Pamela Flood - US grants

The principal investigator of this mentored clinical science award is an anesthesiologist who is seeking advanced training in the physiology and pharmacology of general anesthetic action in native neurons. The long-term objectives of this proposal are two-fold. The first objective is to provide the principal investigator with the training that will allow her to become an independent medical scientist. The second objective is to understand the mechanism by which two general anesthetics cause clinically relevant changes in the sympathetic nervous system. The first objective will be obtained through mentored research and non-research activity including graduate classes in physiology and pharmacology. Training will be enhanced with weekly journal club, data review sessions departmental lecture series and interaction with colleagues. The second objective will be pursued with studies of general anesthetic activity at multiple levels of the sympathetic nervous system. General anesthetic modulation of the sympathetic nervous system allows the patient to undergo surgery without hemodynamic changes that would otherwise be detrimental. Modulation of postsynaptic sympathetic nAChRs will be studied using patch clamp recording of dispersed sympathetic ganglia neurons. General anesthetic activity at presynaptic nAChRs will be studied by monitoring the frequency of spontaneous synaptic transmission between dispersed sympathetic ganglia neurons and visceral motor neuron explants. The effects of anesthetics on excitatory input from the hypothalamus will be studied using patch clamp recording from dispersed hypothalamic neurons. The resulting information will provide understanding of the molecular mechanism underlying one of the anesthetic effects that limit anesthetic safety.

hyperalgesia; pain threshold; anesthesia complication; isoflurane; gender difference; clinical research; human subject;

DESCRIPTION (provided by applicant): Pain is a major public health issue that affects 1 in 5 Americans. After surgery, 70-80% of patients experience moderate to severe pain despite "state of the art" treatment with opioids and other drugs. Lecithin and phosphatidylcholine are nutritional supplements that are widely marketed to increase choline intake in humans. There is considerable evidence from animal models that choline supplementation has pain-relieving properties and can reduce inflammatory and postoperative pain. Choline is thought to have analgesic properties in animals by activating a7 nicotinic acetylcholine receptors in neurons and/or inflammatory cells. We propose a pilot clinical study to determine whether supplementation with lecithin and phosphatidylcholine to increase plasma choline concentrations before gynecological surgery will decrease post-operative pain. We will conduct a linked pharmacokinetic/ pharmacodynamic trial with the primary outcome variable of reported pain score after surgery. In this placebo-controlled double-blind study all patients will receive the optimal postoperative pain regimen with morphine via PCA. We will assess whether choline supplementation affects patients'use of pain medication and satisfaction with pain relief. Furthermore, we will conduct an exploratory analysis of subject macrophages for a7 receptor expression level and activity in subject macrophages. We will determine whether heterogeneity in a7 nicotinic receptors is predictive of intra-individual variation in choline efficacy. PUBLIC HEALTH RELEVANCE: This is a pilot pharmacokinetic/pharmacodynamic study to determine whether nutritional supplementation with lecithin increases plasma choline concentration and decreases pain after surgery. In an exploratory analysis we will determine whether supplementation reduces the activity of subject macrophages through an alpha 7 nicotinic receptor dependent pathway.