Opioid Peptide Hybrids as Multifunctional Analgesic Ligands: Emphasis on Intracellular Signaling.
- 1Department of Biomolecular Chemistry, Medical University of Lodz, ul. Mazowiecka 6/8, 92-215 Lodz, Poland.
Abstract
Opioid peptide hybrids are multifunctional molecules in which an opioid pharmacophore is covalently integrated with a second opioid or non-opioid pharmacophore within a single molecular entity. Their development is driven by a major challenge in analgesic pharmacotherapy: although μ-opioid receptor (MOR) agonists remain among the most effective agents for the treatment of moderate-to-severe pain, their therapeutic use is limited by adverse effects and risks associated particularly with prolonged or high-dose exposure, including tolerance, constipation, respiratory depression, physical dependence, and abuse liability. Especially, chronic and neuropathic pain involves complex interactions among multiple receptor systems, neurotransmitter networks, and intracellular signaling pathways. Accordingly, hybrid peptide ligands provide a rational multitarget strategy aimed at achieving analgesia through the coordinated modulation of complementary pharmacological targets rather than selective modulation of a single receptor system. This approach may enhance analgesic efficacy and potentially improve the therapeutic profile of opioid-based treatments by reducing some of the dose-limiting adverse effects associated with conventional opioid analgesics. In this review, we discuss the functional and pharmacological interactions between opioid receptors and other receptor systems involved in pain perception and modulation, with emphasis on those for which peptide-based hybrid ligands with demonstrated antinociceptive activity have been developed.
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BibTeX
@article{cecherz2026opioid,
title = {{Opioid Peptide Hybrids as Multifunctional Analgesic Ligands: Emphasis on Intracellular Signaling.}},
author = {Igor Cecherz and Jakub Waśkiewicz and Alicja Dudek and Dariusz Polatyński and Karol Wtorek and Justyna Piekielna-Ciesielska},
journal = {Pharmaceuticals (Basel, Switzerland)},
year = {2026},
month = sep,
doi = {10.3390/ph19101550},
url = {https://europepmc.org/article/MED/42943247},
note = {CC BY},
}
RIS
TY - JOUR
TI - Opioid Peptide Hybrids as Multifunctional Analgesic Ligands: Emphasis on Intracellular Signaling.
AU - Igor Cecherz
AU - Jakub Waśkiewicz
AU - Alicja Dudek
AU - Dariusz Polatyński
AU - Karol Wtorek
AU - Justyna Piekielna-Ciesielska
PY - 2026
DA - 2026/09/30
JO - Pharmaceuticals (Basel, Switzerland)
DO - 10.3390/ph19101550
UR - https://europepmc.org/article/MED/42943247
AB - Opioid peptide hybrids are multifunctional molecules in which an opioid pharmacophore is covalently integrated with a second opioid or non-opioid pharmacophore within a single molecular entity. Their development is driven by a major challenge in analgesic pharmacotherapy: although μ-opioid receptor (MOR) agonists remain among the most effective agents for the treatment of moderate-to-severe pain, their therapeutic use is limited by adverse effects and risks associated particularly with prolonged or high-dose exposure, including tolerance, constipation, respiratory depression, physical dependence, and abuse liability. Especially, chronic and neuropathic pain involves complex interactions among multiple receptor systems, neurotransmitter networks, and intracellular signaling pathways. Accordingly, hybrid peptide ligands provide a rational multitarget strategy aimed at achieving analgesia through the coordinated modulation of complementary pharmacological targets rather than selective modulation of a single receptor system. This approach may enhance analgesic efficacy and potentially improve the therapeutic profile of opioid-based treatments by reducing some of the dose-limiting adverse effects associated with conventional opioid analgesics. In this review, we discuss the functional and pharmacological interactions between opioid receptors and other receptor systems involved in pain perception and modulation, with emphasis on those for which peptide-based hybrid ligands with demonstrated antinociceptive activity have been developed.
SN - 1424-8247
ER -