The encoding of noxious stimuli by peripheral nociceptive terminals remains one of the least understood processes in sensory physiology, despite its central role in pain perception. These terminals, comprising fine arborized endings embedded within tissue, represent the first site where harmful stimuli are detected and transformed into electrical signals. However, due to their minute size and inaccessibility, direct in vivo functional analysis of these terminals has long been considered unfeasible. Our project addresses a fundamental and unresolved question in pain biology: How does a single nociceptive terminal encode, integrate, and transmit noxious signals under both normal and pathological conditions? To investigate this, we developed and implemented a novel in vivo optical voltage imaging platform that enables direct, subcellular-resolution recording of membrane potential changes from individual nociceptive terminals and fibers in intact tissue. This represents a significant advancement in the field. For the first time, we can quantify the input-output relation of single nociceptive terminals, identify their spontaneous and evoked firing patterns, and dissect the molecular underpinnings of these responses in models of inflammation. We will further combine this with innovative calcium imaging and computational modeling to study signal integration across terminal trees. The outcomes of this research will redefine our understanding of peripheral pain encoding, uncover novel mechanisms of hyperexcitability and pain amplification, and lay a conceptual and technical foundation for the development of selective, peripherally acting pain therapies. This paradigm-shifting approach opens new avenues for deciphering the logic of pain at its source.

Supervisors: Prof. Alexander Binshtok, Dr. Yoav Adam