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Immune or Genetic-Mediated Disruption of CASPR2 Causes Pain Hypersensitivity Due to Enhanced Primary Afferent
John M Dawes1, Greg A Weir1, Steven J Middleton1
1Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK.
Abstract:
Human autoantibodies to contactin-associated protein-like 2 (CASPR2) are often associated with neuropathic pain, and CASPR2 mutations have been linked to autism spectrum disorders, in which sensory dysfunction is increasingly recognized. Human CASPR2 autoantibodies, when injected into mice, were peripherally restricted and resulted in mechanical pain-related hypersensitivity in the absence of neural injury. We therefore investigated the mechanism by which CASPR2 modulates nociceptive function. Mice lacking CASPR2 (Cntnap2-/-) demonstrated enhanced pain-related hypersensitivity to noxious mechanical stimuli, heat, and algogens. Both primary afferent excitability and subsequent nociceptive transmission within the dorsal horn were increased in Cntnap2-/- mice. Either immune or genetic-mediated ablation of CASPR2 enhanced the excitability of DRG neurons in a cell-autonomous fashion through regulation of Kv1 channel expression at the soma membrane. This is the first example of passive transfer of an autoimmune peripheral neuropathic pain disorder and demonstrates that CASPR2 has a key role in regulating cell-intrinsic dorsal root ganglion (DRG) neuron excitability.
Insights
Autoantibodies to contactin-associated protein-like 2 (CASPR2) can cause neuropathic pain. Loss of CASPR2 increases pain sensitivity by enhancing nerve cell excitability, demonstrating its role in pain regulation.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Autoantibodies to contactin-associated protein-like 2 (CASPR2) are linked to neuropathic pain.
- CASPR2 mutations are associated with autism spectrum disorders, involving sensory dysfunction.
Purpose of the Study:
- Investigate the mechanism by which CASPR2 modulates nociceptive function.
- Determine the role of CASPR2 in pain signaling and neuronal excitability.
Main Methods:
- Injected human CASPR2 autoantibodies into mice.
- Studied pain-related hypersensitivity in mice lacking CASPR2 (Cntnap2-/-).
- Examined dorsal root ganglion (DRG) neuron excitability and Kv1 channel expression.
Main Results:
- Human CASPR2 autoantibodies caused peripheral mechanical pain hypersensitivity without neural injury.
- Cntnap2-/- mice showed enhanced hypersensitivity to mechanical stimuli, heat, and algogens.
- CASPR2 deficiency increased primary afferent excitability and dorsal horn nociceptive transmission, cell-autonomously.
Conclusions:
- CASPR2 plays a critical role in regulating cell-intrinsic DRG neuron excitability.
- This study provides the first example of passive transfer of autoimmune peripheral neuropathic pain.
- CASPR2 is a key regulator of nociceptive function and neuronal excitability.
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