Yu-Jun Wang

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 CLA ^Glu neurons connect to the mediodorsal thalamus (MD), forming a pathway that modulates itch sensations. Optogenetic manipulation of the CLA ^Glu -MD pathway demonstrates that its inhibition decreases scratching behavior, whereas activation increases it. Notably, CLA ^Glu neurons highly express KORs, and treatment with Nalfurafine markedly inhibits histamine-induced CLA ^Glu neuronal activation. Conditional knockdown of KORs in CLA ^Glu neurons or the CLA ^Glu -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.

The κ-opioid receptor (KOR) is recognized as a promising therapeutic target for the development of nonaddictive analgesics. However, the clinical utility of typical KOR agonists is limited by central adverse effects. SLL-022CCP is a novel KOR-selective ligand derived from a northebaine-based 4,5-epoxymorphinan scaffold, and we have previously demonstrated its high binding affinity for KOR. In this study, we performed a systematic evaluation of SLL-022CCP through in vitro and in vivo assays. In vitro, SLL-022CCP acted as an extremely potent full agonist at the KOR, inhibiting cAMP production with an EC₅₀ of 0.002 nM, and exhibited high receptor subtype selectivity over the μ-opioid receptor (MOR, EC₅₀ = 1.6 nM) and δ-opioid receptor (DOR, EC₅₀ = 30.0 nM). SLL-022CCP recruited β-arrestin at the KOR with an EC₅₀ of 15.5 nM and at the MOR with an EC₅₀ of 668.0 nM. Molecular docking data for SLL-022CCP revealed that it maintains canonical interactions with the KOR orthosteric site while extending its terminal phenyl moiety into a hydrophobic subpocket. In vivo, SLL-022CCP produced potent antinociception in the hot plate test (ED₅₀ = 1.816 mg/kg), acetic acid-induced writhing test (ED₅₀ = 0.113 mg/kg), and significant antipruritic effects in the histamine-induced itch test (ED₅₀ = 0.079 mg/kg) and CFA-induced itch test (ED₅₀ = 0.105 mg/kg). The antinociceptive effects of SLL-022CCP were antagonized by the KOR-selective antagonist Nor-BNI, but not by the MOR antagonist CTAP (1 mg/kg, i.p.), supporting primarily KOR-mediated activity. Importantly, at the antinociceptive dose, SLL-022CCP did not elicit significant motor incoordination or conditioned place aversion (CPA) under current experimental conditions, while eliciting transient sedation, distinguishing it from the typical arylacetamide derivatives, like U50,488H. Collectively, these results identify SLL-022CCP as a highly potent and selective KOR agonist with a unique pharmacological profile that exhibits robust antinociceptive and antipruritic effects with low central side effects.

Multiple lines of evidence, including clinical and preclinical, associate depression with dysregulated glutamate homeostasis in the central nervous system. The astrocyte-enriched cysteine/glutamate antiporter, xCT, plays a pivotal role in maintaining this homeostasis, and its dysfunction is linked to depressive-like behaviors induced by chronic stress. However, the exact mechanism through which chronic stress results in xCT dysfunction remains poorly understood. In this study, we demonstrate that chronic social defeat stress (CSDS) downregulates xCT expression in the prelimbic cortex (PL), a key cortical region involved in the aetiology of depression, through astroglial kappa opioid receptor (KOR)-dependent, p38 MAPK-mediated upregulation of miR-3084-5p expression, which in turn downregulates xCT expression by inhibiting mRNA that encodes xCT. Knockdown of KORs as well as overexpression of xCT in the PL astrocytes significantly attenuates CSDS-induced depressive-like behaviors. Blockade of p38 MAPK activity or suppression of miR-3084-5p function restores xCT expression and alleviates depressive-like behaviors. Together, this study reveals a novel mechanism by which chronic stress deregulates glutamate homeostasis and consequently results in depression.