Recent progress in non-opioid analgesic peptides

Pain is a prevalent complex medical problem, characterized by physically debilitating and mentally destabilizing conditions. Current pain therapeutics mainly include non-steroidal anti-inflammatory drugs and narcotics (opioids), but they exhibit limitations in efficacy, unwanted side effects and the problem of drug abuse. To overcome these issues, the discovery of different molecular players within pain pathways could lead to new opportunities for therapeutic intervention. Among other strategies, peptides could be powerful pharmaceutical agents for effective opioid-free medications for pain treatment. This review is a compendium of representative non-opioid analgesic peptides acting directly or indirectly at different ion channels and receptors distributed in nociceptive pathways. They include peptides targeting Ca²⁺, Na⁺ and K⁺ voltage-gated ion channels, the neuronal nicotinic receptors (nAChR), transient receptor potential channels (TRP), and different non-opioid G-protein coupled receptors (GPCRs), like the calcitonin gen-related peptide (CGRP), cannabinoid, bradykinin and neurotensin receptors, among others. Peptides engineered from protein-protein interactions among pain-related receptors and regulatory proteins also led to new therapeutic approaches for pain management. Following some successful examples, already in the clinics or under clinical trials, the improved understanding of pain mechanisms, and the advances in peptide permeation and/or delivery, could afford new analgesic peptides in the near future.