Brainstem enkephalinergic neural circuit underlying cold-induced pain relief in mice

Application of cold or cold-mimicking chemicals to injury has long been recognized as an effective means of pain relief and is widely utilized in daily life. However, underlying neural mechanisms remain elusive. Here, we identified a cold-responsive neuronal subset within lateral parabrachial nucleus (lPBN), the thermosensory relay region in the hindbrain, that mediates cold-induced analgesia in mice. Selective activation of these neurons and their projection to ventrolateral periaqueductal gray (vlPAG) increased nociceptive threshold via opioid receptor signaling in vlPAG. Conversely, ablation of these neurons attenuated analgesia induced by cold-mimicking chemicals. We further identified that these neurons express precursor gene of enkephalin, which is released into vlPAG for pain relief. Activation of cold-responsive neurons in descending pain modulation circuitry reduced spinal cord responses to noxious stimuli, suggesting the involvement of top-down pain modulation pathway. These findings propose a central mechanism underlying cold-induced pain relief, which could be a novel therapeutic target.