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. However, underlying neural mechanisms remain elusive. Here, we identified a cold-responsive neuronal subset within the lateral parabrachial nucleus (lPBN), the thermosensory relay region in the hindbrain, that mediates cold-induced analgesia in mice. Activation of these neurons and their projection to ventrolateral periaqueductal gray (vlPAG) increased the nociceptive threshold, while ablation of these neurons attenuated analgesia induced by cold-mimicking chemicals. We further identified that these neurons express precursor gene of enkephalin (Penk), which is necessary for TRPM8 (transient receptor potential melastatin 8)-mediated pain relief. Mechanistically, cold-responsive lPBN neurons frequency-dependently released enkephalin peptide into vlPAG to activate the descending pain modulation circuitry via disinhibition. Activation of cold-responsive neurons reduced spinal cord responses to noxious stimuli, suggesting the involvement of a top-down pain modulation pathway. These findings propose a central mechanism underlying cold-induced pain relief, which could be a novel therapeutic target.