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

Iwasaki, M.; Lefevre, A.; Althammer, F.; Lapies, O.; Hilfiger, L.; Kerspern, D.; Melchior, M.; Kueppers, S.; Krablicher, Q.; Patwell, R.; Herpertz, S.; Ditzen, B.; Schoenig, K.; Bartsch, D.; Sterm, J. E.; Darbon, P.; Grinevich, V.; Charlet, A.

doi:10.1101/2022.02.23.481531

bioRxiv · 10.1101/2022.02.23.481531

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

Iwasaki, M.·Lefevre, A.·Althammer, F.·Lapies, O.·Hilfiger, L.·Kerspern, D.·Melchior, M.·Kueppers, S.·Krablicher, Q.·Patwell, R.·Herpertz, S.·Ditzen, B.·Schoenig, K.·Bartsch, D.·Sterm, J. E.·Darbon, P.·Grinevich, V.·Charlet, A.

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Abstract

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

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Iwasaki, M., Lefevre, A., Althammer, F., Lapies, O., Hilfiger, L., Kerspern, D., Melchior, M., Kueppers, S., Krablicher, Q., Patwell, R., Herpertz, S., Ditzen, B., Schoenig, K., Bartsch, D., Sterm, J. E., Darbon, P., Grinevich, V., Charlet, A.. 2022-02-24. A novel analgesic pathway from parvocellular oxytocin neurons to the periaqueductal gray. https://doi.org/10.1101/2022.02.23.481531

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