Breakthrough in Making Much Less Addictive Opioids

Important research this is, for it shows that the powerful pain relief opioids provide doesn’t have to be such a dangerous double-edged sword.

In the US, more than one-third of the population experiences some form of acute or chronic pain; in older adults this number rises to 40 percent.

The most common condition linked to chronic pain is chronic depression, which is a major cause of suicide.

To relieve severe pain, people go to their physician for powerful prescription painkillers, opioid drugs such as morphine, oxycodone and hydrocodone.

Almost all the currently marketed opioid drugs exert their analgesic effects through a protein called the “mu opioid receptor” (MOR).

MORs are embedded in the surface membrane of brain cells, or neurons, and block pain signals when activated by a drug.

However, many of the current opioids stimulate portions of the brain that lead to additional sensations of “rewarding” pleasure, or disrupt certain physiological activities. The former may lead to addiction, or the latter, death.

Which part of the brain is activated plays a vital role in controlling pain. For example, MORs are also present in the brain stem, a region that controls breathing.

Activating these mu receptors not only dulls pain but also slows breathing. Large doses stop breathing, causing death.

Activating MORs in other parts of the brain, including the ventral tegmental area and the nucleus accumbens, block pain and trigger pleasure or reward, which makes them addictive. But so far there is no efficient way to turn these receptors “on” and “off” in specific areas.

But there is another approach because not all opioids are created equal. Some, such as morphine, bind to the receptor and activate two signaling pathways: one mediating pain cessation and the other producing side effects like respiratory depression.

Other drugs favor one pathway more than the other, like only blocking pain – this is the one we want.

“Biased opioids” to kill pain

But MOR isn’t the only opioid receptor. There are two other closely related proteins called kappa and delta, or KOR and DOR respectively, that also alter pain perception but in slightly different ways.

Yet, currently there are only a few opioid medications that target KOR, and none that target DOR. One reason is that the function of these receptors in the brain neurons remains unclear.

Recently KOR has been getting attention as extensive studies from different academic labs show that it blocks pain without triggering euphoria, which means it isn’t addictive.

Another benefit is that it doesn’t slow respiration, which means that it isn’t lethal. But although it isn’t as dangerous as MOR, activating KOR does promote dysphoria, or unease, and sleepiness.

This work suggests it is possible to design a drug that only targets the pain pathway, without side effects. These kind of drugs are called “biased” opioids.

[…]

The exciting news is that researchers in the Roth lab have discovered several promising compounds based on the KOR structure that selectively binds and activates KOR, without cavorting with the more than 330 other related protein receptors.

Now our challenge is to transform these molecules into safer drugs.

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Google+ photo

You are commenting using your Google+ account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

w

Connecting to %s