Non-Opioid Peptides Targeting Opioid Effects.

Katarzyna Kaczyńska,Piotr Wojciechowski

doi:10.3390/ijms222413619

Abstract

Opioids are the most potent widely used analgesics, primarily, but not exclusively, in palliative care. However, they are associated with numerous side effects, such as tolerance, addiction, respiratory depression, and cardiovascular events. This, in turn, can result in their overuse in cases of addiction, the need for dose escalation in cases of developing tolerance, and the emergence of dose-related opioid toxicity, resulting in respiratory depression or cardiovascular problems that can even lead to unintentional death. Therefore, a very important challenge for researchers is to look for ways to counteract the side effects of opioids. The use of peptides and their related compounds, which have been shown to modulate the effects of opioids, may provide such an opportunity. This short review is a compendium of knowledge about the most important and recent findings regarding selected peptides and their modulatory effects on various opioid actions, including cardiovascular and respiratory responses. In addition to the peptides more commonly reported in the literature in the context of their pro- and/or anti-opioid activity—such as neuropeptide FF (NPFF), cholecystokinin (CCK), and melanocyte inhibiting factor (MIF)—we also included in the review nociceptin/orphanin (N/OFQ), ghrelin, oxytocin, endothelin, and venom peptides.

Highlights

The repertoire of various peptides that fall into the category of compounds that affect opioid properties include neuropeptide FF (NPFF), cholecystokinin (CCK), melanocyte inhibiting factor (MIF) [9,10], nociceptin/orphanin (N/OFQ) [11] and several other peptides such as ghrelin, oxytocin, and endothelin A [12]
Tyr-MIF-1 shows mostly anti-opioid activity; it significantly decreases the analgesic effect of morphine in acute pain models [59], and impairs the development of morphine antinociceptive tolerance [61]
Potent opioid analgesics remain the mainstay of therapy for the relief of moderate to severe acute nociceptive pain

Summary

Tyr-MIF-1 Family Peptides

The Tyr-MIF-1 family consists of at least four small peptides exhibiting heterogeneous properties and binding sites (Table 2). Tyr-MIF-1 shows mostly anti-opioid activity; it significantly decreases the analgesic effect of morphine in acute pain models [59], and impairs the development of morphine antinociceptive tolerance [61]. A second peptide with affinity for its own and mu receptors is Tyr-W-MIF-1 When administered icv, it can antagonize morphine- and DAMGO-induced analgesia, most likely through blockade of the supraspinal mu 1 receptor [56]. It can antagonize morphine- and DAMGO-induced analgesia, most likely through blockade of the supraspinal mu 1 receptor [56] It shows opioid-like activity and, when administered centrally, it can induce naloxone-reversible analgesia in rats, occurring mostly via stimulation of mu 2 receptor [56,57]. The last member of the family that does not bind to opioid receptors, Tyr-K-MIF-1, inhibits the analgesic effect of morphine and induces antinociception through histamine release and stimulation of postsynaptic H1- and H2-receptors [55,58]. It was displayed that MIF-1, at high doses, has blood pressure-lowering effects in experimental animals [66,67]

Ghrelin

Endothelin

Venom Peptides

10. Conclusions