GABAergic Gbx1 neurons of the superficial dorsal horn are critical elements of a spinal circuit for stress-induced analgesia.

Acute stress is a powerful inducer of endogenous analgesia. Several brainstem and midbrain areas have been identified that are activated during stress and send descending axons to suppress spinal nociception. The spinal effector circuits and neurons have, however, remained largely elusive. Here, we demonstrate that GABAergic interneurons of the superficial dorsal horn expressing the transcription factor gastrulation brain homeobox 1 (Gbx1) are key elements of these circuits. Their inhibition had little effect on nociception under resting conditions but completely abolished swim stress-induced analgesia. Retrograde monosynaptic tracing revealed input from several brain areas, most prominently from the rostral ventromedial medulla (RVM). Optogenetic circuit tracing demonstrated that this input is inhibitory and that Gbx1 neurons in turn inhibit projection neurons targeting the lateral parabrachial nucleus, a key area in supraspinal pain relay. Our results thus identify a subpopulation of GABAergic neurons in the superficial dorsal horn as key elements of a disinhibitory circuit for stress-induced analgesia.