酮后增加了NK1的内在化和CFO； iii）与NMDA拮抗或PKC抑制作用的MU耐受性逆转。简而言之，这些研究试图阐明调节受体调节脊柱伤害感受性流出的复杂前和突触后机制。