From Pain Resilience Genes Toward Therapeutic, Non-Opiate Modulation: An iPSC-Based Approach

安全有效地治疗慢性疼痛是一项未得到满足的医疗需求，这反过来又促成了

Safe and effective treatment for chronic pain is an unmet medical need, which in turn has contributed to the opioid crisis. The experience of pain varies from person to person, with some individuals relatively resilient to pain compared to others. Individual-to-individual variation in pain, while observed in the clinics, has not been accurately modeled in the laboratory nor has its mechanistic underpinnings carefully examined. This is partially because pain involves detection by the peripheral nervous system and perception in the central nervous system, and may be modulated by many factors including genetic, epigenetic, environmental and social. Our studies of blood relatives with inherited erythromelalgia (IEM) with varying degrees of pain despite carrying the same Nav1.7 mutation (S241T) have allowed us to identify modulatory gene variants/mutations expressed in sensory neurons using whole exome sequencing as modulators of pain in these patients. In this proposal, we will build upon our discovery of “pain resilience genes” and evaluate the potential of pharmacological modulators of Kv7 channels to reduce hyperexcitability of human sensory neurons derived from genetically validated subjects with chronic pain, as a way to identify safe and effective strategies that steer away from opioids in the treatment of chronic pain.