Fluorescence imaging may identify new molecules that increase the efficacy of pain medications

Engineered surface delivery of the delta opioid receptor as a strategy to develop novel analgesics

Manoj Puthenveedu, M.D., Ph.D.

Carnegie Mellon University

Funded in November, 2016: $200000 for 3 years
LAY SUMMARY . ABSTRACT .

LAY SUMMARY

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Fluorescence imaging may identify new molecules that increase the efficacy of pain medications

Investigators will use fluorescence imaging in a mouse model of chronic pain to identify small molecules that might potentially manage the pain without the addicting properties and other side effects of currently used medications.

All currently used pain medications (called “opioids” or “analgesics”) target a specific protein called the “mu opioid receptor (MOR).” This protein “receptor” is located on the surface of all pain-sensing neurons in the central nervous system (brain and spinal cord) and peripheral nervous system (rest of the body). Opioid pain medications, such as morphine and oxycontin, bind to this receptor and lessen the sensation of pain. Activation of these mu receptors, though, also activates the pathway for the “reward” neurotransmitter called dopamine. It is through this pathway that people taking opioids for chronic pain become drug-dependent and addicted.  Scientists, therefore, have been searching for a better pain management strategy, such as identifying a target other the mu pain receptor.  

In fact, an alternative target does exist. It is called the “delta opioid receptor (DOR).”  The DOR receptors potentially can bind to medications that manage most classes of pain:  nociceptive pain (sharp, aching or throbbing pain in tissues, such as produced by a burn or turned ankle); inflammatory pain (produced by immune cell chemicals interacting with damaged tissues); and neuropathic pain (caused by damage to nerves, producing burning or numbness).  Many drugs that bind to DOR receptors have been developed, but unfortunately their promising animal model results were dashed in human studies where the drugs were ineffective at low doses and produced convulsions at higher doses.  These investigators undertook “proof of principle” experiments in an animal model of chronic pain based upon their contention that analgesics that act on DOR receptors are ineffective at low doses because the receptors are not located on the neural cells’ surface. Instead, biological processes deliver DOR receptors to structures beneath the cells’ surface. They identified an enzyme that appears to be a “checkpoint” that keeps DOR receptors at this location. When this enzyme was blocked by an agent, however, the DOR receptors were unblocked and many migrated to the cell’s surface. This increased the efficacy of drugs targeting DOR to a point where they effectively inhibited pain in one animal model, without causing convulsions. Unfortunately, however, this agent is not suitable for use in humans. 

Based on the proof of principle, they hypothesize that bypassing this checkpoint using compounds that are suitable for use in humans will stimulate the delivery of DOR receptors to the surface of pain-sensing neurons and improve the potency of non-addicting medications that bind to DOR receptors to make them effective at low doses and without major side effects.  They first will validate their “proof of principle” findings in multiple animal models for pain. Then they will use a fluorescence imaging to identify small molecules that have a similar enzyme-blocking action but that are suitable for human use. They will test those compounds in the animal model. If the compounds reduce pain-related behaviors in the animal model, the research will lead to human testing of the compounds.  

Significance: The research is anticipated to form the basis for developing new non-addictive therapies that are effective in managing chronic pain safely at low doses.

 

ABSTRACT

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Engineered surface delivery of the delta opioid receptor as a strategy to develop novel analgesics

Pain is the most common symptom presented at hospitals in the US. It affects half of the US population, and costs the U.S. economy approximately $635B per year. Pain is currently managed mainly by morphine derivatives, whose use is highly limited due to serious adverse effects, as well as the development of addiction. Drug addiction is a major socioeconomic problem in its own right. Importantly, all the currently available opioid analgesics target the mu opioid receptor (MOR) in the brain. Activation of MOR also activates the reward pathway, which is the primary reason for dependence and addiction. The thousands of MOR agonists that have been developed all share these same concerns. Therefore, we need to identify an alternate target. The delta opioid receptor (DOR) is a functionally analogous receptor expressed in pain-sensing neurons, including in neurons that mediate pain modalities not targeted by morphine. The many DOR agonists developed, although they were expected to be good analgesics based on in vitro data, are not effective in vivo. We have discovered that this limited efficacy is because DOR delivery to the surface of sensory neurons is limited by a critical checkpoint in the trafficking pathway. We hypothesize that bypassing this checkpoint will stimulate surface DOR delivery and rescue the analgesic potency of existing DOR agonists to make them therapeutically effective. As a proof of mechanism, we have identified a pharmacological manipulation that bypasses this checkpoint, stimulates surface DOR delivery, increases sensitivity to DOR agonists in neurons, and, importantly, increases the potency of DOR agonists to a therapeutically usable level in an animal model of chronic pain. The compounds used in this proof of mechanism, while effective in animals, are not ideal for use in humans. Therefore, the goal of this proposal is to initiate experiments to identify clinically usable compounds that will increase the surface delivery of DOR. We anticipate that this transformative strategy will be the basis to define new convergent formulations that will increase the efficacy of drugs targeting DOR in treating pain.

INVESTIGATOR BIOGRAPHIES

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Manoj Puthenveedu, M.D., Ph.D.

Dr. Manoj Puthenveedu is an Associate Professor of Biological Sciences at Carnegie Mellon University, Pittsburgh. After his initial training as a physician in the Govt. Medical College, Calicut, India, he conducted his Ph.D. research in Carnegie Mellon University on the molecular mechanisms of membrane trafficking. His postdoctoral research at UCSF focused on the cell biology of G protein-coupled receptors, and he developed innovative fluorescence imaging methods to study the behavior of these signaling receptors in real time in living neurons. His current research integrates these approaches to address the molecular basis of drug addiction. He focuses on how sub-cellular structures coordinate spatial encoding of signaling by opioid receptors, the key target of abused drugs like morphine and heroin, and related G protein-coupled receptors relevant to drug addiction, in neurons. Additionally, he is developing computational machine-learning approaches to rapidly integrate data acquisition, analysis, and modeling, to understand the dynamic changes in neuronal signaling associated with changes in the environment. He is a recipient of the Pathway to Independence award from the NIH, the Eberly Family Professorship, the Samuel and Emma Winters Foundation Award, and the Curci Foundation award.

KEYWORDS


Anatomy:
Neuropeptides
Neurotransmitter
Conditions: Addiction
Chronic Pain
Substance Abuse
Trigeminal Neuralgia
Function: Nociception
Pain
Technology:
Neuropharmacology
Psychopharmacology