Sound—including music and noise—can relieve pain in humans, but the underlying neural mechanisms remain unknown. We discovered that analgesic effects of sound depended on a low (5-decibel) signal-to-noise ratio (SNR) relative to ambient noise in mice. Viral tracing, microendoscopic calcium imaging, and multitetrode recordings in freely moving mice showed that low-SNR sounds inhibited glutamatergic inputs from the auditory cortex (ACx ^Glu ) to the thalamic posterior (PO) and ventral posterior (VP) nuclei. Optogenetic or chemogenetic inhibition of the ACx ^Glu →PO and ACx ^Glu →VP circuits mimicked the low-SNR sound–induced analgesia in inflamed hindpaws and forepaws, respectively. Artificial activation of these two circuits abolished the sound-induced analgesia. Our study reveals the corticothalamic circuits underlying sound-promoted analgesia by deciphering the role of the auditory system in pain processing.

Remifentanil-induced hyperalgesia (RIH) is a severe but common postoperative clinical problem with elusive underlying neural mechanisms. Here, we discovered that glutamatergic neurons in the thalamic ventral posterolateral nucleus (VPL^Glu) exhibited significantly elevated burst firing accompanied by upregulation of Ca_v3.1 T-type calcium channel expression and function in RIH model mice. In addition, we identified a glutamatergic neuronal thalamocortical circuit in the VPL projecting to hindlimb primary somatosensory cortex glutamatergic neurons (S1HL^Glu) that mediated RIH. In vivo calcium imaging and multi-tetrode recordings revealed heightened S1HL^Glu neuronal activity during RIH. Moreover, preoperative suppression of Ca_v3.1-dependent burst firing in VPL^Glu neurons or chemogenetic inhibition of VPL^Glu neuronal terminals in the S1HL abolished the increased S1HL^Glu neuronal excitability while alleviating RIH. Our findings suggest that remifentanil induces postoperative hyperalgesia by upregulating T-type calcium channel-dependent burst firing in VPL^Glu neurons to activate S1HL^Glu neurons, thus revealing an ion channel–mediated neural circuit basis for RIH that can guide analgesic development.

Diabetic patients frequently experience neuropathic pain, which currently lacks effective treatments. The mechanisms underlying diabetic neuropathic pain remain unclear. The anterior cingulate cortex (ACC) is well-known to participate in the processing and transformation of pain information derived from internal and external sensory stimulation. Accumulating evidence shows that dysfunction of microglia in the central nervous system contributes to many diseases, including chronic pain and neurodegenerative diseases. In this study, we investigated the role of microglial chemokine CXCL12 and its neuronal receptor CXCR4 in diabetic pain development in a mouse diabetic model established by injection of streptozotocin (STZ). Pain sensitization was assessed by the left hindpaw pain threshold in von Frey filament test. Iba1⁺ microglia in ACC was examined using combined immunohistochemistry and three-dimensional reconstruction. The activity of glutamatergic neurons in ACC (ACC^Glu) was detected by whole-cell recording in ACC slices from STZ mice, in vivo multi-tetrode electrophysiological and fiber photometric recordings. We showed that microglia in ACC was significantly activated and microglial CXCL12 expression was up-regulated at the 7-th week post-injection, resulting in hyperactivity of ACC^Glu and pain sensitization. Pharmacological inhibition of microglia or blockade of CXCR4 in ACC by infusing minocycline or AMD3100 significantly alleviated diabetic pain through preventing ACC^Glu hyperactivity in STZ mice. In addition, inhibition of microglia by infusing minocycline markedly decreased STZ-induced upregulation of microglial CXCL12. Together, this study demonstrated that microglia-mediated ACC^Glu hyperactivity drives the development of diabetic pain via the CXCL12/CXCR4 signaling, thus revealing viable therapeutic targets for the treatment of diabetic pain.

Light has been shown to relieve pain, but the underlying neural mechanisms remain unknown. Here, we show that low-intensity (200 lux) green light treatment exerts antinociceptive effects through a neural circuit from the visual cortex projecting to the anterior cingulate cortex (ACC) in mice. Specifically, viral tracing, in vivo two-photon calcium imaging, and fiber photometry recordings show that green light activated glutamatergic projections from the medial part of the secondary visual cortex (V2M^Glu) to GABAergic neurons in the ACC, which drives inhibition of local glutamatergic neurons (V2M^Glu→ACC^GABA→Glu). Optogenetic or chemogenetic activation of the V2M^Glu→ACC^GABA→Glu circuit mimics green-light-induced antinociception in both neuropathic and inflammatory pain model mice. Artificial inhibition of ACC-projecting V2M^Glu neurons abolishes the antinociception induced by green light. Taken together, our study shows the V2M-ACC circuit as a potential candidate mediating green-light-induced antinociceptive effects.