Activation of Brainstem Pro-opiomelanocortin Neurons Produces Opioidergic Analgesia, Bradycardia and Bradypnoea

Opioids are widely used medicinally as analgesics and abused for hedonic effects, actions that are each complicated by substantial risks such as cardiorespiratory depression. These drugs mimic peptides such as β-endorphin, which has a key role in endogenous analgesia. The β-endorphin in the central nervous system originates from pro-opiomelanocortin (POMC) neurons in the arcuate nucleus and nucleus of the solitary tract (NTS). Relatively little is known about the NTS(POMC) neurons but their position within the sensory nucleus of the vagus led us to test the hypothesis that they play a role in modulation of cardiorespiratory and nociceptive control. The NTS(POMC) neurons were targeted using viral vectors in a POMC-Cre mouse line to express either opto-genetic (channelrhodopsin-2) or chemo-genetic (Pharmacologically Selective Actuator Modules). Opto-genetic activation of the NTS(POMC) neurons in the working heart brainstem preparation (n = 21) evoked a reliable, titratable and time-locked respiratory inhibition (120% increase in inter-breath interval) with a bradycardia (125±26 beats per minute) and augmented respiratory sinus arrhythmia (58% increase). Chemo-genetic activation of NTS(POMC) neurons in vivo was anti-nociceptive in the tail flick assay (latency increased by 126±65%, p<0.001; n = 8). All effects of NTS(POMC) activation were blocked by systemic naloxone (opioid antagonist) but not by SHU9119 (melanocortin receptor antagonist). The NTS(POMC) neurons were found to project to key brainstem structures involved in cardiorespiratory control (nucleus ambiguus and ventral respiratory group) and endogenous analgesia (periaqueductal gray and midline raphe). Thus the NTS(POMC) neurons may be capable of tuning behaviour by an opioidergic modulation of nociceptive, respiratory and cardiac control.