Acute stress can dramatically reduce pain perception, but the underlying neural mechanisms have remained elusive. A new study by Karen Haenraets, Hendrik Wildner, Hanns Ulrich Zeilhofer and colleagues at UZH identifies a specific spinal circuit that is essential for stress-induced analgesia. The findings reveal how descending signals from the brainstem engage inhibitory neurons in the spinal cord to block pain transmission.
In moments of acute stress, even severe injuries can feel surprisingly painless – a phenomenon known as stress-induced analgesia. While previous research has identified key brain regions involved in this process, the spinal circuits that ultimately suppress pain signals have remained largely unclear. Addressing this gap, the researchers focused on a specific population of inhibitory neurons in the superficial dorsal horn of the spinal cord, marked by the transcription factor Gbx1. Using a combination of genetic targeting, circuit tracing, and functional manipulation, they investigated how these neurons contribute to the modulation of pain under stress.
Strikingly, the experiments revealed that these Gbx1-positive neurons act as a critical “gate” for stress-induced analgesia. Under normal conditions, silencing these neurons had little effect on pain sensitivity. However, when mice were exposed to acute stress, such as a brief forced swim, pain responses dropped dramatically. This effect completely disappeared when Gbx1 neurons were inhibited. Conversely, artificially activating these neurons was sufficient to strongly reduce sensitivity to heat, cold, and mechanical stimuli, with some animals reaching maximum thresholds in standard pain tests. In simple terms, these neurons behave like a switch: when they are turned on, pain signals are effectively blocked. Circuit mapping further showed that these neurons are normally kept in check by inhibitory input from the brainstem, particularly the rostral ventromedial medulla. During stress, this inhibition is lifted, allowing Gbx1 neurons to suppress pain-transmitting projection neurons in the spinal cord.
Taken together, these findings reveal a neural circuit that allows the brain to quickly dampen pain during acute stress. More broadly, the study shows how the brain can adjust pain signals depending on the situation by acting directly on circuits in the spinal cord. By identifying a specific group of neurons that can effectively switch pain transmission on or off, this work highlights a potential target for new pain therapies. Future studies will need to explore how this system interacts with other pathways involved in pain regulation and whether it can be targeted to develop treatments for chronic pain conditions in human patients.
Reference: Haenraets K, Ganley RP, Pietrafesa F, MacDonald DI, Sousa M, Schalbetter S, Mendes R, Luzi F, Wildner H, Zeilhofer HU. GABAergic Gbx1 neurons of the superficial dorsal horn are critical elements of a spinal circuit for stress-induced analgesia. Neuron. 2026. https://doi.org/10.1016/j.neuron.2026.01.03
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