Peripheral Ca2.2 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 Ca2.2 channel activity in skin controls rapid and transient heat hypersensitivity induced by intradermal capsaicin via IL-1α cytokine signaling. Ca2.2 channels are not, however, involved in mechanical hypersensitivity that developed in the same animal model. Here, we show that Ca2.2 channels are also critical for heat hypersensitivity induced by the intradermal () 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 Ca2.2 channel activity in skin is required for the full development and week-long time course of heat hypersensitivity induced by CFA. Ca2.2 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 Ca2.2 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 Ca2.2 channel activity and the release of IL-6 in skin and show that Ca2.2 channels have a privileged role in the induction and maintenance of heat hypersensitivity during chronic forms of neuroinflammation in skin.