Mu-Opioid Receptors Drive Tolerance in Mice

Mu-Opioid Receptors on Nociceptors, Not Microglia, Drive Morphine Tolerance and Hyperalgesia in Mice | Pain Research Forum | by Matthew Soleiman – Feb 2017

By genetically removing mu-opioid receptors (MORs) from peripheral nociceptive neurons, the researchers found that they could reduce both tolerance and OIH while maintaining analgesia in mice receiving daily doses of morphine.

“The main take-away from the paper is that you can dissociate the side effects of opioids from the main effect of analgesia,”

What’s more, administration of morphine along with a peripherally restricted MOR antagonist also lessened tolerance and OIH without diminishing analgesia in models of perioperative and chronic pain.  

Since the antagonist, methylnaltrexone bromide (MNB), is an FDA-approved drug, there’s hope that the combined drug strategy could be effective and safe in patients who use opioids for pain relief.

A role for microglia?

Together, a handful of studies have made the case that opioids trigger tolerance and hyperalgesia by binding to MORs on dorsal horn microglia.

When given injections of morphine twice daily, wild-type mice developed signs of these side effects as well as microglial activation, compared to mice that received saline.

Global MOR knockout animals, however, only showed microglial activation.

Chronic morphine, then, seemed to cause tolerance and hyperalgesia, but not microglial activation, through MORs.

As a possible explanation for these findings, the researchers failed to detect MOR messenger RNA or protein in microglia. But they found both in pain-signaling neurons (marked by calcitonin gene-related peptide) in the dorsal root ganglia.

A new culprit

So the researchers went on to test if morphine was instead acting on peripheral pain-sensing neurons, rather than microglia, to produce opioid side effects.

Over 10 days, they gave daily subcutaneous injections of morphine to wild-type mice, as well as to mice with MORs genetically deleted from nociceptive neurons expressing the transient receptor potential vanilloid type 1 (TRPV1) ion channel.

More recently, researchers have discovered so-called biased agonists for both the MOR and the kappa-opioid receptor.

These agonists produce analgesia without affecting breathing, motor activity, or reward-related circuits, at least in rodents (see PRF related stories here and here).

But the combined drug strategy stands out because MNB (methylnaltrexone bromide ) is already used to treat opioid-induced constipation.

As a result, “I don’t think MNB would need any other translational data” to move into clinical trials, said Tawfik.

“I think our data put out there the possibility that we could improve these opioid side effects with this peripherally restricted drug.”

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One thought on “Mu-Opioid Receptors Drive Tolerance in Mice

  1. Kahty C

    Interesting, but we should all be suspicious. A drug that is currently on the Market apparently helps with the side Effects. This seems convenient. It reminds me of an old Joke. A guy lost a Quarter, so he is looking under a streetlamp. A curios onlooker asks him where he lost it, he replies, in my bedroom. The onlooker then asks, why are you looking here. he replies “The light is better.”
    This morning i received an e-mail, from the FDA. It contained this link, https://www.hhs.gov/blog/categories/health-care, to a U-tube video explaining how Mike Sauers is fighting “Misleading Pharma Ads.” I suppose it looks good a former Drug Rep who is supposed to be fighting misleading advertising. We are in the post Fact Era now, so why the heck not. They seem to be unaware that Heaven did nto open up because of a new Pharma Product, as portrayed in the Commercials that run non stop.
    Since we are Post Fact, and big Pharmas last piece of “legislation was to help them maintain prices and make even more money from “Orphan Drugs” They are suddenly going through the Stockpile and remarketing old drugs as “New.” Those of us int he general public have no idea if this piece of “Research” was done because it was significant, or because this drug was already on the market. It should be mentioned that during the years of Trials, this significant “Finding” did not come up. Even when they started promoting it and Prescribing it to a lot of people, no Physician noticed this “Groundbreaking” information.
    Since we are Post Science, we can discard these findings because it is more likely that the Pharma Company Paid these “Researchers” to come up with more After Market “Cures” for a drug they pushed t on the Market for Constipation. These “Findings” would have been discovered before the “Trials” if they were using Science. They really aren’t Researching New Drugs, they are merely recycling old ones. They found that was a lot more profitable. With the current environment of pseudo Science and industry Insiders at the FDA, this stuff only has to be slightly better than Placebo, and not kill anyone in an outright manner. The only information we can rely on anymore is Anecdotal, and due to the demonization of Pain Patients and the ridicule heaped on people with that Side Effect, no one is talking. They have silenced us all. Perhaps we should Poll our Online groups, and make sure their Personal Information is hidden. We certainly can’t ask this question on Facebook, or other Social Media outlets. They have already been destroyed by Big Pharma, and the greed of Steve Zuckerberg. He thought it would be profitable to sell the names of people in Patient Groups to big Pharma and the Medical Industry. They directed the conversation away from the Big issues, to a “Tel Your Story” Narrative. That way the industries could say these groups were just a “Pity Party” for pathetic lonely people.
    We have virtually no Patient Groups anymore since they were all Funded to promote big Pharma, or the New Age “Alternative Medicine” Nonsense. Instead of discussing facts, they were told to express feelings. This was not accidental, the Industries had to undermine these discussions. They had to derail any meaningful discourse or Groups that could effectively point to facts. If there were any credibility to this “Research” people would have already discovered it. All the Pharma Industry has to do is disseminate some of their “Research” to the Media, it does not even have to be Scientific, it just has to show that they “researched” something and made an overstated claim. When they ad some Sciencey stuff about Mu Receptors it sounds more legit. Again with e Mice, which often does nto translate to humans, so to promote this in a Corporate Medai venue, which will be next. This is just the Pre Release. “Pain Relief Forum” I really don;t have the energy to track down their Information. It is hard to tell the legitimacy of any of the “Groups.” Some are set up by Big Pharma or Device manufacturers to give apparent credibility to their Products.

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