Mu Opioid Receptor Knockout in Rostral Ventromedial Medulla Neurons Versus Presynaptic Terminals Has Divergent Effects on Acute Pain Phenotypes in Mice

The rostral ventromedial medulla (RVM) is a key hub for descending pain modulation. It receives input from the periaqueductal grey (PAG) and other regions and sends projections to the dorsal horn of the spinal cord. Opioids act in part through µ opioid receptors (MORs) in the RVM to modulate pain sensation. Injection of opioid agonists into the RVM produces potent analgesia, and inactivation of the RVM prevents systemically administered opioids from achieving their full effect. However, the function of presynaptic vs. postsynaptic RVM MOR signaling in top-down pain modulation and analgesia remain unclear. In this study, we utilize a conditional knockout approach to delete MORs locally in RVM neurons or in presynaptic terminals and assess the impact of this manipulation on reflexive pain responses and systemic opioid analgesia. We found that local RVM MOR knockout increases Hargreaves response latency compared to controls, but that there is no difference in latency between control and edited animals following CFA injection. Conversely, presynaptic MOR knockout decreased hot plate response latency in edited animals, compared to controls. Neither local nor retrograde MOR knockout affected morphine analgesia. Given the heterogeneity of RVM neurons and the complexity of descending pain pathways, these findings highlight the need to investigate the role of MORs on specific RVM neuronal subtypes to better understand how the RVM contributes to pain modulation and analgesia.