Peripheral Ca_V2.2 channels in 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 neuro-immune 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 capsaicin via IL-1α cytokine signaling. Ca_V2.2 channels are not, however, involved in mechanical hypersensitivity that developed in the same animal model. Here, we show that Ca_V2.2 channels are also critical for heat hypersensitivity induced by the intradermal (id) Complete Freund's Adjuvant (CFA) model of chronic neuroinflammation that involves ongoing cytokine signaling for days. Ongoing CFA-induced cytokine signaling cascades in skin lead to pronounced edema, and hypersensitivity to sensory stimuli. Peripheral Ca_V2.2 channel activity in skin is required for the full development and week-long time course of heat hypersensitivity induced by id CFA. Ca_V2.2 channels, by contrast, are not involved in paw edema and mechanical hypersensitivity. CFA induced increases in cytokines in hind paws including IL-6 which was dependent on Ca_V2.2 channel activity. Using IL-6 specific neutralizing antibodies, we show that IL-6 contributes to heat hypersensitivity and, neutralizing both IL-1α 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 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 skin.