Peptides for pain sensation and peptides for pain relief: Fighting fire with fire

Peptides play crucial roles in pain regulation. Following tissue injury or insults, many endogenous excitatory peptides, such as calcitonin gene-related peptide, substance P, nerve growth factor, bradykinin, hemokinin-1, cholecystokinin, and endothelin, are generated, which are eventually responsible for pain sensation. To alleviate pain physiologically, many endogenous inhibitory peptides are generated, including opioid peptides, neuropeptide Y, oxytocin, and orexin A. As peptides can induce pain, the use of pain-alleviating peptides is like fighting fire with fire. Although increasing evidence has revealed new mechanisms of peptides in the transmission and perception of pain, comprehensive descriptions regarding how endogenous peptides modulate pain are lacking. This review describes the role of endogenous peptidergic pathways in pain processing, persistence, and resolution. Targeting endogenous peptides by activating inhibitory pathways or antagonizing excitatory pathways might be a promising natural way to alleviate pain. This review also focuses on peptide-associated pathways and the therapeutic applications of peptides that reduce pain in the treatment of various diseases. Additionally, we sought to investigate peptide-based target-specific drug discovery to treat pain-related disorders. • Endogenous excitatory and inhibitory peptides regulate pain through complex signaling cascade mechanisms. • The mechanism of pharmacological action of endogenous and exogenous peptides relating to pain is summarized. • The peptide treatments target pain by enhancing analgesic pathways or blocking harmful algesic mechanisms are discussed. • Future work should focus on discovering peptide-based drugs to treat pain and overcome limitations of current analgesics.