Region-specific involvement of ventral striatal dopamine D2 receptor-expressing medium spiny neurons in nociception

The ventrolateral striatum (VLS), a subregion of the ventral striatum (VS), possesses distinct neuronal Ca²⁺ activities and functions in reward-oriented behavior, compared with the ventromedial striatum (VMS) based on the anatomical feature. We hypothesized that the VLS exhibits unique neuronal activity and function in nociceptive processing, a part of aversive processing. Using fiber photometry to monitor the neuronal Ca²⁺ activities, we demonstrated that acute noxious mechanical stimuli like tail-pinch increased the Ca²⁺ activity of dopamine D2 receptor-expressing medium spiny neurons (D2-MSNs) in the VLS in correlation with the stimulus intensities in mice, whereas mechanical stimuli increased the VMS D2-MSN activity independent of the stimulus intensities. Likewise, thermal stimuli decreased the VLS and VMS D2-MSN Ca²⁺ activities during nociceptive behaviors in the hot plate test. Furthermore, the VLS D2-MSNs increased their Ca²⁺ activity accompanied by formalin-induced nociceptive behaviors in mice, whereas the VMS D2-MSNs decreased it. The optogenetic inhibition of VLS D2-MSN activity increased the formalin-induced pain-related behavior in mice, thus suggesting the inhibitory effect of VLS D2-MSN activity on chemical nociceptive behavior, in contrast to previous reports that the VMS D2-MSNs could not involve the behavior. Therefore, the VLS D2-MSNs exhibited region-specific roles in nociception.