내인성 단백질 기반 말초신경계 내 통증 조절 기전 연구 : GLP-1에 의한 TRPV1 억제와 c-Met 수용체 매개 이온 채널 활성 변화 = Study on Endogenous Protein-Based Pain Modulation Mechanism in the Peripheral Nervous System: GLP-1-Induced TRPV1 Inhibition and c-Met Receptor-Mediated Ion channel Activity Changes

다국어 초록 (Multilingual Abstract)

Pain is generally controlled through intrinsic pain modulation systems that maintain balance under normal physiological conditions. However, in pathological scenarios such as neuropathic pain, inflammation, or diabetes-induced nerve damage, these systems can become compromised. This impairment leads to an overactivation of pain pathways and the onset of chronic pain. This study aims to explore key mechanisms involved in pain modulation, with a focus on innovative strategies targeting two distinct pathways to address chronic pain conditions. Chapter 1 investigates the role of glucagon-like peptide-1 (GLP-1) and its derivatives in modulating nociceptive signaling. It highlights how GLP-1-based peptides, particularly exendin 9–39 and exendin 20–29, provide effective relief from acute and chronic pain. These peptides are shown to act on TRPV1 channels, offering significant analgesic effects without triggering thermoregulatory disturbances, thereby presenting a safer alternative for pain management. Chapter 2 explores the c-Met receptor pathway, focusing on the NK1 splice variant of hepatocyte growth factor (HGF). This variant selectively activates c-Met, modulating neuronal excitability through the regulation of voltage-gated sodium channels. The findings underscore its potential in reducing chronic pain while avoiding excessive cell proliferation. By leveraging this pathway, a targeted therapeutic approach can be employed to address chronic pain effectively. Together, these studies shed light on intrinsic pain regulation mechanisms and present innovative therapeutic options for managing chronic pain, providing valuable insights into improving patient outcomes.

목차 (Table of Contents)

• Abstract 1
• Contents 3
• List of figures 5
• Background 7
• 1. Pain Pathway in the Peripheral Nervous System 7
• 2. Damage in Intrinsic Pain Modulation System in Chronic Pain States 9
• 3. Novel Insight into Endogenous Proteins 11
• Purpose 13
• CHAPTER 1: Direct Inhibition of TRPV1 by GLP-1 and Its Derived Peptides: Novel Analgesic Mechanisms Without Thermoregulatory Effects 14
• Abstract 15
• Introduction 16
• Materials and Methods 19
• Results 25
• Discussion 56
• Contribution 60
• CHAPTER 2: The Role of NK1, a Natural Splice Variant of Hepatocyte Growth Factor, in Modulating Pain Through c-Met Activation in DRG Neurons 61
• Abstract 62
• Introduction 63
• Materials and Methods 65
• Results 72
• Discussion 81
• Contribution 83
• Reference 84
• 국문초록 95