Research into Turning Off Pain Receptors Progressing

‘Off switch’ for pain discovered: Activating the adenosine A3 receptor subtype is key to powerful pain relief

Date:
November 26, 2014
Source:
Saint Louis University Medical Center
Summary:
A way to block a pain pathway in animal models of chronic neuropathic pain has been discovered by researchers, suggesting a promising new approach to pain relief.
Pain is an enormous problem. As an unmet medical need, pain causes suffering and comes with a multi-billion dollar societal cost. Current treatments are problematic because they cause intolerable side effects, diminish quality of life and do not sufficiently quell pain.
Credit: © Feng Yu / Fotolia
In research published in the medical journal Brain, Saint Louis University researcher Daniela Salvemini, Ph.D. and colleagues within SLU, the National Institutes of Health (NIH) and other academic institutions have discovered a way to block a pain pathway in animal models of chronic neuropathic pain including pain caused by chemotherapeutic agents and bone cancer pain suggesting a promising new approach to pain relief.

The scientific efforts led by Salvemini, who is professor of pharmacological and physiological sciences at SLU, demonstrated that turning on a receptor in the brain and spinal cord counteracts chronic nerve pain in male and female rodents. Activating the A3 receptor — either by its native chemical stimulator, the small molecule adenosine, or by powerful synthetic small molecule drugs invented at the NIH — prevents or reverses pain that develops slowly from nerve damage without causing analgesic tolerance or intrinsic reward (unlike opioids).

An Unmet Medical Need

Pain is an enormous problem. As an unmet medical need, pain causes suffering and comes with a multi-billion dollar societal cost. Current treatments are problematic because they cause intolerable side effects, diminish quality of life and do not sufficiently quell pain.

The most successful pharmacological approaches for the treatment of chronic pain rely on certain “pathways”: circuits involving opioid, adrenergic, and calcium channels.

For the past decade, scientists have tried to take advantage of these known pathways — the series of interactions between molecular-level components that lead to pain. While adenosine had shown potential for pain-killing in humans, researchers had not yet successfully leveraged this particular pain pathway because the targeted receptors engaged many side effects.

A Key to Pain Relief

In this research, Salvemini and colleagues have demonstrated that activation of the A3 adenosine receptor subtype is key in mediating the pain relieving effects of adenosine.

“It has long been appreciated that harnessing the potent pain-killing effects of adenosine could provide a breakthrough step towards an effective treatment for chronic pain,” Salvemini said. “Our findings suggest that this goal may be achieved by focusing future work on the A3AR pathway, in particular, as its activation provides robust pain reduction across several types of pain.”

Researchers are excited to note that A3AR agonists are already in advanced clinical trials as anti-inflammatory and anticancer agents and show good safety profiles. “These studies suggest that A3AR activation by highly selective small molecular weight A3AR agonists such as MRS5698 activates a pain-reducing pathway supporting the idea that we could develop A3AR agonists as possible new therapeutics to treat chronic pain,” Salvemini said.


Story Source:

The above story is based on materials provided by Saint Louis University Medical Center. Note: Materials may be edited for content and length.


Journal Reference:

  1. J. W. Little, A. Ford, A. M. Symons-Liguori, Z. Chen, K. Janes, T. Doyle, J. Xie, L. Luongo, D. K. Tosh, S. Maione, K. Bannister, A. H. Dickenson, T. W. Vanderah, F. Porreca, K. A. Jacobson, D. Salvemini. Endogenous adenosine A3 receptor activation selectively alleviates persistent pain states. Brain, 2014; DOI:10.1093/brain/awu330

Cite This Page:

Saint Louis University Medical Center. “‘Off switch’ for pain discovered: Activating the adenosine A3 receptor subtype is key to powerful pain relief.” ScienceDaily. ScienceDaily, 26 November 2014. <www.sciencedaily.com/releases/2014/11/141126132639.htm>.
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Pill may be coming that can reset the body’s clock

  • Researchers have found a mechanism that controls how people react to long-haul travel or working irregular hours
  • Tests on mice revealed an enzyme which controls their body clock 
  • By deleting the gene which produces the enzyme scientists reset this clock 
  • Although human genes can’t be deleted, scientists are working on a pill that blocks it from producing the enzyme
  • This pill could be on the shelves within five years, said researchers

By BEN SPENCER

 

A pill to treat jet lag could be on the shelves within five years, thanks to a discovery which allows scientists to reset the human body clock.

Researchers at Manchester University have found the mechanism that governs how people react to long-haul travel or working irregular hours.

Their tests on specially bred mice revealed an enzyme which controls how the body’s clock can be reset.

 
During tests, researchers at Manchester University found a gene that produces an enzyme which controls how the body's clock can be reset. Drug companies are using the discovery to develop a pill to ease the impact of sleep deprivation, jet lag and changes to daily routine. Stock image pictured

 

During tests, researchers at Manchester University found a gene that produces an enzyme which controls how the body’s clock can be reset. Drug companies are using the discovery to develop a pill to ease the impact of sleep deprivation, jet lag and changes to daily routine. Stock image pictured

 

HOW WOULD THE PILL WORK?

 

The researchers discovered the gene which produces an enzyme that controls part of the circadian clock.

They then deleted the gene in mice to stop them producing the enzyme, called casein kinase 1epsilon. 

The team studied the mice for changes by timing the lights switches in their cages to replicate a weekend flight to New York.

The mice without the crucial enzyme adapted much faster to the new day-night pattern and displayed much smaller metabolic disruption.

Deleting the gene would not be possible in humans, but the finding has allowed pharmaceutical firms to investigate a pill to block the enzyme.

Drug companies are using the discovery to develop a pill to ease the impact of sleep deprivation, jet lag and changes to daily routine. 

Dr David Bechtold, who led the research, said a treatment could even be ready within five or ten years.

 Pharmaceutical giant Pfizer, which collaborated with the Manchester team, has a treatment in pre-clinical development, and other companies are thought to be investigating other lines of research for similar products.

Dr Bechtold told the MailOnline: ‘The drugs that we have used are amenable for development, they will work and it is a matter of optimising them for clinical use. 

‘This development opens a line of work which could very realistically lead to human treatment.

‘Within five to ten years the availability of drugs which can be used to target the body clock in people will start to become a reality.’

 
Using mice, stock image pictured, researchers discovered that if they deleted the gene, it would stop the mice producing the enzyme, called casein kinase 1epsilon. Deleting the gene would not be possible in humans, but the finding has allowed pharmaceutical firms to investigate ways to block it

 

Using mice, stock image pictured, researchers discovered that if they deleted the gene, it would stop the mice producing the enzyme, called casein kinase 1epsilon. Deleting the gene would not be possible in humans, but the finding has allowed pharmaceutical firms to investigate ways to block it

 

WHAT CAUSES JET LAG?

 

Nearly all living things have an internal mechanism – known as the circadian rhythm or body clock – which synchronises bodily functions to the 24-hour pattern of the Earth’s rotation.

In humans and other mammals, the clock is regulated by the bodily senses – most importantly the way the eye perceives light and dark and the way skin feels temperature changes.

When we work late, or travel to different time zones, the light our body expects to see – based on how long we’ve been awake – for example, is different, and this causes our body clock to fall out of sync. 

This causes the feeling of jet lag. 

But the pressures of modern living mean we are now increasingly working against our clocks and risking long term health problems from metabolic disease.

Separate studies have found that people who work night shifts or who get too little sleep are more susceptible to diseases including depression, cancer, diabetes and dementia. 

The researchers discovered the gene which produces an enzyme that controls part of the circadian clock. They deleted the gene in mice to stop them producing the enzyme, called casein kinase 1epsilon.

The team studied the mice for changes by timing the lights switches in their cages to replicate a weekend flight to New York.

The mice without the crucial enzyme adapted much faster to the new day-night pattern and displayed much smaller metabolic disruption.

Deleting the gene would not be possible in humans, but the finding has allowed pharmaceutical firms to investigate a pill to block the enzyme.

Dr Bechtold, whose research is published in the journal Current Biology, said: ‘By tackling this enzyme we can wind the body clock back or forwards, we can modulate the clock.

‘So jet lag could be eliminated by using inhibitors on the family of enzymes which sets the speed of the clock.

He added: ‘We already know that modern society poses many challenges to our health and wellbeing – things that are viewed as commonplace, such as shift-work, sleep deprivation, and jet lag disrupt our body’s clocks.

‘We are not genetically predisposed to quickly adapt to shift-work or long-haul flights, and as so our bodies’ clocks are built to resist such rapid changes.

‘Unfortunately, we must deal with these issues today, and there is very clear evidence that disruption of our body clocks has real and negative consequences for our health.

‘As this work progresses in clinical terms, we may be able to enhance the clock’s ability to deal with shift work, and importantly understand how maladaptation of the clock contributes to diseases such as diabetes and chronic inflammation.’

Read more: http://www.dailymail.co.uk/sciencetech/article-2585340/Getting-rid-jet-lag-soon-simple-taking-pill-Scientists-way-reset-body-clocks-long-flights.html#ixzz2wXPpr0Ia 
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