Creating PK/PD models for oxytocin action in humans and bridging to intranasal delivery

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Project 3 Summary Surgery benefits most patients, but for some, it results in chronic pain and disability. Under current funding, we have moved the state of research in this area forward by developing and applying methods to more precisely map the speed of recovery in individual patients after surgery. In addition, we have shown that recovery after surgery in animals and humans is quicker if surgery occurs around the time of delivery, and this hastened recovery reflects oxytocin (OXT) actions. Although OXT’s effects on multiple neurologic disorders have been probed in animals, translational testing in humans is hampered by a route of administration (intranasal [i.n.]) with undetermined distribution in the brain or the periphery. Project 3 will build on these observations and translate, with guidance by Projects 1 and 2 and support by the PK/PD Core, critical testing of OXT’s actions on somatosensation and the sensory and affective dimensions of pain. Specifically: Aim 1. Create PK models of OXT in plasma after IV and i.n. administration and test covariates This Aim will determine oxytocin pharmacokinetics (PK) after IV and i.n. administration in plasma and test whether key biologic variables (sex, age, weight, race, ethnicity) affect this disposition. These data will be used to determine appropriate dosing to target sites of peripheral or central drug action, including pain relief. Aim 2: Define OXT actions at peripheral sites of somatosensation Using either pain report from a 5 minute heat stimulus or paradigms to be tested by our Swedish collaborators (under their funding by the Wallenberg Foundation outside this P01), we will create and validate a PK/PD (pharmacodynamic) model for OXT on somatosensation including pain in the periphery. This model will guide OXT dosing under a subaward in Sweden to directly test the effects of OXT on sensory afferents using microneurographic recording and by us to test the effects of OXT on light touch as well as pain fibers. Aim 3: Validate hippus as a measure of OXT action and bridge IV studies to intranasal administration We will for the first time establish a PK/PD model for oxytocin in the brain, using pupil diameter oscillations (hippus) as an outcome measure. We will then apply knowledge from Aims 1 and 2 to create PK/PD models for pain relief and central nervous system action after i.n. OXT administration. These models will guide dosing for future clinical trials of i.n. OXT to treat pain and other neurologic disorders.