Probing pain mechanisms: from molecules to physiology

/ Abstract Nociception is the process whereby a subset of somatosensory nerve fibers (called nociceptors) detects noxious stimuli and transmits this information to the central nervous system, ultimately producing a percept of discomfort or pain. Nociceptors are faced with the complex task of recognizing disparate environmental and endogenous signals of both a physical and chemical nature; these include temperature, pressure, irritants, pruritogens, and inflammatory agents. Consequently, nociceptor activation elicits acute pain as well as injury-evoked pain hypersensitivity and can contribute to so-called ‘maladaptive’ processes underlying persistent pain syndromes. Our goal is to understand how nociceptors detect, integrate, and transmit these signals under numerous environmental and physiological conditions. This proposal is aimed at identifying and characterizing molecules, cells, and mechanisms that contribute to nociception in the context of acute (protective) or pathological (chronic) pain states. Our approach is multifaceted and ranges from structural biology to integrative physiology. At the most reductionist level, we will use biophysical, biochemical, and pharmacological tools to elucidate structural mechanisms underlying ion channel function, with an emphasis on identifying proteins and other cellular elements that physically and functionally engage with members of the TRP ion channel family that play key roles in nociception. We will also leverage cutting edge approaches in electron cryo-microscopy and tomography to visualize these channels and signaling complexes in cellular membranes and, ultimately, in their native environment of the primary afferent nociceptor. At a more integrative level, we shall probe mechanisms of intero-nociception by asking how primary afferent nociceptors interact with tissues to detect noxious signals and transmit this information to the spinal cord. We will focus on the intestine and joints, using mice as genetically tractable models for understanding mechanisms underlying chronic visceral or osteoarthritic (OA) pain. We will employ state-of-the-art techniques, such as genetically encoded neurotransmitter sensors and single cell sequencing, to characterize interactions between nociceptors and sensory epithelial cells in the gut or subchondral bone in joints. Because visceral and OA pain are more prevalent in women, we will ask if these interactions or other properties of resident nociceptors differ with sex or with age, which is also a significant factor contributing to OA. Models of OA or visceral hypersensitivity will be used to ask if genetic, functional, or anatomical characteristics of nociceptors change under maladaptive states. Visceral and OA pain remain poorly managed, reflecting our current lack of mechanistic insight into these common debilitating disorders. Together, these studies will help bridge this knowledge gap and facilitate the development of novel analgesic therapies. Project Number: 1R35NS142941-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: David Julius | Institution: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, SAN FRANCISCO, CA | Award Amount: $1,179,715 | Activity Code: R35 | Study Section: Special Emphasis Panel[ZNS1 SRB-P (16)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11136086