Kappa opioids suppress histaminergic itch by inhibiting mediodorsal thalamus-projecting claustrum glutamatergic neurons.

Itch, an uncomfortable sensation that induces scratching, is suppressed by activation of kappa opioid receptors (KORs). KOR agonists, such as Nalfurafine, offer potent central antipruritic effects, yet the underlying mechanisms are not fully understood. In this study, we report the important role of glutamatergic neurons in the claustrum (CLA) in itch modulation. Chemogenetic inhibition of these neurons significantly reduces histamine-induced scratching behavior, whereas their activation heightens scratching behavior. These CLAGlu neurons connect to the mediodorsal thalamus (MD), forming a pathway that modulates itch sensations. Optogenetic manipulation of the CLAGlu-MD pathway demonstrates that its inhibition decreases scratching behavior, whereas activation increases it. Notably, CLAGlu neurons highly express KORs, and treatment with Nalfurafine markedly inhibits histamine-induced CLAGlu neuronal activation. Conditional knockdown of KORs in CLAGlu neurons or the CLAGlu-MD circuit diminishes Nalfurafine's antipruritic effects. These findings provide insight into the neural circuits involved in histaminergic itch and the action of KOR agonists.