Central oxytocin mechanisms of pain recovery following nerve injury

Oxytocin produces antinociception in rodents in a variety of pain states, however the mechanisms by which this occurs and the importance of peripheral versus central effects are unclear. Prior studies have typically used systemic administration of oxytocin, with dosing-to- effect strategies in the absence of pharmacokinetic data or consideration of brain penetrance. These studies can only be extrapolated to the clinic after relevant dosing parameters have been determined experimentally to achieve peripheral and central oxytocin exposure across rodents and humans, and using such parameters to compare antinociceptive efficacy against different outcome measures, with subsequent exploration of potential mechanisms. This Project translates and is informed by Projects 1 and 3 to define the pharmacokinetics of oxytocin in awake and anesthetized rats in brain and blood and determine the relevance of peripheral and central action of oxytocin on complex behaviors following nerve injury. Three specific aims are proposed. The first aim will define the pharmacokinetics of oxytocin in plasma and brain using i.v. bolus, and these data will be used to design targeted concentration infusion paradigms in the PK/PD core. The rate of brain entry and loss will also be assessed. The second aim will take advantage of a novel transgenic rat developed by our group that expresses Cre recombinase selectively in oxytocinergic neurons. We will determine the role of endogenous oxytocin circuits in modulation of complex behaviors after peripheral nerve injury using Cre dependent neuronal ablative strategies, expressing mutated caspase 3 in targeted neurons. We have developed novel behavioral methods that assess impairment of attention, fear avoidance, and affective and sensory modalities of pain after nerve injury and use these innovative behavioral methods for this aim. The third aim combines the knowledge gained from Aims 1 and 2 to assess the efficacy of oxytocin in mitigating the behavioral changes induced by peripheral nerve injury, tests the potential for oxytocin to produce long-lasting, disease-modifying effects in behavior and afferent physiology, and the role of endogenous circuits in these effects. This project interacts with Project 1 to assess the contribution of altered primary sensory afferent signaling in complex behaviors and the relevance of oxytocin and with Project 3 to target relevant peripheral levels of oxytocin in humans for peripheral and central action.