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TREK-1 shows potential, according to study

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By Sharon Kingman
Staff Writer

 

LONDON – It may soon be possible to develop new analgesics that are as good as morphine when it comes to killing pain, yet do not have any of the unpleasant and sometimes dangerous side effects of that drug, such as constipation and respiratory depression.

Researchers in France said they believe such ideal painkillers are within reach, following their investigation of an ion channel, called TREK-1, which operates downstream of the receptor on which morphine acts.

Alain Eschalier, professor of pharmacology at the University Hospital in Clermont-Ferrand, France, told BioWorld Today: “Morphine is widely used but its side effects present clinical problems. In addition, there is an increasing public health problem due to wider prescribing of morphine for chronic noncancer pain, which means that many people now have a dependency on this drug. Until now, no one has been able to propose compounds that will have the same efficacy as morphine, but without any of these side effects. With the discovery of the role of TREK-1, we believe it will be possible to develop new analgesics with these characteristics.”

Eschalier and colleagues, in collaboration with the group of Michel Lazdunski at the Sophia Antipolis University of Nice, France, reported the findings in a paper in the Dec. 17, 2013, issue of Nature Communications, titled “Activation of TREK-1 by morphine results in analgesia without adverse side effects.”

The analgesic effect of morphine is brought about by that drug’s stimulation of the mu opioid receptors. In mice that lack those receptors, morphine has no analgesic effect, nor does it cause adverse effects such as constipation or respiratory depression.

Results of some earlier studies, however, suggested that there might be ways to modulate the signaling pathways downstream of the mu opioid receptors, and that one possibility might be to target ion channels of the type called TREK-1.

That channel is found on sensory neurons, particularly those that detect pain, as well as throughout the central nervous system. When TREK-1 is activated, it allows potassium ions to exit the neuron, thus inducing hyperpolarization of the cell membrane and, in turn, reducing the activity of the neurons involved in pain transmission.

“We postulated that, if instead of activating the mu opioid receptors, we activated the TREK-1 receptors, we might have the analgesic effects without the side effects,” Eschalier explained.

In order to explore further, the team used transgenic mice that lacked any functional copies of the gene that encoded TREK-1.

“We showed that in these mice, there was a marked decrease in the analgesic effect of morphine, so this indicated that the TREK-1 channel is needed for its analgesic effect,” Eschalier said. “We were also able to demonstrate, using electrophysiological studies, that there was an interaction between the mu opioid receptors and the TREK-1 channels.”

Next, the researchers studied the side effects of morphine in the transgenic mice. “In these experiments, we failed to show any involvement of TREK-1 in morphine side effects, including depressive respiratory effects, constipation or induction of dependency,” Eschalier added.

“Our results suggest that it will be possible to dissociate the benefit effects of morphine from the adverse side effects of morphine, by directly activating the TREK-1 channel. If we can develop novel analgesics that target TREK-1, therefore, the result will be a large improvement in pain management,” he noted.

The group now will go ahead with collaborative work to identify analgesic compounds. “We have set up an analgesia partnership, which includes pharmacologists, chemists and several private companies,” Eschalier said. “We will have the capacity to synthesize new candidate analgesic compounds and to develop these for clinical use.”