Home Investigators Jennifer Whistler, Ph.D. Research
Research Interest PDF Print E-mail
My research focuses on the mechanisms of membrane protein trafficking and the role this process plays in regulating signal transduction. Specifically we study the regulated endocytosis of G protein coupled receptors such as opioid receptors. Opiate analgesia, tolerance and dependence are mediated by drug-induced activation of opioid receptors. A fundamental question in addiction biology is why opiate drugs such as morphine and heroin have a high liability for inducing tolerance and addiction while endorphins and enkephalins, the native ligands for opioid receptors do not.

Opioid receptors belong to the large superfamily of heptahelical G protein-coupled receptors (GPCRs). As a class, GPCRs are of great importance because they mediate the physiological actions of the majority of known neurotransmitters and hormones by communicating from the outside to the inside of cells through their unique topology spanning the plasma membrane. Opioid receptors are fascinating members of this receptor family because they can be activated both by the endogenously produced opioid peptides like endorphins and enkephalins, and by exogenously administered opiate drugs such as morphine and heroin.

While opiates such as morphine remain the analgesic of choice, a major limitation to their long-term use is the development of physiological tolerance, a profound decrease in analgesic effect observed in all patients during prolonged administration of opiate drug. In addition, long-term use of opiates causes physiological dependence in some patients, a requirement for continued administration of increasing doses of drug to prevent the development of symptoms of opiate withdrawal. The molecular mechanisms that mediate tolerance and dependence to drugs of abuse are poorly understood. Our studies of opiate receptor signaling provide a unique and powerful approach towards understanding the molecular mechanisms underlying these complex physiological and pathophysiological processes precisely because the receptors can apparently be activated in ways that both do and don't cause tolerance, dependence and addiction. Elucidating these mechanisms could lead to the development of new therapies for the management of important side effects of opioid analgesia, thereby significantly improving the treatment of chronic pain. They may also contribute to our understanding of the mechanisms underlying the development of addiction and thus provide novel insight for the management of this pathological condition.

Role of endocytosis in distinguishing opiate drugs and native opiate ligands.
Following activation by native peptide ligands, opioid receptors, like many GPCRs, are regulated by numerous mechanisms designed to rapidly attenuate signaling. However, recent studies from our lab and others indicate that the highly addictive opiate drug morphine is deficient in its ability to induce the desensitization receptors. Specifically, morphine-activated opioid receptors elude desensitization by failing to uncouple from G protein and internalize into the cell through the process of endocytosis. Our research focuses on indentifying the molecular mechanisms that differentiate morphine activated receptors from receptors activated by native ligands, with the goal of elucidating what role(s) regulation of receptor mediated signaling by endocytosis plays in the complex neurobiological processes of tolerance and addiciton.

Changes in cell physiology and gene expression associated with the switch from acute to chronic response to drugs of abuse.
Opioid receptors are coupled to intracellular signaling second messengers through the inhibitory G protein Gi. However, following chronic exposure to opiate drug, many of the signal transduction pathways no longer respond in the same way to the drug as they did in cells in the naive state. My lab is evaluating the changes in signal transduction and gene expression associated with this switch from "acute" to "chronic" response to drug. Opioid drugs are not unique in their ability to promote differential signaling in acute versus chronically treated cells. Our work and the work of others have demonstrated that signaling via dopamine, ethanol, cannabinoids and serotonin also show this biphasic cellular response, suggesting this phenomenon may underlie physiological changes associated with addiction to many drugs of abuse. Understanding the mechanisms associated with this switch in cell physiology may thereby provide molecular insight into the changes in plasticity associated with the development of tolerance, dependence and addiction.