Final Report Summary - SIAMCP (Follow the PAIN: Novel Somatotopically-Based Integrative Approach to Study Mechanisms of Detection, Transmission and Perpetuation of Nociceptive, Inflammatory and Neuropathic Pain)
Inadequate treatment of chronic pain has afflicted mankind throughout recorded history. The most successful current treatments will yield only partial improvement in only 30% of cases. A comprehensive and detailed understanding of pain mechanisms is urgently required to enable the development of more effective treatments. Biologically speaking, pain is a complex multidimensional phenomenon, which involves sensory component as well as cognitive and emotional aspects. All these components collectively comprise pain phenomenon. Painful stimuli activates complex circuits spanning the entire nervous system, from the peripheral neuron to neuronal circuits in the central nervous system. All these parts are susceptible to changes which underlie the transition from a normal physiological response to noxious stimuli, to pathological chronic pain, which in many cases is detached from any seemingly cause. Our project is aimed to integrate analysis at different levels of pain perception in normal and pathological conditions in order to elucidate mechanisms underlying chronic pain. The first part of the project was to analyze the mechanism by which the peripheral neurons detect and transmit pain related information. The results of the first part of the project enabled us, for the first time, to investigate how peripheral pain neurons detect pain related information in live animals. To that end, we devised a beyond the cutting edge strategy, allowing us to study the fundamental site of signal detection - the terminal of the pain-related sensory neurons. We further studied how peripheral nerves differentiate between various noxious stimuli, in particular between stimuli which generate pain and ones generating itch. We discovered distinctive populations of peripheral neurons that detect and code itch and pain. Moreover we have revealed that different itch-generating stimuli activate distinct neuronal sub-populations, and devised a strategy for selective blockade of itch. We also studied the changes in pain perception during pathological conditions and we have revealed novel key molecules which acts on peripheral pain generating neurons and modulates their activity thus leading to inflammatory pain. The next stage of the project was to to follow the stimulus propagation from the periphery to spinal cord and from there via thalamus to cortex and to define pain specific neuronal circuits. To complete this aim we have developed a beyond state of the art technique enabling for the first time to map the location of the axonal branches (“arbors”) of many individual neurons simultaneously, at the resolution of individual axons. Thus, by “seeing” many axons in the same preparation, it becomes possible to understand how specific neurons in one region are wired to other neuronal types and other regions. This approach is in some ways analogous to the principle used in a Global Positioning System (GPS) receiver, which uses distances from three or more satellites to triangulate its position. For this reason the new technique is called “Neuronal Positioning System” (NPS). Using the NPS technique we can study what defines the routes along which the neurons in general and pain neurons in particular, send their projections, as well as their targets. Thus, NPS enables us to comprehend how the information flows and how it is processed in the nervous system, and how changes in the neuronal organization affect neuronal function. We can also learn how the wiring of the neuronal circuits changes during development of chronic pain.
The results of this work already yielded and will yield significant novel and fundamental insights into the molecular mechanisms of pain sensation and will elucidate new potential targets for the treatment of inflammatory and neuropathic pain.
The results of this work already yielded and will yield significant novel and fundamental insights into the molecular mechanisms of pain sensation and will elucidate new potential targets for the treatment of inflammatory and neuropathic pain.