The cellular and molecular mechanisms underlying nociception and pain

PROJECT SUMMARY The perception of pain is caused by intense or damaging noxious stimuli, such as extremes in temperature or force. The ability to detect noxious stimuli is fundamental for survival as it provides a salient reminder to animals of imminent or persistent danger. There have been significant efforts in understanding how the brain generates the perception of pain. Notably, our most efficacious pharmacological treatment for pain target opiate receptors, which are notorious for their potential for abuse and act primarily on neural circuits in the brain. Strikingly, there is a comparatively little known about how noxious stimuli are detected initially by primary sensory neurons known as nociceptors. Nociceptors act as the ?first-responders? by detecting noxious stimuli through axonal projections present in peripheral organs, such as the skin. This information is then relayed to the brain via synaptic connections made with spinal cord neurons. In order to develop new pain therapeutics, there is a fundamental need to advance our cellular and molecular understanding of the peripheral nociceptors. In a recently published study, I performed scRNA-seq on hundreds of thousand sensory neurons, which identified multiple previously unknown and highly distinct subtypes of nociceptor neurons, likely with distinct functional roles. In this proposal, the laboratory will focus on implementing our recently developed molecular genetic tools and approaches to fundamentally advance our understanding of the first step in pain-processing. We will highlight a three-tiered plan, in which I will thoroughly examine (Tier 1) the anatomical/biophysical features of nociceptor subtypes, (Tier 2) the molecular mechanisms underlying noxious stimuli detection by nociceptor subtypes and (Tier 3) the behavioral consequences during activating/silencing of each nociceptor subtype. we aim to take advantage of my extensive prior research experience, as well as key preliminary advances, to develop a molecular and cellular understanding of how nociceptors detect noxious stimuli.