Pain Pathways Rewired: Moving Past Peripheral Ion Channel Strategies
A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".
Deadline for manuscript submissions: 31 March 2026
Special Issue Editor
Interests: TRPA1; TRP ion channels; drug discovery; cardiac electrophysiology; chronic pain; neuropathic and osteoarthritis pain
Special Issues, Collections and Topics in MDPI journals
Special Issue Information
Dear Colleagues,
Recent advances in drug discovery are beginning to offer new pharmacological options for treatment of pain. A major milestone is the approval of Suzetrigine, a highly selective NaV1.8 channel blocker, which represents a promising non-opioid treatment for acute pain.
Despite this progress, the field still faces significant challenges. Many clinical trials have failed, and several candidates that were once considered promising—such as TRPM8 and TRPA1 antagonists, NaV1.7 channel blockers, and the NGF-neutralizing antibody Tanezumab—have not met expectations. This raises a critical question: Why has it been so difficult to consistently develop safe and effective analgesics?
One approach to reduce risk has been to use human genetics to validate pain targets. However, even genetically linked targets have failed in clinical trials, suggesting that genetic validation alone is not enough. Clearly, there are missing pieces in translating preclinical and genetic insights into effective therapies.
A single gain-of-function mutation in an excitatory ion channel can trigger pain. However, in disease conditions affecting the general population, it is possible that multiple excitatory ion channels are activated simultaneously. This suggests that targeting several transducing ion channels at once could provide more effective pain relief than blocking just one.
For instance, the analgesic effect of Tanezumab may be due to its ability to regulate the expression of multiple ion channels. Similarly, compounds like capsaicin and resiniferatoxin defunctionalize sensory nerve afferents that express several ion channels, contributing to their pain-relieving properties.
Moreover, several excitatory ion channels were recently found to contribute to subthreshold membrane potential oscillations, which are believed to drive repetitive action potential firing in chronic pain. This finding suggests that selectively blocking a single transducing ion channel may be redundant, as its function could be compensated by other channels.
Historically, drug development favored peripherally restricted ion channel blockers to avoid central nervous system (CNS) side effects and improve drug-likeness. However, lipophilic CNS-penetrating compounds often suffer from poor solubility, metabolic instability, CYP3A inhibition, and potential toxicity.
Yet, peripheral pain-sensing neurons synapse in the spinal cord, where they regulate glutamate release in the dorsal horn. This suggests that a neuron-centric, peripheral-only approach may not fully leverage the therapeutic potential of novel analgesics.
A more effective strategy may involve blocking pain signal transduction, conduction, and amplification along the entire pain pathway, from peripheral terminals to central synapses. Supporting this, Suzetrigine blocks NaV1.8 channels in both peripheral and central terminals at therapeutic doses.
Additionally, a recent genome-wide association study found that most pain intensity-related target proteins are expressed in the CNS, further emphasizing the importance of central mechanisms. The contribution of non-neuronal cells to chronic pain is only beginning to be understood. Recent studies using human multiomic data have revealed that dendritic cells, macrophages, osteoclasts, fibroblasts, endothelial cells, and glial cells play key roles in driving pain within the microenvironment of peripheral nerve terminals and in the dorsal root ganglion.
This Special Issue aims to explore innovative approaches to chronic pain treatment that go beyond peripheral nerves, with the goal of achieving more effective and balanced analgesia.
Dr. Ari-Pekka Koivisto
Guest Editor
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Keywords
- central mechanism of action
- central terminal
- chronic pain
- multichannel block
- NaV channel
- non-neuronal cell
- novel analgesics
- pain transduction
- subthreshold membrane potential oscillation
- TRP channel
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