Exploiting Opioid Receptor Variants

Exploiting Opioid Receptor Variants for Safer Analgesics | Pain Research Forum |  by Stephani Sutherland on 22 Feb 2016

A recent PRF webinar examined the effects of mu-opioid receptor gene splicing on analgesic and off-target effects of drugs

Patients respond differently—and unpredictably—to opioid drugs in terms of efficacy and side effects; these individual variations arise from genetic differences.

Although the drugs act at the mu-opioid receptor (MOR), which is encoded by a single gene, genetic splicing gives rise to at least 20 different variants.  

Roadblocks to safer opioids

Pain—and pain relief—are subjective experiences that patients have difficulty describing. “This makes a readout of efficacy of drugs difficult, and has made the whole area more of an art rather than a science,” Pasternak said to start his talk.

Despite their shortcomings, “the opiates remain among some of the most impressive drugs we have for the relief of pain,” he said.

They work not by interfering with signal transduction, as anesthetics do, but by engaging the endogenous opioid system.

As a result, opioid drugs affect pain without altering consciousness or impairing overall sensation.

Most people don’t understand that opioids do NOT numb, but rather selectively dampen nociception, which is the physical sensation of pain.

But pain is extremely complex—it includes nociceptive sensation as well as mental and emotional components, which can vary greatly depending on the situation.

“The opiates can take care of the nociceptive pain, but they won’t necessarily impact the suffering associated with the meaning of the pain,” Pasternak said.

This is perfect for those of us who have mechanical causes of our chronic pain, like the micro-tears resulting from connective tissue disorders like EDS.

We only need to block the nociception coming from the damaged tissues, which does not involve anything further like the “meaning of pain”.

Adding to the complexity of opioid analgesia, Pasternak said, is that people respond very differently to these drugs.

“The relative potency and effectiveness of analgesics can vary unpredictably among patients, with some responding very well to one drug and not another, and then the next patient having a totally reversed sensitivity profile.”

Patients also differ wildly in their experience of side effects, which can sometimes be avoided simply by switching to another opioid. “This variability—the inability to predict the response—has made the use of these drugs relatively complicated. There are many things that can impact the potency of drugs, and the genetic impacts are clear.”

When it seems to be well-known and scientifically proven that patients have such a wide variety of responses to opioids, how can the CDC justify its arbitrary “standard doses” and limits?

A new way forward

Pasternak then introduced the concept of biased signaling.

The mu-opioid receptor variants, like other GPCRs, interact with both G proteins and beta-arrestin, which activate separate intracellular signaling pathways.

“By changing the relative strength of one pathway to another, you can change the pharmacological activities of the molecule,” he said. “There is evidence to suggest that avoiding beta-arrestin activation can give you drugs that will produce less respiratory depression and perhaps less constipation.”

“The concept of biased signaling has a lot of potential value in drug development, and it really helps in understanding what we see with our patients,” Pasternak said.

Imagine a quintet playing “Row, Row, Row Your Boat.” Suppose the trumpet and violin play very loudly, and the sax, clarinet, and bass play very softly.

Now suppose the trumpet and the violin play very softly and the others play loudly.

“It’s the same tune. It’s the same instruments playing the same notes, and the same musicians, but there are subtle differences.”

Much in the same way, opioid drugs all work through mu-opioid receptors—the common tune—but biased signaling results in slightly different outcomes.  

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