Microglia and Pain

Microglia may be the missing clue to solve the opioid epidemic – Sara WhitestoneNeuroscience – Université de Bordeaux – May 2019

neuroscientists have discovered a new therapeutic target for managing pain: microglia.

Pain, as an acute sensation, serves as a warning to help your body prevent injury or avoid further harm.

the message from your stubbed toe is forced to go through a series of checkpoints—or gates—which will either open or shut to control the intensity of pain you perceive.

When pain becomes chronic, this signaling and the gate controls go haywire. Nerves become hyper-sensitive, firing off messages to the brain even in the absence of an injury.  

Opioids are particularly effective at relieving pain because neurons in the brain and spinal cord contain specialized receptors, called Mu opioid receptors (MOR).

Opiodergic drugs, like morphine or oxycodone, bind to these receptors, overriding the pain signals between neurons and creating an analgesic affect

Microglia are the smallest of the glial cells found in the brain and spinal cord, and act as the primary system of defense in the central nervous system.They are essentially first-responders in cases of injury, helping to guide the immune response

Drugs like Naloxone, used in cases of overdose, basically just unbind this connection, reversing the effects of the drug.

…recently, researchers from France have found that microglia express, or produce, opioid receptors.

These receptors are located on the outside of the cell, or its membrane. When an opioidergic drug binds to this receptor, it will change its configuration, and ultimately the action of the cell. This means that opioidergic drugs, like methodone, don’t only act on neurons—it turns out they have a direct impact on microglia, too.

It seems like the more we learn, the more aspects of our biochemistry become more complicated.

This situation seems analogous to when we finally sequenced the genome only to discover that it’s not just about the genes (which are set at birth), but whether they’re turned on or off (changes throughout our lifetime).

Previous studies investigating the role of microglia had not been able to definitely prove that microglia interacted with opioidergic drugs. However, these studies were done on cultured microglia grown in a lab dish. Scientists know that these kinds of cultured cells can have very different gene expression than those found in vivo, meaning in a living organism.

Yet, if such experiments were truly not useful or indicative of potential, why would they ever be done at all?

And scientists who did try to find MOR expression in microglia in vivo had contradictory findings; they couldn’t conclude if the drug interaction was with microglia directly, via the involvement of other cell-types.

But finally, an interdisciplinary team from France decided earlier this year to use a handful of large datasets from other researchers who have compiled genomic data specifically for this kind of analysis.

Their goal was to isolate the specific gene responsible for expressing the MOR in microglia, Oprm1/OPRM1. Then, the researchers genetically designed mice with fluorescent cells that light up if they have this gene, allowing the scientists to visually see the MOR protein in microglia.

The researchers ultimately successfully found microglia with MOR expression in both the brain and spinal cord.

By showing that these microglia carry the genetic code for opioid receptors, the study supports the hypothesis that microglia are directly involved in opioid tolerance or addiction—contradicting previous research.

In addition to pain relief, targeting microglia might also be a way to prevent opioid tolerance, or explain opioid-induced hyperalgesia, when the exposure to opioids actually makes the sensation of pain worse. Future combined drug strategies might allow patients to have the pain-relieving effects of opioids without the unwanted or dangerous side-effects or addiction.

Peer Commentary:

Jenna Sternberg

…recent work demonstrating that opioid signaling through pain receptors (neurons) and not microglia in the periphery is required for morphine tolerance (Corder et al., Nat Medicine 2017). At the same time, these authors did not find opioid receptor expression in microglia, which is at odds with the French report. So the jury is still out on the role of opioid receptors in microglia and the contribution of microglia to pain processing.

Aarthi Gobinath

an interesting study from Dr. Staci Bilbo’s group… points to an interesting role for microglia protecting neurons from developing opioid dependence in mice, but more from the immune function of microglia.

They examined microglia-neuron communication in opioid addiction by creating a transgenic mouse models (males only) that deleted an immune signalling protein specifically in microglia. Without this immune signal from microglia, mice showed increased opioid addiction-like behavior as well as increased production of new neurons in the hippocampus, a region important for learning and memory.

The causes of chronic pain are so diverse, and prescribing opioids for all of these different conditions seems like a sledgehammer approach.

Then it’s just as true that  NOT “prescribing opioids for all of these different conditions seems like a sledgehammer approach”.

Either way, standard doses of standard medications are completely inappropriate for individuals, especially when we all react to opioids so very differently.

Uncovering the different mechanisms for chronic pain to develop more precise treatments is more closely aligned with how complicated pain is in the nervous system.

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