Scripps Florida Scientists Awarded $3 Million to Develop New, More Effective Pain Treatments

We profiled Dr. Laura Bohn research in one of our news stories. We are excited to share the news.Dr. Laura Bohn

JUPITER, FL, February 29, 2012 – Scripps Florida scientists have been awarded $3.1 million by the National Institute on Drug Abuse, part of the National Institutes of Health, to study and develop several new compounds that could prove to be effective in controlling pain without the unwanted side effects common with opiate drugs, such as morphine, Oxycontin®, and Vicoden®.

Laura Bohn, an associate professor in the Department of Molecular Therapeutics and Neuroscience at Scripps Research, and Thomas Bannister, an assistant professor in the Department of Chemistry and associate scientific director in the Translational Research Institute at Scripps Research, will serve as joint principal investigators for the new five-year study.

Their study will focus on four new classes of compounds that appear to differ fundamentally from opiates inthe side effects that they can produce.

“Once we more fully understand how these compounds work, we expect to optimize and develop them as novel drugs,”said Bohn. “We hope to produce potent pain relievers without the problems associated with current treatments.” Full article: http://www.scripps.edu/news/press/20120229bohn-bannister.html

We wish her great success in her research aimed at discovering improved solution for managing pain.

The Quest for Better Pain Therapies

G- protein coupled receptor (GPCR) and Drug Responsiveness

About Dr. Laura Bohn 

bohn1

Dr. Laura Bohn

 Background:

Spring 2009-Associate Professor (tenured) at The Scripps Research Institute, Department of Molecular Therapeutics, Jupiter, FL.

10/2007- Associate Professor (tenured), The Ohio State University College of Medicine, Departments of Pharmacology and Psychiatry, Program in Pharmacogenomics

8/2003-9/2007 Assistant Professor, The Ohio State University College of Medicine,

1/1999–8/2003 Post-Doc/Assistant Research Professor. Duke University Medical Center, Department of Cell Biology. Durham, NC. 

 

 

My company’s foundation is built on serving pain researchers. As a result, I have the good fortune of working with customers and collaborators who openly share the subtleties of their research and the future impact it could have on improving pain therapies.

Pain is complex. Today, pain therapies often fall short and are rife with unwelcome side effects. This undesrcores why I am pleased to feature Dr. Laura Bohn. She and her team are probing ways to improve  response effectiveness and reduce side effects.

 Beginnings

The story starts with Laura’s Post Doc work in Dr. Marc Caron’s lab at Duke University.  Marc in Collaboration with Dr. Dr. Robert Lefkowitz genetically engineered mice that lacked a protein switched called  “beta-arrestin 2.”  This switch is part of the opioid pathway that regulates how we perceive pain. The GPCR, muOpioid (mOR) is the primary target for narcotic pain killers, like morphine.

In her initial work, Laura found that morphine treated mice lacking the beta-arrestin2 switch swere able to tolerate  mild pain stimuli up to 3X longer than normal mice.  These mice had a higher level of sensitivity to morphine both in magnitude and duration. 

Bingo. This path for Laura’s excellent journey is now lit…understanding how the molecular regulation of G protein coupled receptors (GPCR) can translate to overall drug responsiveness in vivo.  Getting better response from lower dose is all good.

Current Work

As a researcher at Ohio State University, Laura and her team have continued to broaden and deepen their understanding of  GPCR signaling and beta-arrestin desensitivation (figure 1).

gpcr_regulation 

She is currently doing research with mice that have genetic deletions of GRKs (GRK3, GRK4, GRK5, and GRK6; heterozygotes for GRK2) and barrestin-2.

This expands the playing field. This expansion includes  studying other GCPR related pathways. Serotonin 2A receptors (5-HT2ARs), for example, are molecular targets for drug-induced hallucinations:

Cullen L. Schmid, Kirsten M. Raehal, and Laura M. Bohn. Agonist-directed signaling of the serotonin 2A receptor depends on β-arrestin-2 interactions in vivo. Published online on January 14, 2008, 10.1073/pnas.0708862105.

The conclusion: 5-HT2AR–β-arrestin interaction may be particularly important in receptor function in response to endogenous serotonin levels, which could have major implications in drug development for treating neuropsychiatric disorders such as depression and schizophrenia.

Future Considerations

I look for Laura and her team to continue the quest of doing more for less when it comes to novel pain and other therapies. Further success would provide the foundation for the development of therapies that would require less dosing, better response and reduced side effects.

Laura mentioned to me that further directions could involve the use of gene silencing tools like siRNA. The effects of silencing GPCR-beta-Arrestin receptors in-vivo would be an important study as it would enable she and her team to study  impact of  desensitivation on the repsonse to morphine and other drugs by normal mice.

Featuring Dr. Laura Bohn

Dr. Laura Bohn

Dr. Laura Bohn

January’s Story: Decoupling GPCR Pain Therapies from Destructive Side Effects. 

We are pleased to have Dr. Laura Bohn as our “coming soon” featured researcher. 

She caught my attention when she referenced one of our  Opioid Receptor Antibodies in the publication: C. E. Groer, K. Tidgewell, R. A. Moyer, W. W. Harding, R. B. Rothman, T. E. Prisinzano, and L. M. Bohn. An Opioid Agonist that Does Not Induce µ-Opioid Receptor—Arrestin Interactions or Receptor Internalization. DOI: 10.1124/mol.106.028258.

She, her team and callaborators are focused on an interesting and important aspect of pain therapies discovery…finding ways to de-couple the benefits of opiate based pain medications from their current side-effects including constipation, respiratory suppression and addiction.

I am looking forward to drilling into the specifics of this important research.

Dr. Philippe Sarret Team and Potential New Pain Targets

Shedding Light on New Pain Pathways

There is no joy in Painville. Our answer to pain is: “make it go away”! It spoils quality of life. The socio-economic costs for treatments, loss of productivity and absenteeism, are measured in billions USD$.

Today, moderate to severe pain is treated mostly with NSAIDs, narcotics or tricyclics (anti-depressants). Properly prescribed, these effectively alleviate pain. However, for cases of sustained chronic pain, they become problematic. More than 30% of the population coping with chronic pain are insensitive to morphine derivatives or other pain treatments. They can lose their effectiveness (tolerance), most can be abused and are addictive (dependence), but overall, given in multitherapy, their side effects are additive and deleterious. These problems arise from a lack of comprehension in their mode of action. This is not good news for neuropathic and chronic pain sufferers looking for long term relief.

Research that could lead to discovery of non-narcotic drugs signaling via opioidergic-independent pathways is part of the solution for people coping with chronic pain. This brings us to our back story featuring Dr. Philippe Sarret and his Research Team at the University of Sherbrooke.


About Dr. Philippe Sarret

-Masters (biochemistry), University of Nice in 1994.

-Diploma (DEA, cellular and molecular biology), University of Nice 1996.

-PhD (pharmacology), Institute of Molecular and Cellular Pharmacology, Sophia Antipolis 2000

-Post-doctorate (Neuroscience), Montreal Neurological Institute (MNI), McGill University, Montreal 2004.

-Professor, Faculty of Medicine and Health Sciences, University of Sherbrooke in 2004 -present

Sarret Website-In English

Sarret Website-In French

Tél.: (819) 820-6868, poste 12554
Téléc.: (819) 820-6887
Courriel: Philippe.Sarret@USherbrooke.ca

I asked Dr. Nicolas Beaudet, a Sarret lab member, why he joined the lab. He said, “ Philippe is a great communicator. He has the ability to articulate his complex research in a way that is easy to understand, visionary and exciting”. The aspect that Nicolas finds most intriguing is the systems approach that Philippe and the team take in understanding the mechanisms of pain. This enables them to work at them molecular level up to the whole animal. This is a key step in finding potential new pain therapies.

Drilling Down

Philippe and his team centered their efforts on G Protein Coupled Receptors (GPCRs) such as apelin, chemokines and neurotensin. As a common point, they were all recently identified in the central nervous system to provide a potential role in pain modulation.

Lately, the focus has been on the roles of Neurotensin Receptor 1 (NTS1) and Neurotensin Receptor 2 (NTS2). Recent studies have highlighted the role of these receptors in pain modulation and more is to come…:

  • Geneviève Roussy, Marc-André Dansereau , Louis Doré-Savard, Karine Belleville, Nicolas Beaudet, Elliott Richelson and Philippe Sarret. Spinal NTS1 receptors regulate nociceptive signaling in a rat formalin tonic pain model.Journal of Neurochemistry 105: 1100 – 1114
  • Sarret, P, Perron, A, Stroh, T and Beaudet, A (2003). Immunohistochemical distributionmof NTS2 neurotensin receptors in the rat central nervous system. J Comp Neurol 461: 520–538.
  • Sarret, P, Esdaile, MJ, Perron, A, Martinez, J, Stroh, T and Beaudet, A (2005). Potent spinal analgesia elicited through stimulation of NTS2 neurotensin receptors. J Neurosci 25: 8188–8196.
  • Dobner, PR (2006). Neurotensin and pain modulation. Peptides 27: 2405–2414.
  • Maeno, H, Yamada, K, Santo-Yamada, Y, Aoki, K, Sun, YJ, Sato, E et al. (2004). Comparison of mice deficient in the high- or low-affinity neurotensin receptors, Ntsr1 or Ntsr2, reveals a novel function for Ntsr2 in thermal nociception. Brain Res998: 122–129.      

The wow factor for me was the clever way Philippe and his team used a new technology of 27mer NTS2 Dicer Duplex siRNA (DsiRNA) delivery in vivo as a proof for the potential of DisRNAs-based pain therapies.

Louis Doré-Savard, Geneviève Roussy, Marc-André Dansereau, Michael A Collingwood, Kim A Lennox, Scott D Rose, Nicolas Beaudet, Mark A Behlke and Philippe Sarret. Central Delivery of Dicer-substrate siRNA: A Direct Application for Pain Research. Molecular Therapy (2008); Jul;16(7):1331-9. Epub 2008 Jun 3 doi:10.1038/mt.2008.98.

Using ultra low dose of DsiRNAs complexed with Neuromics’ i-Fect ™, they were able to successfully reduce NTS2 gene expression by up to 86% in rat lumbar Dorsal Root Ganglia after only two intrathecal injections. This was confirmed by Western Blot and qPCR analysis.

What Happened

Using an acute pain model, anti-nociceptive effects of NTS2, induced by a selective agonist, were significantly reduced following NTS2 silencing This resulted in rats showing an increased sensitivity to pain. By day four, the knockdown effects showed a decrease with the NTS2 function returning to normal.

What ‘s next

So we have a great start. We know that agonists binding to NTS2 in the CNS lead to analgesia. We know that DsiRNA can be used to alter the expression of this gene in vivo. We have provided a key step in learning how the NTS2 receptors can be manipulated to block pain. However, now we need to unravel the underlying mechanisms explaining these spinal analgesic properties.

It is my hope that Philippe and his team are appropriately funded. This would catalyze further discoveries in how expression of G Protein Coupled Receptors like NTS1, NTS2, APJ, CCR2 can be targeted to modulate pain. By using rodents, the team can develop tools like DsiRNA to increase the potency and duration of pain blockade. Moreover, potential toxicity and side effects need to be addressed in order to move forward towards clinical studies. These pre-clinical models prove invaluable in taking the step to studies in humans.These therapies hold the promise of providing relief for chronic pain (neuropathic, arthritic, diabetic, cancer pain, etc.) sufferers without the current side effects. Stay tuned as I will be reporting the good news as it unfolds.