A brainstem circuit for coordinated pain-control

Abstract Supraspinal brain regions are involved in modifying nociceptive signals in response to environmental stimuli and stressors including mechanisms that elevate thresholds to noxious stimuli (pain suppression). However, details such as the cells, the circuits, and the molecular mechanisms, by which nociceptive responses are suppressed are incompletely understood. Therefore, we searched for unrecognized brain nuclei involved in these processes. Examination of neurons activated by noxious stimuli revealed catecholaminergic neurons in the caudal ventrolateral medulla that were stimulated by multiple noxious challenges. We found that, upon activation, these neurons operate in a diffuse feed-forward inhibitory loop to attenuate nociceptive reflexes via a descending locus coeruleus to spinal cord pathway. Importantly, this circuit is sufficient to attenuate injury induced allodynia and inhibit glucoprivation induced analgesia and is required for counter-stimulus induced analgesia. Our findings molecularly define a component of the brain pain modulatory system which can coordinate antinociceptive responses.