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.

Fig. 1

Via Gi/o proteins coupling, NOP receptor inhibits adenylate cyclase, hence reducing intracellular cAMP, increases inwardly rectifying K+ channels conductance, and closes Cav2.2 N-type channels. The β-γ-subunit regulates phosphatidylinositol 3-Kinase (PI3K) and Src-kinase pathways. Moreover, NOP receptor activates ERK1/2, JNK (c-Jun N-terminal kinase), p38 MAPK, and NF-Κb pathways. When phosphorylated by G protein-coupled receptor kinase 3 (GRK3), NOP receptor participates in arrestin-dependent JNK-ROCK (Rho-associated coiled-coil-containing protein kinase) signaling

Fig. 2

Bioavailability of buprenorphine, after sublingual tablet absorption, is nearly 50%, while the naloxone has extremely poor bioavailability. However, in the case of misuse, if the product is crushed and then injected, both buprenorphine and naloxone become active, leading to an uncomfortable mild-to-moderate withdrawal reaction