Characterization of methadone as a β-arrestin-biased μ-opioid receptor agonist

Abstract

BackgroundMethadone is a unique µ-opioid receptor agonist. Although several researchers have insisted that the pharmacological effects of methadone are mediated through the blockade of NMDA receptor, the underlying mechanism by which methadone exerts its distinct pharmacological effects compared to those of other µ-opioid receptor agonists is still controversial. In the present study, we further investigated the pharmacological profile of methadone compared to those of fentanyl and morphine as measured mainly by the discriminative stimulus effect and in vitro assays for NMDA receptor binding, µ-opioid receptor-internalization, and µ-opioid receptor-mediated β-arrestin recruitment.ResultsWe found that fentanyl substituted for the discriminative stimulus effects of methadone, whereas a relatively high dose of morphine was required to substitute for the discriminative stimulus effects of methadone in rats. Under these conditions, the non-competitive NMDA receptor antagonist MK-801 did not substitute for the discriminative stimulus effects of methadone. In association with its discriminative stimulus effect, methadone failed to displace the receptor binding of MK801 using mouse brain membrane. Methadone and fentanyl, but not morphine, induced potent µ-opioid receptor internalization accompanied by the strong recruitment of β-arrestin-2 in µ-opioid receptor-overexpressing cells.ConclusionsThese results suggest that methadone may, at least partly, produce its pharmacological effect as a β-arrestin-biased µ-opioid receptor agonist, similar to fentanyl, and NMDA receptor blockade is not the main contributor to the pharmacological profile of methadone.

Methadone's effects on pentylenetetrazole‐induced seizure threshold in mice: NMDA/opioid receptors and nitric oxide signaling

“…We used a noneffective dose of NTX that did not have a significant impact on seizure threshold . Moreover, methadone has high affinity for µ‐opioid receptors . Therefore, it may be concluded that one of the possible interactions between the application of methadone along with the noneffective dose of NTX is mediated via the µ‐opioid receptors.…”

Do All Opioid Drugs Share the Same Immunomodulatory Properties? A Review From Animal and Human Studies

“…For example unlike opioids such as morphine, fentanyl and methadone, buprenorphine does not recruit β-arrestin to the receptor (86) and as described above buprenorphine has been reported to be devoid of immunosuppressive properties. Indeed morphine is a balanced agonist, and its ability to recruit arrestin after receptor binding is lower than that of fentanyl or methadone that have been suggested to be a β-arrestin biased compounds (85,87). However, morphine and fentanyl have comparable immunosuppressive activity, while methadone is a weaker immunomodulator and therefore the concept of biased agonist is not sufficient to explain differences.…”

Methadone against cancer: Lost in translation

“…TLR signaling and respective downstream effects are modulated by β‐arrestin proteins, for example, by forming a complex with TRAF6, eventually inhibiting NfĸB activity . Since d , l ‐methadone (but not morphine) is known to be a potent (∼1 µM) β‐arrestin‐recruiting opioid receptor desensitizer, the negatively regulating impact of ß‐arrestin on NfĸB functionality might be abolished by chronic opioid receptor activation. In other words, if β‐arrestin is constantly distracted from the NfĸB complex, d , l ‐methadone could indirectly influence the pro‐apoptotic NfĸB pathway by trapping β‐arrestin proteins to opioid receptors.…”