We think that our data could potentially explain why degranulation occurs as a side effect of opioid ligands morphine and other drugs , something that is well-known but not well-understood. The findings are significant not only because they offer a potential explanation for opioid-induced itching, but also because the data suggest a way to characterize the function of the orphan receptor MRGRPX2.
Currently there are about orphan receptors in humans. They are "orphan" because, though we know they exist, we don't yet know what they do. The Roth lab screens these receptors against thousands of small molecules to find out what might activate them. This process involves a combination of physical screening and computational modeling.
Once that tentative picture was in place, we were able to use computational tools to create a more precise model of the site. The computer modeling, performed by co-first author Joel Karpiak, a graduate student at the University California at San Francisco, tested 3.
The physical data combined with the computational models allowed the researchers to create a chemical probe designed to interact specifically with MRGRPX2.
This new tool made it possible to gain a more precise understanding of this receptor's effects without the noise of other receptors. An opioid might activate the orphan receptor, but it might also activate other receptors that it interacts with.
Imagine trying to recreate a musical score by listening to an orchestra perform a piece of music. Understanding what triggers the itching response could help pharmacologists develop an antagonist for this receptor to reduce the itching side effect.
In other cases, clinicians may want to induce histamine release, thereby boosting the immune response, as in the case of vaccine adjuvants, where an increased immune response may improve immunity. We found that this isoform is specifically required for relaying morphine-induced itch. Very interestingly and unexpectedly, we found that this isoform is not involved in morphine analgesia.
So this, actually, is the first evidence to show that a morphine isoform has nothing to do with morphine analgesia. And we believe MOR1D is the only isoform involved in morphine-induced itch.
There are so many other isoforms, and some of the isoforms we know, they are also expressed in the spinal cord. The brain has four main types of receptors that respond to opioids, and every type has many structural variants, called isoforms. Most opioids are nonspecific, which means they bind to all the isoforms. This leads to powerful pain relief, although scientists do not know exactly why. Louis showed that only one opioid receptor isoform is responsible for itching—and it is not involved in pain.
Mice bred to have fewer of these particular receptors did not scratch themselves when given an opioid, but they did exhibit the telltale mouse signs of pain relief, such as less flinching when researchers flicked their tails. Now that scientists know that pain relief and itching can be decoupled, they will try to make itch-free opioid drugs a reality. Already a subscriber? Sign in.
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