Antagonism of the mu-delta opioid receptor heterodimer enhances opioid antinociception by activating Src and calcium/calmodulin-dependent protein kinase II signaling

Keresztes, Attila; Olson, Karin; Nguyen, Paul; Lopez-Pier, Marissa A.; Hecksel, Ryan; Barker, Nelson W.; Li, Yi; Hruby, Victor J.; Konhilas, John P.; Langlais, Paul; Streicher, John M.

doi:10.1097/j.pain.0000000000002320

Cited by 14 publications

(12 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We showed that this compound was ~90‐fold selective for the MDORH over either monomer and reduced morphine withdrawal in mice (Olson et al, 2018). We further showed that D24M suppressed opioid anti‐nociception via suppression of Src and CaMKII signalling in the brain, also supporting this hypothesis (Keresztes et al, 2022). These results are more clear for the role of the MDORH, because they use a ligand with a high selectivity and defined molecular pharmacology.…”

Section: Opioid Receptor Heterodimerssupporting

confidence: 86%

Strategies towards safer opioid analgesics—A review of old and upcoming targets

Varga

Streicher

Majumdar

2022

British J Pharmacology

Self Cite

View full text Add to dashboard Cite

Opioids continue to be of use for the treatment of pain. Most clinically used analgesics target the μ opioid receptor whose activation results in adverse effects like respiratory depression, addiction and abuse liability. Various approaches have been used by the field to separate receptor-mediated analgesic actions from adverse effects. These include biased agonism, opioids targeting multiple receptors, allosteric modulators, heteromers and splice variants of the μ receptor. This review will focus on the current status of the field and some upcoming targets of interest that may lead to a safer next generation of analgesics.

show abstract

Section: Opioid Receptor Heterodimerssupporting

confidence: 86%

Strategies towards safer opioid analgesics—A review of old and upcoming targets

Varga

Streicher

Majumdar

2022

British J Pharmacology

Self Cite

View full text Add to dashboard Cite

show abstract

“…In addition to this previously unidentified negative feedback mechanism through AMPK, other negative feedback signaling molecules and circuits have been identified that restrain opioid activity in both the brain and spinal cord. Work from our laboratory and others has shown that the μ and δ opioid receptors heterodimerize and that this heterodimer reduces the antinociceptive effects of opioids (25,26). Cholecystokinin neurons in the rostroventral medulla act as an "anti-opioid" system to reduce opioid-induced analgesia and enhance side effects (27,28).…”

Section: Discussionmentioning

confidence: 99%

HSP90 inhibition in the mouse spinal cord enhances opioid signaling by suppressing an AMPK-mediated negative feedback loop

Gabriel

Streicher

2023

Sci. Signal.

Self Cite

View full text Add to dashboard Cite

Opioids and other agonists of the μ-opioid receptor are effective at managing acute pain, but their chronic use can lead to tolerance that limits their efficacy. We previously reported that inhibiting the chaperone protein HSP90 in the spinal cords of mice promotes the antinociceptive effects of opioids in a manner that involved increased activation of the kinase ERK. Here, we found that the underlying mechanism involves the relief of a negative feedback loop mediated by the kinase AMPK. Intrathecal treatment of male and female mice with the HSP90 inhibitor 17-AAG decreased the abundance of the β1 subunit of AMPK in the spinal cord. The antinociceptive effects of 17-AAG with morphine were suppressed by intrathecal administration of AMPK activators and enhanced by an AMPK inhibitor. Opioid treatment increased the abundance of phosphorylated AMPK in the dorsal horn of the spinal cord, where it colocalized with a neuronal marker and the neuropeptide CGRP. Knocking down AMPK in CGRP-positive neurons enhanced the antinociceptive effects of morphine and demonstrated that AMPK mediated the signal transduction between HSP90 inhibition and ERK activation. These data suggest that AMPK mediates an opioid-induced negative feedback loop in CGRP neurons of the spinal cord and that this loop can be disabled by HSP90 inhibition to enhance the efficacy of opioids.

show abstract

“…The KOR selective antagonist norBNI (10 mg/kg, s.c.) , and NXAZ (10 mg/kg, i.p. ) , were administered 120 min before the hot plate trial. The delta latency (s) for each animal was calculated using this equation: Δlatency (s) = latency after treatment (s) – baseline latency (s).…”

Section: Methodsmentioning

confidence: 99%

A Novel Leu-Enkephalin Prodrug Produces Pain-Relieving and Antidepressant Effects

Hohenwarter,

Puil,

Rouhollahi

et al. 2024

Mol. Pharmaceutics

View full text Add to dashboard Cite

Persistent pain is a significant healthcare problem with limited treatment options. The high incidence of comorbid chronic pain and depression significantly reduces life quality and complicates the treatment of both conditions. Antidepressants are less effective for pain and depression than for depression alone and they induce severe side effects. Opioids are highly efficacious analgesics, but rapid development of tolerance, dependence, and debilitating side effects limit their efficacy and safe use. Leucineenkephalin (Leu-ENK), the endogenous delta opioid receptor agonist, controls pain and mood and produces potent analgesia with reduced adverse effects compared to conventional opioids. High proteolytic instability, however, makes Leu-ENK ineffective after systemic administration and limits its clinical usefulness. KK-103, a Leu-ENK prodrug, was developed to overcome these limitations of Leu-ENK via markedly increased plasma stability in mice. We showed rapid and substantially increased systemic adsorption and blood plasma exposure of KK-103 compared to Leu-ENK. We also observed brain uptake of radiolabeled KK-103 after systemic administration, indicating a central effect of KK-103. We then established KK-103's prolonged antinociceptive efficacy in the ramped hot plate and formalin test. In both models, KK-103 produced a comparable dose to the maximum antinociceptiveeffect relationship. The pain-alleviating effect of KK-103 primarily resulted from activating the delta opioid receptor after the likely conversion of KK-103 to Leu-ENK in vivo. Finally, KK-103 produced an antidepressant-like activity comparable to the antidepressant desipramine, but with minimal gastrointestinal inhibition and no incidence of sedation.

show abstract

Antagonism of the mu-delta opioid receptor heterodimer enhances opioid antinociception by activating Src and calcium/calmodulin-dependent protein kinase II signaling

Cited by 14 publications

References 53 publications

Strategies towards safer opioid analgesics—A review of old and upcoming targets

Strategies towards safer opioid analgesics—A review of old and upcoming targets

HSP90 inhibition in the mouse spinal cord enhances opioid signaling by suppressing an AMPK-mediated negative feedback loop

A Novel Leu-Enkephalin Prodrug Produces Pain-Relieving and Antidepressant Effects

Contact Info

Product

Resources

About