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

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.

The aim of this study was to assess whether overexpressing CASPR2 could be a potential approach to treat pain.

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.

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.

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.