Parabrachial nucleus activity in nociception and pain in awake mice

Abstract

The parabrachial nuclear complex is a nexus for aversion, and for the sensory and affective components of pain perception. We have previously shown that, during chronic pain, parabrachial neurons in anesthetized rodents have amplified activity. We report a method to record from parabrachial neurons of behaving, head-restrained mice, while applying reproducible noxious stimuli. We find that both spontaneous and evoked activity are considerably higher in awake animals. We show that these neurons can be rapidly conditioned to respond to innocuous stimuli, after pairing these with nociceptive stimuli. In both males and females with neuropathic or inflammatory pain, responses of parabrachial neurons remain amplified for at least 6 weeks, in parallel with increased pain metrics. Fiber photometry of calcium responses from CGRP-expressing parabrachial neurons in male mice demonstrate that they respond to nociceptive stimuli, and that their responses are amplified in inflammatory pain. In contrast, in females these neurons evoke smaller responses at baseline, and only small increases in neuropathic pain. This sex difference may relate to our finding that, in females, a small percentage of neurons expresses CGRP. Finally, we show that changes in parabrachial activity are correlated with changes in arousal, measured as changes in pupil diameter.