Abstract: The peripheral terminals of primary sensory neurons detect histamine and non-histamine itch-provoking ligands through molecularly distinct transduction mechanisms. It remains unclear, however, whether these distinct pruritogens activate the same or different afferent fibers. Using a strategy of reversibly silencing specific subsets of murine pruritogen-sensitive sensory axons by targeted delivery of a charged sodium-channel blocker, we found that functional blockade of histamine itch did not affect the itch evoked by chloroquine or SLIGRL-NH2, and vice versa. Notably, blocking itch-generating fibers did not reduce pain-associated behavior. However, silencing TRPV1(+) or TRPA1(+) neurons allowed allyl isothiocyanate or capsaicin, respectively, to evoke itch, implying that certain peripheral afferents may normally indirectly inhibit algogens from eliciting itch. These findings support the presence of functionally distinct sets of itch-generating neurons and suggest that targeted silencing of activated sensory fibers may represent a clinically useful anti-pruritic therapeutic approach for histaminergic and non-histaminergic pruritus.
Abstract: Obsessive-compulsive disorder (OCD) is a relatively common psychiatric disorder characterized by intrusive thoughts and behaviors that dominate daily living, like an itch patients cannot ignore. Deficits in executive functioning are common in OCD and are thought to be related to dysfunctional frontal-striatal systems. One of those executive functions is cognitive flexibility, defined as the ability to rapidly switch response strategies following changes in task-relevant information. The temporal stability of cognitive flexibility impairments in OCD has been incompletely investigated since previous studies have suggested both state and trait dependency. In this study, 16 OCD patients performed a functional magnetic resonance imaging version of a task-switching paradigm twice, intervened by a follow-up period of on average 6 months. Results show that functional abnormalities in the dorsal frontal-striatal circuit and anterior cingulate cortex at baseline normalized at follow-up. This change in the recruitment of task-related brain circuits correlated with change in disease severity. These results support the view that the imbalance between the dorsal and ventral frontal-striatal circuits is at least partly state-dependent, and is associated with a reduction in symptom severity.
Abstract: Itch is triggered by somatosensory neurons expressing the ion channel TRPV1 (transient receptor potential cation channel subfamily V member 1), but the mechanisms underlying this nociceptive response remain poorly understood. Here, we show that the neuropeptide natriuretic polypeptide b (Nppb) is expressed in a subset of TRPV1 neurons and found that Nppb(-/-) mice selectively lose almost all behavioral responses to itch-inducing agents. Nppb triggered potent scratching when injected intrathecally in wild-type and Nppb(-/-) mice, showing that this neuropeptide evokes itch when released from somatosensory neurons. Itch responses were blocked by toxin-mediated ablation of Nppb-receptor-expressing cells, but a second neuropeptide, gastrin-releasing peptide, still induced strong responses in the toxin-treated animals. Thus, our results define the primary pruriceptive neurons, characterize Nppb as an itch-selective neuropeptide, and reveal the next two stages of this dedicated neuronal pathway.
