Specific overexpression of contactin-associated protein-like 2 and its effects on pain-related behaviour in mice
Abstract. Introduction:. Hyperexcitability, particularly of DRG neurons, is a key driver of persistent pain states including neuropathic pain. Contactin-associated protein-like 2 (CASPR2) is transmembrane protein known to interact and regulate the function of Kv1 channels, important determinants of...
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| Format: | Article |
| Language: | English |
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Wolters Kluwer
2025-08-01
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| Series: | PAIN Reports |
| Online Access: | http://journals.lww.com/painrpts/fulltext/10.1097/PR9.0000000000001309 |
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| author | Mandy Tseng Steven J. Middleton Adham Farah Sarosh R. Irani John M. Dawes David L. Bennett |
| author_facet | Mandy Tseng Steven J. Middleton Adham Farah Sarosh R. Irani John M. Dawes David L. Bennett |
| author_sort | Mandy Tseng |
| collection | DOAJ |
| description | Abstract. Introduction:. Hyperexcitability, particularly of DRG neurons, is a key driver of persistent pain states including neuropathic pain. Contactin-associated protein-like 2 (CASPR2) is transmembrane protein known to interact and regulate the function of Kv1 channels, important determinants of neuronal excitability. Patients with autoantibodies (-Abs) against CASPR2 commonly have neuropathic pain, and these patient-Abs enhance the excitability of DRG neurons secondary to Kv1 channel disruption, leading to pain-related hypersensitivity. This is also observed after genetic ablation of CASPR2. Conversely, increasing CASPR2 levels in DRG neurons reduces excitability.
Objectives:. The aim of this study was to assess whether overexpressing CASPR2 could be a potential approach to treat pain.
Methods:. We generated a Cre-dependent mouse line to express human CASPR2 (R26LSL:hCNTNAP2(+/+) (CASPR2OE)) and crossed this with either Hoxb8Cre or Nav1.8Cre mice for CASPR2 overexpression in either all DRG neurons or to target nociceptors more selectively.
Results:. In both lines, CASPR2 was significantly overexpressed in DRG neurons, including at the cell membrane. In comparison to control littermates, overexpression of CASPR2 did not affect acute pain–related behaviour to mechanical or thermal stimulation or nerve injury–induced pain-related hypersensitivity. However, in both overexpression mouse lines, there were significantly reduced nocifensive responses to capsaicin. Although CASPR2 overexpression increased the contribution of α-dendrotoxin–sensitive Kv1 channels to the slowly inactivating outward current IKD, it did not affect total IKD.
Conclusion:. CASPR2 overexpression in DRG neurons can affect nociception, reducing pain-related behaviours to the noxious stimulant capsaicin, yet is insufficient to reduce mechanical pain–related hypersensitivity caused by nerve injury. |
| format | Article |
| id | doaj-art-bc3ec164f1b94e77a29d39ab1da8935a |
| institution | Matheson Library |
| issn | 2471-2531 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Wolters Kluwer |
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| series | PAIN Reports |
| spelling | doaj-art-bc3ec164f1b94e77a29d39ab1da8935a2025-07-25T06:42:12ZengWolters KluwerPAIN Reports2471-25312025-08-01104e130910.1097/PR9.0000000000001309PR90000000000001309Specific overexpression of contactin-associated protein-like 2 and its effects on pain-related behaviour in miceMandy Tseng0Steven J. Middleton1Adham Farah2Sarosh R. Irani3John M. Dawes4David L. Bennett5a Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdoma Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdoma Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdoma Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdoma Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdoma Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United KingdomAbstract. Introduction:. Hyperexcitability, particularly of DRG neurons, is a key driver of persistent pain states including neuropathic pain. Contactin-associated protein-like 2 (CASPR2) is transmembrane protein known to interact and regulate the function of Kv1 channels, important determinants of neuronal excitability. Patients with autoantibodies (-Abs) against CASPR2 commonly have neuropathic pain, and these patient-Abs enhance the excitability of DRG neurons secondary to Kv1 channel disruption, leading to pain-related hypersensitivity. This is also observed after genetic ablation of CASPR2. Conversely, increasing CASPR2 levels in DRG neurons reduces excitability. Objectives:. The aim of this study was to assess whether overexpressing CASPR2 could be a potential approach to treat pain. Methods:. We generated a Cre-dependent mouse line to express human CASPR2 (R26LSL:hCNTNAP2(+/+) (CASPR2OE)) and crossed this with either Hoxb8Cre or Nav1.8Cre mice for CASPR2 overexpression in either all DRG neurons or to target nociceptors more selectively. Results:. In both lines, CASPR2 was significantly overexpressed in DRG neurons, including at the cell membrane. In comparison to control littermates, overexpression of CASPR2 did not affect acute pain–related behaviour to mechanical or thermal stimulation or nerve injury–induced pain-related hypersensitivity. However, in both overexpression mouse lines, there were significantly reduced nocifensive responses to capsaicin. Although CASPR2 overexpression increased the contribution of α-dendrotoxin–sensitive Kv1 channels to the slowly inactivating outward current IKD, it did not affect total IKD. Conclusion:. CASPR2 overexpression in DRG neurons can affect nociception, reducing pain-related behaviours to the noxious stimulant capsaicin, yet is insufficient to reduce mechanical pain–related hypersensitivity caused by nerve injury.http://journals.lww.com/painrpts/fulltext/10.1097/PR9.0000000000001309 |
| spellingShingle | Mandy Tseng Steven J. Middleton Adham Farah Sarosh R. Irani John M. Dawes David L. Bennett Specific overexpression of contactin-associated protein-like 2 and its effects on pain-related behaviour in mice PAIN Reports |
| title | Specific overexpression of contactin-associated protein-like 2 and its effects on pain-related behaviour in mice |
| title_full | Specific overexpression of contactin-associated protein-like 2 and its effects on pain-related behaviour in mice |
| title_fullStr | Specific overexpression of contactin-associated protein-like 2 and its effects on pain-related behaviour in mice |
| title_full_unstemmed | Specific overexpression of contactin-associated protein-like 2 and its effects on pain-related behaviour in mice |
| title_short | Specific overexpression of contactin-associated protein-like 2 and its effects on pain-related behaviour in mice |
| title_sort | specific overexpression of contactin associated protein like 2 and its effects on pain related behaviour in mice |
| url | http://journals.lww.com/painrpts/fulltext/10.1097/PR9.0000000000001309 |
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