An analgesic pathway from parvocellular oxytocin neurons to the periaqueductal gray in rats

Mai Iwasaki, Arthur Lefevre, Ferdinand Althammer, Etienne Clauss Creusot, Olga Łąpieś, Hugues Petitjean, Louis Hilfiger, Damien Kerspern, Meggane Melchior, Stephanie Küppers, Quirin Krabichler, Ryan Patwell, Alan Kania, Tim Gruber, Matthew K. Kirchner, Moritz Wimmer, Henning Fröhlich, Laura Dötsch, Jonas Schimmer, Sabine C. Herpertz, Beate Ditzen, Christian P. Schaaf, Kai Schönig, Dusan Bartsch, Anna Gugula, Aleksandra Trenk, Anna Blasiak, Javier E. Stern, Pascal Darbon, Valery Grinevich () and Alexandre Charlet ()
Additional contact information
Mai Iwasaki: Institute of Cellular and Integrative Neuroscience
Arthur Lefevre: Institute of Cellular and Integrative Neuroscience
Ferdinand Althammer: University of Heidelberg
Etienne Clauss Creusot: Institute of Cellular and Integrative Neuroscience
Olga Łąpieś: Institute of Cellular and Integrative Neuroscience
Hugues Petitjean: Institute of Cellular and Integrative Neuroscience
Louis Hilfiger: Institute of Cellular and Integrative Neuroscience
Damien Kerspern: Institute of Cellular and Integrative Neuroscience
Meggane Melchior: Institute of Cellular and Integrative Neuroscience
Stephanie Küppers: University of Heidelberg
Quirin Krabichler: University of Heidelberg
Ryan Patwell: University of Heidelberg
Alan Kania: University of Heidelberg
Tim Gruber: Van Andel Institute
Matthew K. Kirchner: Georgia State University
Moritz Wimmer: University Hospital Heidelberg
Henning Fröhlich: University Hospital Heidelberg
Laura Dötsch: University Hospital Heidelberg
Jonas Schimmer: University of Heidelberg
Sabine C. Herpertz: University of Heidelberg
Beate Ditzen: Heidelberg University Hospital
Christian P. Schaaf: University Hospital Heidelberg
Kai Schönig: University of Heidelberg
Dusan Bartsch: University of Heidelberg
Anna Gugula: Jagiellonian University
Aleksandra Trenk: Jagiellonian University
Anna Blasiak: Jagiellonian University
Javier E. Stern: Georgia State University
Pascal Darbon: Institute of Cellular and Integrative Neuroscience
Valery Grinevich: University of Heidelberg
Alexandre Charlet: Institute of Cellular and Integrative Neuroscience

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: Abstract The hypothalamic neuropeptide oxytocin (OT) exerts prominent analgesic effects via central and peripheral action. However, the precise analgesic pathways recruited by OT are largely elusive. Here we discovered a 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 targeted by OT projections are GABAergic. Ex vivo stimulation of parvocellular OT axons in the vlPAG induced local OT release, as measured with OT sensor GRAB. In vivo, optogenetically-evoked axonal OT release in the vlPAG of as well as chemogenetic activation of OTR vlPAG neurons resulted in a long-lasting increase of vlPAG neuronal activity. This lead to an indirect suppression of sensory neuron activity in the spinal cord and strong analgesia in both female and male rats. Altogether, we describe an OT-vlPAG-spinal cord circuit that is critical for analgesia in both inflammatory and neuropathic pain models.

Date: 2023
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DOI: 10.1038/s41467-023-36641-7

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