Distinct Roles of Dopamine Receptor Subtypes in the Nucleus Accumbens during Itch Signal Processing.

Ventral tegmental area (VTA) dopaminergic neurons, which are well known for their central roles in reward and motivation-related behaviors, have been shown to participate in itch processing via their projection to the nucleus accumbens (NAc). However, the functional roles of different dopamine receptor subtypes in subregions of the NAc during itch processing remain unknown. With pharmacological approaches, we found that the blockade of dopamine D1 receptors (D1R), but not dopamine D2 receptors (D2R), in the lateral shell (LaSh) of the NAc impaired pruritogen-induced scratching behavior in male mice. In contrast, pharmacological activation of D2R in both the LaSh and medial shell (MeSh) of the NAc attenuated the scratching behavior induced by pruritogens. Consistently, we found that dopamine release, as detected by a dopamine sensor, was elevated in the LaSh rather than the MeSh of the NAc at the onset of scratching behavior. Furthermore, the elevation of dopamine release in the LaSh of the NAc persisted even though itch-relieving behavior was blocked, suggesting that the dopamine signal in the NAc LaSh represents a motivational component of itch processing. Our study revealed different dynamics of dopamine release that target neurons expressing two dopamine receptors subtypes within different subregions of the NAc, and emphasized that D1R in the LaSh of the NAc is important in itch signal processing.SIGNIFICANCE STATEMENT Dopamine has been implicated in itch signal processing. However, the mechanism underlying the functional role of dopamine in itch processing remains largely unknown. Here, we examined the role of dopamine D1 receptor (D1R) and D2R in the nucleus accumbens (NAc) shell during pruritogen-induced scratching behavior. We demonstrated that D1R in the NAc lateral shell (LaSh) play an important role in motivating itch-induced scratching behavior, while activation of D2R would terminate scratching behavior. Our study revealed the diverse functional roles of dopamine signals in the NAc shell during itch processing.

Synaptic control of spinal GRPR+ neurons by local and long-range inhibitory inputs.

Spinal gastrin-releasing peptide receptor-expressing (GRPR+) neurons play an essential role in itch signal processing. However, the circuit mechanisms underlying the modulation of spinal GRPR+ neurons by direct local and long-range inhibitory inputs remain elusive. Using viral tracing and electrophysiological approaches, we dissected the neural circuits underlying the inhibitory control of spinal GRPR+ neurons. We found that spinal galanin+ GABAergic neurons form inhibitory synapses with GRPR+ neurons in the spinal cord and play an important role in gating the GRPR+ neuron-dependent itch signaling pathway. Spinal GRPR+ neurons also receive inhibitory inputs from local neurons expressing neuronal nitric oxide synthase (nNOS). Moreover, spinal GRPR+ neurons are gated by strong inhibitory inputs from the rostral ventromedial medulla. Thus, both local and long-range inhibitory inputs could play important roles in gating itch processing in the spinal cord by directly modulating the activity of spinal GRPR+ neurons.

Dynamics and Functional Role of Dopaminergic Neurons in the Ventral Tegmental Area during Itch Processing.

Itchiness triggers a strong urge to engage in scratching behavior, which could lead to severe skin or tissue damage in patients with chronic itch. This process is dynamically modulated. However, the neural mechanisms underlying itch modulation remain largely unknown. Here, we report that dopaminergic (DA) neurons in the ventral tegmental area (VTA) play a critical role in modulating itch-induced scratching behavior. We found that the activity of VTA DA neurons was increased during pruritogen-induced scratching behavior in freely moving male mice. Consistently, individual VTA DA neurons mainly exhibited elevated neural activity during itch-induced scratching behavior as demonstrated by in vivo extracellular recording. In behavioral experiments, the transient suppression of VTA DA neurons with the optogenetic approach shortened the pruritogen-induced scratching train. Furthermore, the DA projection from the VTA to the lateral shell of the nucleus accumbens exhibited strong activation as measured with fiber photometry during itch-elicited scratching behavior. These results revealed the dynamic activity of VTA DA neurons during itch processing and demonstrated the modulatory role of the DA system in itch-induced scratching behavior.SIGNIFICANCE STATEMENT Itchiness is an unpleasant sensation that evokes a scratching response for relief. However, the neural mechanism underlying the modulation of itch-evoked scratching in the brain remains elusive. Here, by combining fiber photometry, extracellular recording, and optogenetic manipulation, we show that the dopaminergic neurons in the ventral tegmental area play a modulatory role in itch-evoked scratching behavior. These results reveal a potential target for suppressing excessive scratching responses in patients with chronic itch.