Bidirectional modulation of nociception by GlyT2 + neurons in the ventrolateral periaqueductal gray.

The midbrain periaqueductal gray (PAG), particularly its ventrolateral column (vlPAG), is part of a key descending pathway that modulates nociception, fear and anxiety behaviours in both humans and rodents. It has been previously demonstrated that inhibitory GABAergic neurons within the vlPAG have a major role in this nociceptive modulation. However, the PAG contains a diverse range of neuronal subtypes and the contribution of different subtypes of inhibitory neurons to nociceptive control has not been investigated. Here, we employed a chemogenetic strategy in mice that express Cre- under the promotor for the glycine transporter 2 (GlyT2::cre) to modulate a novel group of glycinergic neurons within the vlPAG and then investigate their role in nociceptive control. We show that activation of GlyT2-PAG neurons enhances cold and noxious heat responses and increases locomotor activity in both male and female mice. In contrast, inhibition of GlyT2-PAG neurons reduced nociceptive responses, while locomotor behaviours were unaffected. Our findings demonstrate that GlyT2 + neurons in the vlPAG modulate nociception and suggest that strategies targeting GlyT2-PAG neurons could be used to design novel analgesic therapies. Summary statement Neuronal circuits are composed of diverse collections of cell types, each with a distinct set of synaptic connections that determine their role in specific functions. One challenge in neuropharmacology is to design drugs that interact with the brain circuits required to have the desired therapeutic effect and limit their activity at nearby circuits, thus reducing side effects. The current study shows that a genetically identified subpopulation of GlyT2 + neurons that are concentrated in the vlPAG can bidirectionally modulate nociceptive responses and alter locomotion behaviours in mice. These findings provided novel insights into the organization of the nociceptive circuitry of the PAG and identify GlyT2-PAG neurons as a potential target for analgesic drug design.