University of Chicago Hospital

Ongoing research projects:

Project 1 – Blinded Behavioral Studies in Mice and Rats

Determine whether A2A receptors play a role in reversing anesthesia. Preladenant, a specific and potent A2a adenosine receptor antagonist will be tested. If preladenant can accelerate emergence from anesthesia, then A2a receptor knockout mice will be tested. We predict that these mice will be resistant to general anesthesia and will not respond to preladenant. In these animal studies we will also determine optimal caffeine timing for anesthesia reversal.

Project 2 – Blinded Studies in Human Volunteers

Determine whether caffeine accelerates recovery from anesthesia and whether it accelerates recovery of cognitive abilities. We will also determine whether caffeine is effective for all anesthetics. If caffeine accelerates recovery from anesthesia and restores cognitive abilities, then it may have the potential to impact medicine in a positive manner and in a brief time frame.

Project 3 –Studies of Autism Spectrum Disease (ASD)

Two serendipitous observations form the basis of this project. First, we observed that three different rodent models of ASD, out of 3 tested, showed altered sensitivity to general anesthetics. Because GABAA receptors are vital to producing the anesthetic state, we interpreted these observations as evidence that GABAA receptor transmission is altered in all three rodent models of ASD.

Our second observation was that ASD neurons failed to take up Mn2+ in a MRI protocol, symptomatic of altered Ca2+ permeability in these rats. We hypothesized that alterations in GABAA receptor-mediated inputs onto neurons directly regulate Ca2+ signaling to produce the developmental changes that lead to ASD.

Consistent with this prediction, we observed that, an increase in GABAA receptor transmission, reflected in the heightened sensitivity to general anesthetics, led to diminished Ca2+ permeability. We hypothesize that drugs that alter GABAA receptor function or Ca2+ signaling lead to ASD. We hypothesize that development proceeds normally when GABAA receptor activity and Ca2+ channels are in balance; and that imbalanced function leads to either excessive or inadequate [Ca2+]i which in turn alters development.

To directly test this idea the balance will be perturbed with drugs: GABAA receptor inhibitors or potentiators and Ca2+ channel inhibitors or potentiators or a Ca2+ chelator will be administered during development to determine if early disruption of GABAA receptor or Ca2+ channel function or [Ca2+]i levels, thereby perturbing the balance between excitation and inhibition, can induce an ASD-like phenotype in adult animals and establish a causal link between GABAA receptor function, Ca2+ signaling and ASD. We hypothesize that correcting either GABAA receptor function or Ca2+ signaling during development will rescue rodent ASD models. ASD models that involve excessive Ca2+ influx will be treated with drugs that reduce [Ca2+]i whereas ASD models that involve inadequate [Ca2+]i will be treated with drugs that potentiate [Ca2+]i. A similar strategy will be employed for GABAA receptor function. Treatment will take place during early development when the cerebellum is critically important to normal forebrain development. Cerebellar plasticity and social behavior will be assessed in treated animals.

Herbal Medicine Research

Despite the extensive herbal use in this country, there is limited data available to indicate whether these therapies are efficacious and/or safe. At the Tang Center for Herbal Medicine Research in the Department of Anesthesia and Critical Care at the University of Chicago, our botanical investigations have been conducted based on following research strategy:

  1. To evaluate both benefits and risks of commonly used herbal medicines (such as American ginseng), and thus, our study data should have significant impact on the general public;
  2. To pursue both animal laboratory studies and human clinical trials using a translational approach;
  3. To identify herbs’ active single components and their mechanisms of actions to provide an opportunity to develop a novel class of therapeutic agents.

Methylnaltrexone (MNTX) Investigations

Preclinical and human data suggest that the mu opioid receptor (MOR) may be a target for anticancer therapy. MOR knockout mice showed decreased tumor growth and metastasis in NSCLC and melanoma. Infusion of MNTX also reduced growth and metastasis in the Lewis lung cancer model. A polymorphism in the MOR which confers opioid resistance demonstrated significantly improved survival in all stages of human breast cancer. Opioid use has been confirmed as an important co-factor in survival in advanced prostate cancer, and two recent retrospective studies demonstrated that perioperative opiate use is associated with decreased overall survival and increased recurrence in patients undergoing surgery for NSCLC.

Methylnaltrexone (MNTX) is a peripherally restricted MOR antagonist that is FDA approved to treat opioid-induced constipation (OIC) in patients with advanced illness in palliative care who faiI to respond to conventional laxatives. It does not affect centrally mediated analgesia. It was hypothesized that peripheral antagonism of opioid-mediated side effects may attenuate disease progression in cancer patients. We explored pooled data from two randomized, placebo-controlled registration trials in patients with advanced disease being treated for OIC and post hoc examined those with cancer to identify whether MNTX given at regular clinical doses could influence survival during the trial period. We also evaluated tumor progression by AE reporting. Our data suggest that MNTX use in advanced cancer patients treated with opioids is associated with prolonged survival, particularly in those patients that respond with laxation. Potential mechanism is unknown but plausibly through attenuation of opioid-mediated MOR signaling. That there was no similar effect of MNTX on OS in noncancer patients makes improvement in GI motility by MNTX a less likely explanation for our observations. While our findings are in patients with advanced malignancies, the hypothesis that mu opioid antagonism may have a potential therapeutic value also extends to earlier tumors and to the perioperative period.

Nicotinic Receptors

Nicotinic Receptors and Reward Circuitry

Nicotinic receptors are involved in the control of neuronal excitability in brain areas that control reward and aversion. Our lab was the first to demonstrate that nicotine could enhance the induction of long-term synaptic plasticity in the midbrain dopamine system. This effect promotes persistent increases in dopamine release in the nucleus accumbens, which is a critical step toward addiction to nicotine and other drugs. Following up those studies, we have tested the link between nicotinic receptors and somatic stress in the context of drug abuse vulnerability, i.e. the likelihood that an individual will transition from casual drug use to addiction. Our studies suggest that nicotinic receptors are an important aspect of that vulnerability. Recently, we have also identified key intracellular signaling events that link nicotine exposure to long term plasticity of the excitatory inputs to midbrain dopamine neurons, which may lead to novel interventions to help improve the success rate of individuals who are trying to quit smoking. The rewarding effects of nicotine are well-documented, but higher doses of nicotine have intensely aversive effects. The balance of these two effects determines the development and maintenance of nicotine addiction. Recent studies have implicated specific brain areas in these aversive effects of nicotine, and we are currently using optogenetic approaches to explore the downstream neural connections and circuitry that mediate these effects. Our data support the hypothesis that aversion to nicotine is mediated, at least in part by suppression of the reward pathways that are necessary for motivating drug-taking behavior. Again, these studies may identify more efficacious methods for improving the success of quitting attempts by modifying the aversion pathways.

Nicotinic receptors and pain modulation

Nicotine has analgesic properties and some nicotinic drugs relieve pain as effectively as opioids. Previous studies have implicated the descending pain control pathway in nicotinic analgesia, but the underlying cellular mechanisms and receptor subtypes involved are largely unknown. Here we demonstrate that α7 nicotinic receptors are expressed by a subset of neurons in the periaqueductal gray that are distinct from the neurons here that express mu opioid receptors. We demonstrated that activating these receptors with focal agonist administration can relieve tonic pain in an animal model. (Umana et al., in review) Understanding of the role of nicotinic receptors in pain control circuitry may lead to the development of more efficacious treatments for acute and chronic pain.