A non-injurious assay to study mechanisms of transmission of noxious stimulus

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Although pain is still the most common reason why patients seek health care, the mechanisms of transmission and perception of pain are incompletely understood. In order to develop new drugs and techniques to treat pain, it is imperative to undrestand the neurophysiologic mechanisms by which noxious and non-noxious stimuli are perceived. Therefore, clinically relevant animal models of pain are needed to further our understanding of the mechanisms of pain transmission. Currently available models to study transmission of pain use heat, pressure, or chemical stimulation to inflict pain. These models have led to many discoveries in the field but have limitations. Some of the limitations include the fact that heat and pressure can be associated with injury to animals, the stimuli can nonspecifically stimulate several types of nerve fibers (A beta-pressure, A delta-sharp pain, C-slow burning pain), and these stimuli can be associated with habituation learning. In order to study the mechanisms of the transmission of noxious stimuli, we developed a novel and non-injurious nociception assay to preferentially study transmission of noxious stimulus via nerve fibers in a live system. We use a neuro-stimulator that delivers electrical stimuli to the skin at different frequencies and intensities and produces transient discomfort without producing injury. Each of the electrical frequencies used preferentially stimulate a specific type of pain fiber and allows for the measure of vocalization threshold for each type of pain fiber. In the model, we define vocalization as the pain avoiding behavior to the electrical stimulus and use it as the end point to measure current vocalization threshold for each of the pain fibers. Unlike currently used pain models that may produce some tissue-injury in order to induce pain, this assay is non-injurious and preferentially stimulates each type of pain fibers. Therefore it might become a valuable tool for the study of the mechanisms of pain. We completed pilot studies for the development of this assay in mice, developed normative values for the response to each frequency, and have fully developed software application to control the neuro-stimulator, and automated a large portion of the protocol. In addition, we are implementing upgrades to enable automated data collection and storage. We are now using the model to study the impact of aging, differences in gender as well as the role of nitric oxide synthases in the transmission of noxious stimuli in specific nociceptive nerve fibers. We are further developing the model to evaluate pharmacologic interventions such as morphine with systemic and local analgesics, different strains and species of animals, and different pain models.