June 22, 2020 / 2:11 PM / 14 days ago

Opioid receptors inside cells important for pain relief

NEW YORK (Reuters Health) - Activation of delta opioid receptors inside cells is important for the relief of inflammatory pain, researchers report.

“Most medicines targeting receptors are designed to hit receptors at the cell surface and many can’t cross the cell membrane,” Dr. Michelle L. Halls of Monash University, in Parkville, Australia, told Reuters Health by email. “We are finding that in some cases, medicines would be much more effective if they were sent directly to the intracellular site where the receptor is active - in this case, endosomes.”

G protein-coupled receptors (GCPRs), the targets of about a third of approved drugs, are considered to function principally at the cell surface, but endosomes are important sites of continued GPCR signaling. It remains unclear whether opioid receptors at the plasma membrane or in endosomes mediate the endogenous system of pain control.

Dr. Halls and colleagues investigated their hypothesis that opioids from the inflamed colon activate delta opioid receptors (DOPr) in endosomes of pain receptors (nociceptors) to evoke signals that bring long-lasting inhibition of excitability and analgesia and that DOPr in endosomes represent a superior therapeutic target for inflammatory pain.

Opioids from the inflamed colon cause a DOPr-mediated inhibition of nociceptors, and both opioids from the inflamed colon and agonists that evoke DOPr endocytosis cause a sustained decrease in excitability of nociceptors, the researchers report in PNAS.

DOPr endosomal signaling within the peripheral projections of colonic nociceptors appears to induce a sustained inhibition of mechanical sensitivity.

The researchers coupled the DOPr agonist DADLE to a liposome shell for targeting DOPr-positive nociceptors and incorporated it into a silica core for release in the endosomal environment. These nanoparticles activated DOPr at the plasma membrane, were preferentially endocytosed by DOPr-expressing cells and were delivered to DOPr-positive early endosomes.

These nanoparticles provided sustained inhibition of nociceptive excitability and relief from inflammatory pain in mice.

In contrast, similar nanoparticles containing a DOPr antagonist abolished the sustained inhibitory effect of DADLE.

“Prolonged activation of the delta-opioid receptor from endosomes inside the cell (and not at the plasma membrane) is really important for sustained pain relief,” Dr. Halls said. “This occurs normally in response to inflammatory pain in the gut. We were able to cause sustained activation of delta-opioid receptors (and therefore prolonged pain relief) by delivering drugs directly to endosomes in preclinical models of pain.”

Co-author Dr. Nigel W. Bunnett, also at Monash University, told Reuters Health by email, “Nanoparticles that deliver opioids to endosomes of pain-sensing neurons might provide superior relief from inflammatory pain. This finding has implications for treatment of inflammation-associated pain in many tissues - gut, joints, etc. The approach may allow use of lower doses of opioids, with fewer side effects.”

“We can use nanoparticles to deliver simultaneously multiple drugs to relieve pain, thereby targeting the inherent redundancy of pain signaling,” said Dr. Bunnett, a founding scientist of Endosome Therapeutics Inc.

The study did not have commercial funding.

SOURCE: bit.ly/2ANA0o3 PNAS, online June 16, 2020.

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