Current and Future Therapeutic Options in Pain Management: Multi-mechanistic Opioids Involving Both MOR and NOP Receptor Activation

Abstract

Opioids are widely used in chronic pain management, despite major concerns about their risk of adverse events, particularly abuse, misuse, and respiratory depression from overdose. Multi-mechanistic opioids, such as tapentadol and buprenorphine, have been widely studied as a valid alternative to traditional opioids for their safer profile. Special interest was focused on the role of the nociceptin opioid peptide (NOP) receptor in terms of analgesia and improved tolerability. Nociceptin opioid peptide receptor agonists were shown to reinforce the antinociceptive effect of mu opioid receptor (MOR) agonists and modulate some of their adverse effects. Therefore, multi-mechanistic opioids involving both MOR and NOP receptor activation became a major field of pharmaceutical and clinical investigations. Buprenorphine was re-discovered in a new perspective, as an atypical analgesic and as a substitution therapy for opioid use disorders; and buprenorphine derivatives have been tested in animal models of nociceptive and neuropathic pain. Similarly, cebranopadol, a full MOR/NOP receptor agonist, has been clinically evaluated for its potent analgesic efficacy and better tolerability profile, compared with traditional opioids. This review overviews pharmacological mechanisms of the NOP receptor system, including its role in pain management and in the development of opioid tolerance. Clinical data on buprenorphine suggest its role as a safer alternative to traditional opioids, particularly in patients with non-cancer pain; while data on cebranopadol still require phase III study results to approve its introduction on the market. Other bifunctional MOR/NOP receptor ligands, such as BU08028, BU10038, and AT-121, are currently under pharmacological investigations and could represent promising analgesic agents for the future.

Effects of Different Opioid Drugs on Oxidative Status and Proteasome Activity in SH-SY5Y Cells

“…Despite research advancement and the suggestions of new druggable targets for acute and chronic pain treatment, opioids still represent gold-standard analgesics. However, their prolonged use is often hampered by several adverse side effects including the development of analgesic tolerance, opioid-induced hyperalgesia (OIH) and dependence [ 2 ]. Although these phenomena are not yet completely understood, molecular alterations in opioid receptor signaling, neurotransmitter release changes, as well as glia and microglia activation have been suggested as possible mechanisms involved in the development of side effects related to chronic opioid treatment [ 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 ].…”

How to use opioid analgesics effectively and safely. Individual choice of the opioid in patients with cancer pain from the perspective of 2022

“…Dzięki tej ostatniej właściwości (antagonizm) metadon może spowolnić rozwój tolerancji na działanie opioidów. Z tego powodu jest zalecany między innymi w leczeniu bólu jako opioid II wyboru w przypadku, kiedy obserwuje się trudności w leczeniu silnego bólu i narastającą tolerancję na inne (wcześniej stosowane) opioidy [42,50]. Warto dodać, że lek ten jako antagonista receptorów NMDA prawdopodobnie "wygasza" również zjawisko ośrodkowej sensytyzacji oraz hiperalgezji indukowanej opioidami, dwa niekorzystne zjawiska dla przebiegu analgezji, jednak ten aspekt działania metadonu nie został dotąd wystarczajaco potwierdzony [51,52].…”

Design of Analgesic Trivalent Peptides with Low Withdrawal Symptoms: Probing the Antinociceptive Profile of Novel Linear and Cyclic Peptides as Opioid Pan Ligands

“…One novel approach is multifunctional ligands with activity at multiple opioid receptors . However, even compounds endowed with high binding affinity for μ-opioid receptor (MOR) and mixed MOR/δ-opioid receptor (DOR) agonists demonstrate unwanted side effects which render them poorly suitable as drug candidates. , Activation of DOR produces spinally mediated antinociception that is enabled by inflammation, which is generally less pronounced than that produced by MOR stimulation; DOR antagonists may also prevent MOR-mediated tolerance development and dependence/withdrawal . The phenomena of reward/reinforcement involve selective DOR agonists with which the presence of MORs is also required to generate reinforcing properties. − …”

“…5,6 Activation of DOR produces spinally mediated antinociception that is enabled by inflammation, which is generally less pronounced than that produced by MOR stimulation; 6 DOR antagonists may also prevent MORmediated tolerance development and dependence/withdrawal. 7 The phenomena of reward/reinforcement involve selective DOR agonists with which the presence of MORs is also required to generate reinforcing properties. 8−10 K-opioid receptor (KOR) agonists have been shown to produce pain relief and can reduce drug-seeking; however, they can also provoke dysphoria and sedation.…”