Specific overexpression of contactin-associated protein-like 2 and its effects on pain-related behaviour in mice.

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 (R26(LSL:hCNTNAP2(+/+)) (CASPR2(OE))) and crossed this with either Hoxb8(Cre) or Nav1.8(Cre) 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 I(KD), it did not affect total I(KD.) 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.