Pain-Modulating Peptides: Mechanisms of Action and Advances in Analgesic Drug Development

Chronic pain has become a global public health challenge, with a population prevalence of 7% to 24%. Current mainstream analgesics, such as opioids and anticonvulsants, are limited by significant drawbacks like addiction and multi-system adverse effects, creating a clinical need for novel, safer, and more targeted analgesic drugs. Endogenous peptides exhibit a bidirectional role in pain modulation—they can act as key mediators driving the initiation and progression of pain, but also enable physiological analgesia via endogenous pathways. This regulatory paradigm of "pain mediated by peptides, pain relieved by peptides" forms the basis for a novel "fight fire with fire" strategy in analgesic drug development. This article, based on relevant research, systematically summarizes the core logic of pain modulation by endogenous peptides, the R&D strategies for analgesic peptides, the current status of clinical translation, existing bottlenecks, and future development directions.

1. Bidirectional Regulation of Pain by Endogenous Peptides

Endogenous peptides are core components of the body's pain-modulating network. Their primary action is to mediate neuron-immune interactions by binding to corresponding receptors and ion channels, thereby driving two opposing physiological processes: pain sensitization and pain relief.

On one hand, following tissue injury, inflammation, or nerve damage, the body releases excitatory pro-algesic peptides, which become central drivers of pain. This category, represented by substance P, calcitonin gene-related peptide (CGRP), nerve growth factor (NGF), bradykinin, and cholecystokinin, amplifies pain signals through three main pathways: 1) Directly activating their corresponding receptors on nociceptors, upregulating the activity of pro-algesic ion channels like TRPV1 and voltage-gated sodium/calcium channels, inducing neuronal hyperexcitability, and directly triggering pain perception. 2) Driving neurogenic inflammation by recruiting and activating immune cells such as mast cells and macrophages, which release pro-inflammatory cytokines and chemokines, establishing a "inflammation-pain" positive feedback loop. 3) Amplifying nociceptive signals at the spinal and central levels, inducing peripheral and central sensitization, leading to pain chronicity.

On the other hand, the body possesses a balancing system of inhibitory analgesic peptides, constituting the core of the endogenous analgesic system. The most crucial are the endogenous opioid peptides (e.g., β-endorphin, enkephalins, dynorphins), which inhibit adenylate cyclase pathways via opioid receptor binding, inducing neuronal hyperpolarization while reducing the release of pro-algesic neurotransmitters like substance P and glutamate, directly blocking nociceptive signal transmission. Additionally, peptides such as neuropeptide Y, oxytocin, orexin, and galanin can exert physiological analgesic effects by modulating descending pain inhibitory pathways, inhibiting neuroinflammation, or antagonizing pro-algesic ion channels.

The regulatory actions of these two peptide classes are highly dependent on the neuron-immune interaction network: activated neurons at injury sites release pro-algesic peptides that drive immune cell activation, while the activated immune cells can remodel their phenotype and release large quantities of endogenous analgesic peptides, creating a targeted analgesic microenvironment at the injury site, achieving coordinated regulation of inflammation resolution and pain relief.

2. Research and Development Strategies for Analgesic Peptides

Based on the bidirectional regulation mechanism of endogenous peptides, current R&D for analgesic peptides has evolved along four main directions, all centered on the goal of "enhancing analgesic efficacy and reducing adverse effects," with some strategies enabling multi-target synergistic action.

2.1 Antagonizing Excitatory Pro-algesic Pathways

This strategy aims to block the generation and transmission of pain signals at the source. The core approach involves developing antagonistic peptides targeting pro-algesic peptides and their receptors, covering key targets such as CGRP receptors, TrkA/TrkB receptors, NK1 receptors, and bradykinin receptors. These peptides can precisely block the binding of pro-algesic peptides to their receptors, inhibiting downstream pain signaling cascades. They have demonstrated analgesic activity in models of migraine, osteoarthritis pain, and neuropathic pain, and can avoid the central adverse effects associated with non-peptide small molecules. Some dual-target peptides can simultaneously block pro-algesic pathways and activate analgesic pathways, further enhancing efficacy.

2.2 Activating Endogenous Inhibitory Analgesic Pathways

This is currently the most central direction in R&D. The core focus is developing agonist peptides that mimic the action of endogenous analgesic peptides, with opioid receptor-targeting peptides being a major priority. Through structural modifications to achieve receptor bias or multi-target synergy, these peptides can retain potent analgesic activity while significantly reducing the severe adverse effects of traditional opioids, such as addiction and respiratory depression. Several candidate peptides have entered clinical studies. Furthermore, agonist peptides targeting receptors for neuropeptide Y, oxytocin, and galanin have also demonstrated clear analgesic effects in preclinical studies, forming an important branch of non-opioid analgesic peptide R&D.

2.3 Targeting Pain-Related Ion Channels

Ion channels are key mediators of nociceptive signal transmission. Analgesic peptides in this category are often derived from natural animal toxins and are characterized by high target selectivity and potent efficacy. Key targets covered include TRP channels, voltage-gated calcium/sodium channels, acid-sensing ion channels (ASICs), and P2X channels. The only currently marketed analgesic peptide, ziconotide, works by blocking Cav2.2 channels. Multiple peptides targeting TRPV1 and ASIC channels can effectively relieve inflammatory and neuropathic pain while avoiding the side effects associated with small-molecule antagonists, representing a highly promising R&D direction.

2.4 Modulating Key Signaling Pathways in Neuroinflammation

Neuroinflammation is a central mechanism underlying chronic pain persistence. Peptides in this category primarily target inflammatory pathways such as TLR4-MyD88, the NLRP3 inflammasome, and PD-1-PD-L1. They inhibit spinal glial cell activation and regulate macrophage phenotype remodeling, addressing the pathological basis of chronic pain at its root. They have demonstrated long-lasting analgesic effects in various chronic pain models with minimal risk of abuse.

Furthermore, structural engineering modifications—such as cyclization, D-amino acid substitution, PEGylation, and lipidation—can significantly improve the metabolic stability, in vivo half-life, and bioavailability of peptides, addressing the core druggability defects of peptide drugs. This is a foundational optimization strategy applicable to all analgesic peptide R&D.

3. Current Status of Clinical Translation for Analgesic Peptides

The clinical translation progress for analgesic peptides lags significantly behind that of peptide drugs in other therapeutic areas, overall presenting a profile of "abundant preclinical pipelines but scarce marketed products."

Globally, only one analgesic peptide drug, ziconotide, is approved. It is a Cav2.2 channel antagonist derived from conotoxin, administered via intrathecal injection for the treatment of refractory severe chronic pain. It carries no risk of addiction or respiratory depression, but its clinical application is limited by the invasive route of administration and the potential for certain central nervous system adverse effects.

In the clinical pipeline, several analgesic peptides are in various stages of clinical investigation. The biased opioid receptor agonist peptide CYT-1010 has completed Phase I trials, demonstrating good analgesic activity and safety with no respiratory depression, and has now entered Phase II. Orally available Cav2.2 channel antagonist peptide RD2 and galanin receptor agonist peptides from the NAX series have completed preclinical efficacy validation and are advancing towards clinical translation. Additionally, hundreds of analgesic peptide candidates are in preclinical stages, covering the vast majority of pain-related targets, although long-term safety and druggability studies for most remain incomplete.

4. Challenges in Analgesic Peptide R&D and Clinical Translation

Despite the significant R&D advantages demonstrated by analgesic peptides, their clinical translation faces four core bottlenecks, which are also key issues urgently needing breakthroughs in this field.

4.1 Inherent Deficiencies in Druggability

Peptide drugs are susceptible to degradation by endogenous proteases, resulting in extremely short in vivo half-lives. Their strong hydrophilicity and poor biomembrane permeability lead to very low oral bioavailability. The vast majority of peptides can only be administered via injection, severely impacting patient adherence. Additionally, the physicochemical properties of some peptides are unstable, posing challenges for formulation storage and large-scale manufacturing.

4.2 Significant Efficacy Gap Between Preclinical and Clinical Outcomes

Current research is largely based on animal pain models, yet there are fundamental differences in pathophysiology between these models and human chronic pain conditions. The potent analgesic effects often seen preclinically are frequently difficult to replicate in human clinical trials. Moreover, most preclinical studies focus solely on analgesic efficacy, with insufficient investigation into long-term safety and pharmacokinetic profiles, further hindering clinical translation.

4.3 Safety Concerns and Gaps in Target R&D

Some pain-related targets have bidirectional regulatory roles. Insufficient target specificity of peptide drugs might inadvertently induce pain sensitization. Peptides administered centrally may carry potential risks related to cognition and the endocrine system, and systematic data on immunogenicity with long-term administration is lacking. Simultaneously, peptide R&D for a large number of pain-related targets (e.g., GABA receptors, Piezo ion channels) is almost non-existent, indicating that target exploration remains insufficient.

4.4 Difficulties in Large-Scale Manufacturing and Cost Control

Current mainstream synthesis processes for peptide drugs are costly. The synthesis of long-chain modified peptides is challenging, batch-to-batch consistency is hard to guarantee, and the stability of industrial-scale processes is often inadequate. This results in treatment costs for peptide drugs being far higher than those for traditional small molecules. Even if approved, they struggle to achieve broad clinical accessibility.

5. Future Directions for Analgesic Peptide R&D

To break through the aforementioned bottlenecks, future R&D of analgesic peptides will focus on four core directions, aiming for breakthroughs across the entire chain from basic research to clinical translation.

5.1 Precise Engineering Optimization of Peptide Structure

Leveraging structural biology techniques like cryo-electron microscopy and molecular docking to elucidate the binding modes of peptides with their targets, enabling rational design of peptides. Using chemical methods such as backbone modification and site-directed mutagenesis to systematically enhance the metabolic stability, membrane permeability, and oral bioavailability of peptides, overcoming the core limitation of administration routes.

5.2 Novel Target Discovery and Development of Multi-Target Peptides

On one hand, continue to fill the R&D gaps for existing targets and discover novel peptide targets in pain modulation. On the other hand, vigorously develop multifunctional, multi-target peptides. Based on the complex pathology of chronic pain, design peptides that simultaneously cover "pro-algesic pathway blockade, analgesic pathway activation, and inflammation inhibition," achieving the dual goals of synergistic analgesia and reduced adverse effects.

5.3 Systemic Breakthroughs in Novel Drug Delivery Technologies

Focus on developing oral delivery systems, utilizing technologies like permeation enhancers, nanocarrier encapsulation, and enteric coatings to achieve efficient oral delivery of peptides. Simultaneously, advance the development of non-invasive administration technologies such as intranasal and transdermal delivery to improve patient adherence. Employ targeted delivery carriers to achieve precise delivery of peptides to pain-related target sites, reducing the adverse effects associated with systemic administration.

5.4 Interdisciplinary Intelligent R&D Models

Utilize artificial intelligence for high-throughput virtual screening and rational design of analgesic peptides, significantly shortening the R&D cycle. Employ technologies like organoids and microfluidic chips to construct in vitro screening models that simulate the human pain pathology environment, narrowing the efficacy gap between preclinical and clinical outcomes. Through multidisciplinary collaboration, solve the full spectrum of technical challenges from molecular design to industrial-scale production of peptides.

6. Summary

The bidirectional regulatory role of endogenous peptides provides an innovative "fight fire with fire" strategy for pain treatment. Peptide drugs, with their core advantages of high target specificity, low off-target effects, and reduced addiction risk, hold the promise of overcoming the clinical limitations of traditional analgesics and represent a core avenue for future novel analgesic drug development.

Currently, the field still faces multiple bottlenecks including insufficient druggability, difficult clinical translation, and high production costs. Marketed products are scarce, and a large number of R&D pipelines remain in the preclinical stage. However, with the convergence of interdisciplinary fields such as structural biology, materials science, and artificial intelligence, the R&D bottlenecks for analgesic peptides are gradually being broken. In the future, through structural optimization, target innovation, advancements in delivery technologies, and intelligent R&D, it is hopeful to develop a new generation of efficient, safe, conveniently administered, and cost-effective novel analgesic peptide drugs. This would provide superior treatment options for patients with chronic pain and drive innovative development in the field of pain management.

Original Article：

Rahman MM, Shim YW, Kim YH, Park CK. Peptides for pain sensation and peptides for pain relief: Fighting fire with fire. Biomed Pharmacother. 2026 Feb;195:118990.