Peripheral Ca_V2.2 Channels in the Skin Regulate Prolonged Heat Hypersensitivity during Neuroinflammation

Neuroinflammation can lead to chronic maladaptive pain affecting millions of people worldwide. Neurotransmitters, cytokines, and ion channels are implicated in neuroimmune cell signaling, but their roles in specific behavioral responses are not fully elucidated. Voltage-gated Ca_V2.2 channel activity in skin controls rapid and transient heat hypersensitivity induced by intradermal (i.d.) capsaicin via IL-1ɑ cytokine signaling. Ca_V2.2 channels are not, however, involved in mechanical hypersensitivity that developed in the i.d. capsaicin animal model. Here, we show that Ca_V2.2 channels are also critical for heat hypersensitivity induced by i.d. complete Freund adjuvant (CFA). i.d. CFA, a model of chronic neuroinflammation, involves ongoing cytokine signaling for days leading to pronounced edema and hypersensitivity to sensory stimuli. Peripheral Ca_V2.2 channel activity in the skin was required for the full development and week-long time course of heat hypersensitivity induced by i.d. CFA, but paw edema and mechanical hypersensitivity were independent of Ca_V2.2 channel activity. CFA induced increases in several cytokines in hindpaw fluid including IL-6 which was also dependent on Ca_V2.2 channel activity. Using IL-6-specific neutralizing antibodies in vivo, we show that IL-6 contributes to heat hypersensitivity and that neutralizing both IL-1ɑ and IL-6 was even more effective at reducing the magnitude and duration of CFA-induced heat hypersensitivity. Our findings demonstrate a functional link between Ca_V2.2 channel activity and the release of IL-6 in the skin and show that Ca_V2.2 channels have a privileged role in the induction and maintenance of heat hypersensitivity during chronic forms of neuroinflammation in the skin.