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RGSz1 actions in the periaqueductal gray modulate opioid reward and analgesic tolerance

Regulator of G protein signaling z1 (RGSz1), is a member of the RGS family of proteins, and present in several networks expressing mu opioid receptors. Previous studies in our lab have shown that RGSz1 knockout increases the analgesic efficacy of synthetic opioids, and delays the development of tolerance. On the other hand, knockout of RGSz1 decreases the rewarding efficacy of morphine in the place conditioning paradigm and prevents its locomotor sensitizing actions (Gaspari, et al, PNAS 2018). We further demonstrated the impact of RGSz1 in tolerance to synthetic opioids using a three‐week tolerance paradigm. These opposing roles of RGSz1 in reward versus analgesic efficacy make it an interesting target for the development of therapeutic interventions for chronic pain management. The goal of this work is to identify the RGSz1 circuits involved in the modulation of morphine’s rewarding and analgesic actions.