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HCN pacemaker channels and pain: a drug discovery perspective
A D Wickenden1, M P Maher, S R Chaplan
1Johnson & Johnson Pharmaceutical Research & Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, USA.
Current Pharmaceutical Design
|June 13, 2009
Summary
Hyperpolarization-activated, cation nonselective (HCN) channels in sensory nerves are potential targets for new pain relief medications. Selective blockade of HCN1 channels may reduce nerve injury pain without affecting heart rate.
Area of Science:
- Neuroscience
- Pharmacology
- Molecular Biology
Background:
- Hyperpolarization-activated, cation nonselective (HCN) channels generate the Ih current, crucial in neuronal excitability.
- The Ih current is prominent in peripheral sensory nerves, particularly large diameter neurons.
Purpose of the Study:
- To review evidence supporting HCN channels as targets for novel analgesic agents.
- To explore the potential of selective HCN1 channel blockers for treating neuropathic pain.
Main Methods:
- Review of existing electrophysiological and molecular data on HCN channel function in sensory neurons.
- Analysis of the role of different HCN isoforms (HCN1 vs. HCN4) in pain and cardiac function.
Main Results:
- HCN channels, especially HCN1, contribute significantly to Ih in large diameter sensory fibers, supporting abnormal firing after nerve injury.
- HCN4 channels are primarily involved in cardiac pacemaker activity.
- Current HCN blockers lack isoform selectivity, impacting heart rate and limiting their use for pain.
Conclusions:
- HCN1-selective blockers offer a promising strategy for developing analgesics targeting neuropathic pain.
- Overcoming selectivity challenges in HCN channel blocker development is critical for therapeutic success.
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