The complexity of opioid receptor function

Untangling the complexity of opioid receptor function – by Rita J. Valentino & Nora D. Volkow – Sept 2018for science nerds

This is a technical article explaining the differences between different opioid receptors, which turn out to have further layers of complexity. Finding the molecular paths or signals that create and/or transmit pain signals, researchers hope to find new ways to interrupt that process to alleviate pain.

Evidence that opioid receptors form and can function as heteromers suggests another layer of complexity and another route for manipulating opioid receptor function

Mu opioid receptor agonists are among the most powerful analgesic medications but also among the most addictive.  

…access to new molecular, genetic and computational tools have begun to elucidate

  • the structural dynamics of opioid receptors,
  • the scaffolding that links them to intracellular signaling cascades,
  • their cellular trafficking and
  • the distinct ways that various opioid drugs modify them

This mini-review highlights some of the chemical and pharmacological findings and new perspectives that have arisen from studies using these tools

They reveal multiple layers of complexity of opioid receptor function…

By untangling these layers, basic research into the chemistry and pharmacology of opioid receptors is guiding the way towards deciphering the mysteries of tolerance and physical dependence that have plagued the field and is providing a platform for the development of more effective and safer opioids.

The 1970’s heralded a new era in the opioid field with the discovery that opiate drugs produce their effects by binding to specific binding sites in brain, followed by the discovery that brain neurons synthesize opioid-like peptides that produce similar effects through actions at the same receptors

I had no idea this was discovered so “recently”. Perhaps it was because laboratory equipment in those days was crude and it was much harder to detect and measure biochemical sequences like receptor binding.

Advances in imaging technologies have allowed us “see” neurons and “watch” biochemical reactions… and find new variations of what we believed to be simple processes.

Every new discovery seems to reveal further complexity.

Coupled with the findings that naloxone-reversible analgesia could be produced by stimulation of specific brain regions, this solidified the transformative idea that opiates act by mimicking the endogenous opioid systems.

three distinct receptors were cloned,

  1. μ (MOR),
  2. κ (KOR), and
  3. δ (DOR),

with different selectivities for the individual endogenous peptides and for the various opiate drugs used pharmacologically

These examples and others underscore how research on the functions of the three opioid signaling systems is revealing unique and counterbalancing roles as they relate to their regulation of pain, stress, and affect (Fig. 2).

Though the MOR is the main target for opioid analgesics, the DOR and KOR also regulate pain and analgesia and the relative affinities of opioid analgesics for these receptors confers them unique properties.

Specifically, while

  • MOR agonists produce euphoria and promote stress coping,
  • KOR agonists produce dysphoria, stress-like responses and negative affect, while
  • DOR agonistsreduce anxiety and promote positive affect.

The multiplicity of opioid receptors inspired the design of agonists and antagonists with different potencies, efficacies and selectivities for MOR, DOR, and KOR based on structure activity relationships and with different pharmacokinetics in an effort to develop analgesics with less adverse effects.

Although promising, this strategy has yet to yield a potent opioid analgesic that 

  • is not rewarding, 
  • lacks tolerance,
  • does not trigger physical dependence or
  • produce respiratory depression.

This is a silly wish-list because hardly any medications currently used for any condition would qualify according to this list.

First of all, pain relief is always rewarding in and of itself. The anti-opioid folks want to believe it’s euphoria we crave, and deliberately forget that we’re dealing with constant pain without opioids.

Also, the body adjusts to drugs it is fed and habituates to the presence of various medications to the point of being thrown off-balance if that medication is suddenly stopped. Tolerance and withdrawal are not unique to opioids.

Schematic depicting that although agonists at MOR, KOR, and DOR are all analgesic, pharmacological studies, and genetic models reveal that they are at different ends of mood and hedonic continuums.

  • MOR agonists produce euphoria and promote stress coping. At the other end of the hedonic continuum,
  • KOR agonists produce dysphoria and are associated with stress and negative affect.
  • DOR is on the opposite end of the continuum describing mood and DOR agonists have anxiolytic and antidepressant activity. 

New tools and innovative approaches are revealing that opioid receptors are more complex than previously appreciated and this can account for past difficulties in designing ideal ligands.

Isn’t that always the case with scientific knowledge?

The more you learn the more you realize you still have to learn. Every new observation introduces new levels of complexity and spawns more new questions than it answers.

Here we describe studies using state-of-the-art approaches to reveal the structural nuances of opioid receptors in different conformational states and of computational approaches to design drugs based on this information.

Warning: you might not want to go deeper into this review unless you’re a science nerd :-)

The cloning of MOR uncovered the complexity of its gene OPRM1 and the existence of multiple splice variants

It seems nothing about our bodies is ever really simple and straightforward.

There are countless molecules and processes, varying from moment to moment, that influence the chemical reactions that influence the biological functions that influence how our bodies and minds function.

Translating advances in opioid receptor research to the opioid crisis

Here we described how the development of new tools and approaches advanced our knowledge of opioid receptor function.

This is reframing our perspective of the cellular consequences of agonist binding to opioid receptors and revealing novel cellular mechanisms that can be targeted.

Advances in genetics are identifying granular distinctions in receptors that could be a basis for understanding individual differences in vulnerabilities.

It’s obvious scientists know that people have very different responses to the same opioids. That means doctors should know it too if they’re treating people with opioids.

But it sounds like the only facts about opioids doctors know come from pharmacy salespeople.

Instead of reading about the latest studies of the drugs they prescribe, they let themselves be taken out to fancy meals and be spoon-fed biased information by salespeople. I’m all in favor of using opioids for whom they are effective, but some thought has to go into creating the best dosing plans for individual patients.

Though many scientific questions still remain unresolved (Table 1), the new advances, by revealing molecular and cellular fundamentals of opioid receptor function, bring us closer to understanding the mechanisms by which opioids produce tolerance, physical dependence and addiction and towards developing a rational therapeutic design of safe, effective opioid analgesics.

Table at

4 thoughts on “The complexity of opioid receptor function

    1. Zyp Czyk Post author

      How simple our lives would be if we could just take the medication prescribed for our chronic pain, tailored to our specific needs, without all these crazy hassles and roadblocks.

      Instead, we have to push through level after level of hostile gatekeepers who are all concerned about keeping “their numbers” (milligrams of opioid relief) as low as possible. No one is documenting or studying the extra pain we suffer.

      In the current healthcare system, if something isn’t measured, it may as well not even exist. That’s where we’re stuck with our chronic pain. The only thing they are counting is milligrams.

      Liked by 1 person


Other thoughts?

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

You are commenting using your 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 )

Connecting to %s

This site uses Akismet to reduce spam. Learn how your comment data is processed.