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.
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.”