Bidirectional Modulation of Nociception by GlyT2<sup>+</sup>Neurons in the Ventrolateral Periaqueductal Gray
Neda Assareh, Caitlin Fenech, Rebecca Power, Mohammad Nasir Uddin, Yo Otsu, Karin R. Aubrey
Abstract
Abstract The midbrain periaqueductal gray (PAG), particularly its ventrolateral column (vlPAG), is part of a key descending pathway that modulates nociception, fear and anxiety behaviors 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 recombinase 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 (LMA) in both male and female mice. In contrast, inhibition of GlyT2-PAG neurons reduced nociceptive responses, while locomotor behaviors 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.