Shaifali Bhalla, Ph.D.

Project I: Investigating the mechanism of endothelin-A receptor interaction with opioid analgesics
We have found that endothelin-A receptor (ETAR) antagonists potentiate opioid analgesia and reverse analgesic tolerance. Withdrawal symptoms of opioids such as morphine and oxycodone are also reversed by ETAR antagonists. Preliminary findings suggest that the enhancement of analgesia and reversal of tolerance is mediated via a G-protein mediated mechanism. We are currently investigating the role of cAMP signaling mechanisms with acute and chronic exposure to opioids in the presence and absence of ETAR antagonists. The role of calcium signaling events in these phenomena are also being explored.

Project II: Endothelin-B receptors in angiogenesis and neurogenesis in opioid tolerance and withdrawal
In this project we propose to evaluate the role of endothelin-B receptors in opioid tolerance and withdrawal. Using chronic opioid treatment regimens, morphine and oxycodone tolerance will be induced in animal models. Withdrawal will be precipitated using naloxone and the dose-response effect of IRL1620 (endothelin-B receptor selective agonist) on tolerance and withdrawal symptoms will be determined. The expression of endothelin A and B receptors, vascular endothelial growth factor, and nerve growth factor will be determined in the brain. It is anticipated that through use of endothelin-B agonists, tolerance and withdrawal symptoms may be reversed and analgesic efficacy of opioids may be restored.
Opioid & endothelin receptors: cAMP, calcium signaling
Drugs of abuse: tolerance/dependence/withdrawal
Pharmacokinetics of drugs of abuse