Salib, A.-M. N. | bioRxiv Science

bioRxiv2024

Peripheral CaV2.2 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 CaV2.2 channel activity in skin controls rapid and transient heat hypersensitivity induced by intradermal capsaicin via IL-1 cytokine signaling. CaV2.2 channels are not, however, involved in mechanical hypersensitivity that developed in the same animal model. Here, we show that CaV2.2 channels are also critical for heat hypersensitivity induced by the intradermal (id) Complete Freunds 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 CaV2.2 channel activity in skin is required for the full development and week-long time course of heat hypersensitivity induced by id CFA. CaV2.2 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 CaV2.2 channel activity. Using IL-6 specific neutralizing antibodies, we show that IL-6 contributes to heat hypersensitivity and, neutralizing both IL-1 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 CaV2.2 channel activity and the release of IL-6 in skin and show that CaV2.2 channels have a privileged role in the induction and maintenance of heat hypersensitivity during chronic forms of neuroinflammation in skin. Significance StatementNeuroinflammation can lead to chronic maladaptive pain. Neurotransmitters, ion channels, cytokines, and cytokine receptors are implicated in neuron-immune signaling, but their importance in mediating specific behavioral responses are not fully elucidated. We show that the activity of peripheral CaV2.2 calcium ion channels in skin play a unique role in the induction and maintenance of heat hypersensitivity in the CFA model of prolonged neuroinflammation, without accompanying effects on edema and mechanical hypersensitivity. Blocking peripheral CaV2.2 channel activity reduces local cytokine levels in hind paws injected with CFA including IL-6 and neutralizing IL-6 reduces CFA- induced heat hypersensitivity. Our studies define key signaling molecules that act locally in skin to trigger and maintain heat hypersensitivity during chronic neuroinflammation.

neuroscience↗

bioRxiv2023

Interleukin-1α links peripheral CaV2.2 channel activation to rapid adaptive increases in heat sensitivity in skin

Neurons have the unique capacity to adapt output in response to changes in their environment. Within seconds, sensory nerve endings can become hypersensitive to stimuli in response to potentially damaging events. The underlying behavioral response is well studied, but several of the key signaling molecules that mediate sensory hypersensitivity remain unknown. We previously discovered that peripheral voltage-gated CaV2.2 channels in nerve endings in skin are essential for the rapid, transient increase in sensitivity to heat, but not to mechanical stimuli, that accompanies intradermal capsaicin. Here we report that the cytokine interleukin-1 (IL-1), an alarmin, is necessary and sufficient to trigger rapid heat and mechanical hypersensitivity in skin. Of 20 cytokines screened, only IL-1 was consistently detected in hind paw interstitial fluid in response to intradermal capsaicin and, similar to behavioral sensitivity to heat, IL-1 levels were also dependent on peripheral CaV2.2 channel activity. Neutralizing IL-1 in skin significantly reduced capsaicin-induced changes in hind paw sensitivity to radiant heat and mechanical stimulation. Intradermal IL-1 enhances behavioral responses to stimuli and, in culture, IL-1 enhances the responsiveness of Trpv1-expressing sensory neurons. Together, our data suggest that IL-1 is the key cytokine that underlies rapid and reversible neuroinflammatory responses in skin.

neuroscience↗