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Discovery of Chronic Pain Gene and a new drug (N60) to block pain signals to brain


Senior Member
Discovery of Chronic Pain Gene Suggests Previously Unthought of Therapeutic Approaches
August 5, 2010 http://www.prohealth.com/library/
Individuals who carry this gene are more susceptible to chronic pain following nerve injury.

Researchers at the Hebrew University of Jerusalem and elsewhere have succeeded in identifying for the first time a gene associated with susceptibility to chronic pain caused by nerve injury in humans - signaling a significant step toward better understanding and treating the condition.

Their findings were published online Aug 5 by Genome Research (see Susceptibility to chronic pain following nerve injury is genetically affected by CACNG2 ).

Human Susceptibility to Chronic Pain Varies Greatly

Chronic pain is a serious medical problem, afflicting approximately 20% of adults. Some individuals are more susceptible than others, and the degree of pain experienced after injury or surgery is known to be highly variable between patients, even under nearly identical circumstances.

The basis for this has remained largely unknown, prompting researchers to search for the contribution of genetics to chronic pain susceptibility. To accelerate research in this field, animal models are proving to be critical to understanding the underlying biology of chronic pain in human patients.

First, the international research team - led by Profs. Ariel Darvasi and Marshall Devor at The Hebrew University of Jerusalem and including scientists in Canada and Europe - identified a region of mouse chromosome 15 that likely contained a genetic variant or variants contributing to pain.

However, this region contains many genes, and the responsible variant remained unknown. Next, they undertook two fine-mapping approaches to narrow down the chromosomal locus to an interval of 155 genes. By applying bioinformatics approaches and whole genome microarray analysis, they then were able to confidently identify a single gene, CACNG2, as the likely candidate.

Tests Proved the Link to Chronic Pain in Animals

To further test the potential role for CACNG2 in chronic pain, the authors utilized a mouse strain harboring a mutant version of the gene that had previously been used in epilepsy research.

In testing the mice for behavioral and electrophysiological characteristics of chronic pain, they found that the observations were consistent with a functional role for CACNG2 in pain, even though it might be modest.

Significant Association with Chronic Pain in Humans

However, the question still remained as to whether the human version of the gene also is important for chronic pain.

Analyzing a cohort of breast cancer patients who experienced chronic pain half a year or more after they had undergone removal or partial removal of a breast, they found that genetic variants of CACNG2 were significantly associated with this chronic pain.

The authors cautioned that although this association will need to be analyzed further, the result is encouraging in pointing to this gene as a significant factor in experiencing pain.

The immediate significance is the mere awareness that differences in pain perception may have a genetic predisposition, Darvasi explained.

Our discovery may provide insights for treating chronic pain through previously unthought-of mechanisms.

In addition to the scientists from The Hebrew University, other contributors to the study were from the University of Toronto; Sanofi-Aventis, Germany; and the Karolinska Institute Center for Oral Biology, Sweden.

The work was supported by the Israel Science Foundation, the Hebrew University Center for Research on Pain, the Canada Research Chair Program, and the European Communitys 6th Framework Program


Source: The Hebrew University of Jerusalem, news release, Aug 5, 2010 (with modification)

GOOD NEWS! New drug may turn off chronic pain without addiction or tolerance problems; trials at Columbia
July 19, 2010

Four years ago researchers at Columbia University Medical Center, New York, discovered an "On/Off switch" for chronic pain signals.(1) They raised pain patients hopes around the world when they applied for patents to develop a new type of drug that could flip that switch. And now they believe they have one a drug that has proved powerful in animal trials, while avoiding tolerance, addiction, and sedative problems.

The researchers, who have been working to combat injury-related depression, substance abuse, and suicide due to unremitting, persistent pain, have dubbed the new analgesic N60 and now plan human trials. (Meaning, unfortunately, that approval and general availability of the drug, if it fulfills its early promise, is still some time off.)

First, they Discovered the Chronic Pain Pathway

Pain is a perception in the brain triggered by signals sent along nerves in the peripheral nervous system. It is a sensation that serves as a defense mechanism for the organism, but how it works is only beginning to be understood. Scientists now know, though, that there are several pathways by which the brain perceives different types of pain.

The chronic pain team, led by Dr. Richard Ambron, Professor of Pathology & Cell Biology, began to develop N60 after his colleague, Dr. Ying-Ju Sung, Assistant Professor of Clinical Pathology, discovered the pathway that neurons use to inform the brain of an injury.

Left uncontrolled, this pathway persistently alters the electrical properties of the neuron, ultimately causing chronic pain.

Then the On-Off Switch

The Columbia team found that a specific protein in the pathway, called PKG, acts like a switch. As long as the switch is on, the pathway is activated and the brain continues to receive signals that are perceived as pain, even after an injury has healed.
Sung and Ambron quickly realized that PKG would be an excellent target for drug development.

Since PKG is specific for the biochemical signaling involved with chronic pain, shutting off PKG will not prevent a patient from feeling fresh injuries.

It also operates in the peripheral nervous system, rather than the central nervous system (brain & spinal cord). This means that a drug that blocks PKG does not have to cross the blood-brain barrier, a formidable challenge in drug development.

The only drugs that work consistently on chronic pain are opiates and anti-depressants, said Ambron. A significant problem with opiates is that extended use often leads to addiction.

Everyone is looking for a solution that is not addictive, Sung added. Theres increasing concern, from clinicians, patients, and regulatory agencies, with drugs that act on the central nervous system - where addiction can develop.

And Now the Drug

Once they understood the function of PKG:

The team began to work with medicinal chemists in Dr. Donald Landrys group, also at Columbia, to design a compound that would block PKG from sending signals to the brain.

After considerable effort, they discovered N60, which laboratory tests have shown to be a powerful and very selective PKG blocker.
We found in PKG a well-defined target that has been implicated in several types of pain that are particularly refractory to treatment, Ambron said. Now, we have an excellent inhibitor of the target:

Which imparts no evident toxic or behavioral side effects and which also alleviates chronic pain in animal models of nerve injury and inflammation.

N60 is non-addictive and non-sedative, and a single dose attenuates pain for at least 24 hours.

Especially Promising for Military Personnel

Ambron and Sung believe N60 may have particularly meaningful impact for military personnel, who are at particularly high risk of suffering from chronic pain due to combat-related physical injuries and emotional stress.

Recent pilot studies show analgesic effects in an animal model of neuroma, an abnormal growth in nerves. Neuromas can be extremely painful and result from injury to nerves, such as that caused by limb loss from trauma, amputations, or from other surgeries.

Additionally, a growing body of research is finding direct biochemical connections between chronic pain and Post-Traumatic Stress Disorder (PTSD), anxiety, depression, and suicide.

Pharmaceutical Grade Compound Ready for Human Safety Studies

Funding to date has allowed the Columbia team to manufacture pharmaceutical (GMP)-grade compound, ready for studies which will evaluate the safety of the drug.

Weve got the drug, were confident in its efficacy, and we are actively looking for investors and experienced partners to help us put this through clinical testing, explains Jerry Kokoshka, a representative from Columbia Technology Ventures, the university office that oversees commercialization of novel technologies. Anyone who has ever experienced the suffering of chronic pain, personally or through a family member or friend, knows the intense frustration and emotional burden of this problem.

We believe a compound like N60 has significant potential to transform the way chronic pain is treated, Ambron said.

If it works the way we think it can, we may be able to alleviate chronic pain in some of its most intractable forms without the risk of addiction, a problem that conveys a whole set of economic and social issues for our country and society at-large.
1. Columbia University Researchers Discover On/Off Switch for Chronic Pain

Source: Columbia Technology Ventures news release, July 15, 2010,