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.

Stem Cell Research Guidelines Sidebar

As a growing provider of Stem Cell Research Reagents, I am in search of information that cuts through the confusion. My goal is to publish postings that could be of value to my customers and researchers.

On September 5th, Updated Guidelines for Stem Cell Research was released by the National Academies.

One reason for the 2008 modifications is to provide guidance on the derivation and use of new human stem cells that were first developed last year.  These cells — called “induced pluripotent cells” — are made by reprogramming nonembryonic adult cells into a stem-cell-like state, in which they can be manipulated to form a wide array of specialized body cells.  Although induced pluripotent stem cells can be derived without using embryos, the ethical and policy concerns related to their potential uses are similar to those pertaining to human embryonic stem cells.  For example, issues arising from mixing human and animal cells in a single organism are relevant for stem cells from both embryonic and nonembryonic sources.  However, derivation of induced pluripotent stem cells does not require special stem cell expertise and is adequately covered by current Institutional Review Board regulations, the report says.

Copies of 2008 Amendments to the National Academies’ Guidelines for Human Embryonic Stem Cell Research are available from the National Academies Press; tel. 202-334-3313 or 1-800-624-6242 or on the Internet at http://www.nap.edu

Making Gains on Pain

Nicolas Beaudet

Nicolas Beaudet

Neuromics has been helping researchers make “gains on pain” from day one. Our initial sales were Opioid Receptor Antibdies licensed from Dr. Robert Elde’s lab at the University of Minnesota.

From this start, we have expanded our expertise and products. Our reputation in this area has resulted in our forming collaborations and friendships with research teams doing important work in chronic and nociceptive pain research.

Over the past several years, I have worked closely with Dr. Nicolas Beaudet, a member of Dr. Philippe Sarret’s team, at the University of Sherbrooke”. In our next backstory we will feature the vangaurd work they are doing on the Neurotensin (NTS) Receptors and pain.

Manipulation of these receptors-NTS-1, NTS-2 and NTS-3 could represent a therapy for pain independent of the opioid pathway. This means pain could be treated without narcotics meaning a reduction of side effects from current treatments including addiction to pain killers.

Umbilical-Cord Matrix Stem Cells and Cerebral Ischemia

I am winding down on the stem cell story for now as later in the month I will be featuring my good friends at University of Sherbrooke and their research in the area of chronic pain.

I did want to highlight yet another potential application for stem cells. For this, we send kudos to Dr. Yan Xu and his colleagues at University of Pittburgh for their findings on inflammatory response in Golbal Ischemia. Their work was recently published:

Aaron Hirko, Renee Dallasen, Sachiko Jomura, Yan Xu. Modulation of Inflammatory Responses after Global Ischemia by Transplanted Umbilical-Cord Matrix Stem Cells. Stem Cells First published online August 21, 2008; doi:doi:10.1634/stemcells.2008-0075

Secondary to Cardiac Arrest is Brain Damage do to lack of blood flow. This is marked by a delayed loss of Neurons in CA1 hippocampus region of the brain due to inflammatory response.

The story timeline of this response is good then bad with interesting twists. The delay in neuronal loss is linked to initial inflammation. It involves both reactive astrocytes (astrocytosis) and glia. Delaying the loss is, of course, good.

…But then, the reactive astrocytosis and related glial scarring cause a physical and biochemical barrier to regeneration of neurons…a bad thing. Protecting the microglia is a good thing, because they these cells serve as scavengers for clearing the cellular debris. They can also secrete a variety of cytotoxic and protective chemicals.

The wow factor in this research is that  implanted rat umbilical-cord matrix (RUCM) cells can provide partial protection against neuronal injury in rat brains. Rats treated with RUCM cells three days prior to an 8-min CA had only 25-32% neuronal loss in the hippocampal CA1 region compared to the typical 50-68% neuronal loss observed in the untreated or the vehicle-treated animals. This could be due to to the favaorable modulation of the “good-bad” inflammatory response.

The good news in the search for therapies for stroke and cardiac arrest victims is combined, stem-cell-like RUCM cells offer protection against neuronal injury after global cerebral ischemia by enhancing the survivability of the astroglia in the selectively vulnerable regions.

We are pleased that the research team used our GFAP antibody as an marker for astrotytic in their studies.