A novel analgesic pathway from parvocellular oxytocin neurons to the periaqueductal gray

The hypothalamic neuropeptide, oxytocin (OT), exerts prominent analgesic effects via central and peripheral action. Here we discovered a novel subset of OT neurons whose projections preferentially terminate on OT receptor (OTR)-expressing neurons in the ventrolateral periaqueductal gray (vlPAG). Using a newly generated line of transgenic rats (OTR-IRES-Cre), we determined that most of the vlPAG OTR expressing cells being targeted by OT projections are GABAergic in nature. Both optogenetically-evoked axonal OT release in the vlPAG as well as chemogenetic activation of OTR vlPAG neurons results in a long-lasting overall increase of vlPAG neuronal activity. This then leads to an indirect suppression of sensory neuron activity in the spinal cord and strong analgesia. Finally, we describe a novel OT[->]vlPAG[->]spinal cord circuit that seems critical for analgesia in the context of both inflammatory and neuropathic pain. Highlights- We generated a new transgenic knock-in rat line (OTR-IRES-Cre) - A distinct parvOT neuronal population projects to vlPAG but not the SON or spinal cord - OT excites vlPAG OTR neurons which indirectly inhibit SC WDR neurons - This novel parvOT[->]vlPAG[->]SC pathway alleviates nociception but not the affective component of pain