Nucleus raphe magnus serotonin neurones bidirectionally control spinal nociceptive transmission in mice

Zoé Grivet, Aude Verboven, Franck Aby, Rabia Bouali-Benazzouz, Thibault Dhellemmes, Emma Perrot, Anna Beyeler, Lora K. Heisler, Maddalena Balia, Arne Battefeld,, Hugo Martin, Aude Retailleau, François Maingret, Xavier Fioramonti, Marc Landry, Yves De Koninck, Abdelhamid Benazzouz, Pascal Fossat
British Journal of Anaesthesia. 2026-05-01; :
DOI: 10.1016/j.bja.2026.03.069

Grivet Z(1), Verboven A(1), Aby F(1), Bouali-Benazzouz R(1), Dhellemmes T(1), Perrot E(1), Beyeler A(2), Heisler LK(3), Balia M(1), Battefeld A(1), Martin H(4), Retailleau A(5), Maingret F(1), Fioramonti X(4), Landry M(1), De Koninck Y(6), Benazzouz A(1), Fossat P(7).

Author information:
(1)Université de Bordeaux, CNRS, IMN, UMR 5293, Bordeaux, France.
(2)Université de Bordeaux, INSERM, Neurocentre Magendie, U1215, Bordeaux,
France.
(3)The Rowett Institute, University of Aberdeen, UK.
(4)Université de Bordeaux, INRAe, NutriNeuro, UMR, Bordeaux, France.
(5)APATEYA, SAS, Bordeaux, France.
(6)CERVO Brain Research Center, Université Laval, Québec City, QC, Canada;
Department of Psychiatry & Neuroscience, Université Laval, Québec City, QC,
Canada.
(7)Université de Bordeaux, CNRS, IMN, UMR 5293, Bordeaux, France. Electronic
address: .

BACKGROUND: Noxious stimuli are conveyed to and integrated in the dorsal horn of
the spinal cord before being transmitted to supraspinal centres, where pain
perception is generated. Descending pathways from the brainstem dynamically
modulate this integration, either facilitating or inhibiting nociceptive
information based on physiological, emotional, genetic and environmental
factors. Serotonergic neurones in the nucleus raphe magnus (NRM), activating
different spinal 5-hydroxytryptamine (5-HT) receptors, exert bidirectional
control, both facilitatory and inhibitory, but the underlying mechanisms of this
control remain unclear.
METHODS: Serotonergic modulation by the NRM of nociception was investigated in
adult mice using imaging, behavioural, pharmacological, electrophysiological,
chemogenetic and optogenetic approaches.
RESULTS: The action of serotonergic neurones in the NRM on spinal nociceptive
transmission depends on their activation pattern, which targets different spinal
5-HT receptors likely associated with different spinal microcircuits.
Serotonergic neurones of the NRM exert a tonic analgesic effect mediated by
5-HT2c receptor. Low increases in 5-HT activity led to increased analgesia
through spinal inhibitory interneurones expressing 5-HT2c and 5-HT2A receptors.
Prolonged stimulation of serotonergic neurones led to hyperalgesia mediated by
5-HT3 receptors. Comparison of 5-HT receptors in spinal tissue from mice and
humans shows that 5-HT2c receptors have high expression level, comparable
between both species.
CONCLUSIONS: These results propose a bidirectional model of action by serotonin
neurones of nociceptive transmission depending on their level of activity and
show that 5-HT2c receptors mediate the serotonin-induced analgesia.

DOI: 10.1016/j.bja.2026.03.069
PMID: 42173713

Conflict of interest statement: Declaration of interest PF and FA are cofounders
of the biopharma startup APATEYA, SA SIRET n° 938 644 408 00016. The other
authors have no conflicts to declare.