Analgesic Mechanism of Action of Endogenous Opioid Peptides Enkephalins with a Fo

内源性阿片肽脑啡肽的镇痛作用机制

• 批准号: 8525879
• 负责人: Gregory Scherrer
• 金额: $ 24.9万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8525879
• 关键词: Ablation; Acute Pain; Adverse effects; Affinity; Agonist; Analgesics; Behavioral Assay; Behavioral Genetics; Cellular biology; Clinic; Constipation; Dendrites; Development; Disease; Drug Addiction; Drug abuse; Drug usage; Enkephalins; Environment; G-Protein-Coupled Receptors; Genes; Goals; Health; Hyperalgesia; Individual; Injury; Interneurons; Mediating; Mentors; Methods; Morphine; Neurons; Opioid; Opioid Peptide; Opioid Receptor; Pain; Pain Threshold; Pain management; Peptide Receptor; Peptides; Pharmaceutical Preparations; Process; Property; Recruitment Activity; Research; Research Personnel; Resistance; Signal Transduction; Spinal; Spinal Cord; System; Testing; Treatment Efficacy; Universities; Ventilatory Depression; Vomiting; base; career; chronic pain; dorsal horn; endogenous opioids; improved; innovation; knockout gene; mu opioid receptors; neuronal cell body; neurotransmission; novel therapeutics; painful neuropathy; preproenkephalin; receptor; research facility; response; success; trafficking; transmission process

PROJECT SUMMARY The endogenous opioid system regulates pain sensitivity and is targeted by opioid drugs used in the clinic (e.g. morphine) for the management of pathological (disease- or injury-induced) pain. However, current opioid therapies generate significant side effects (i.e. paradoxical hyperalgesia, drug abuse, vomiting, constipation, respiratory depression, etc) and have limited efficacy for the treatment of certain types of chronic pain (i.e neuropathic pain). The endogenous opioid system is composed of several peptide agonists (including enkephalins) and of the delta, kappa and mu opioid receptors (DOR, KOR and MOR, respectively). The contribution of individual opioid receptors and peptides to pain processing has been probed by pharmacological and gene knockout approaches, but surprisingly little is known about the mechanisms by which interactions between these peptides and receptors regulate pain. The objective of the proposed research is to better understand how enkephalins and opioid drugs regulate pain transmission in the spinal cord, where neuroplastic changes leading to chronic pain occur, to develop new therapeutic strategies to treat morphine-resistant types of chronic pain. We will first investigate the cellular mechanisms by which enkephalins regulate activity of spinal neurons known to be critical to chronic pain. We will test the hypothesis that because of distinctions between DOR and MOR cellular biology (e.g. expression by different neurons, different trafficking properties or subcellular localization) activation of the two opioid receptors differentially alters neuronal activity. We will then investigate spinal enkephalinergic circuits and identify both the neurons responding to enkephalins and the opioid receptors mediating these responses (DOR and/or MOR). We will test the hypothesis that release of enkephalins inhibits neighboring projection neurons known to be critical to chronic pain, as well as enkephalinergic neurons themselves (autosignaling). Finally, we will use behavioral assays to test the hypothesis that enkephalinergic neurons are critical to setting pain threshold during chronic pain. The proposed studies should greatly improve our understanding of the mechanisms by which the endogenous opioid system controls pain. In addition, these studies might provide an explanation for the limited efficiency of current therapies and stand to uncover new opioid-based strategies to manage chronic pain. Additionally, both the innovative methods developed in this project and the new information obtained is expected to have a broad impact on our understanding of the mechanism of action of opioid drugs, beyond the pain field (i.e. drug addiction). The mentor, Dr. Amy MacDermott, has a distinguished reputation for productive and relevant research on electrophysiological studies of the spinal pain circuitry. In addition, she has a strong track record of supervising trainees who go on to become productive, independent researchers. Columbia University provides a high-quality environment for the development of Dr. Scherrer's career and research plans. The research facilities, educational opportunities, and intellectual environment are outstanding and will contribute greatly to the success of the proposed activities.

项目总结