Pain Management Research, Kolling Institute, Royal North Shore Hospital Northern Sydney Local Health District and Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales 2065, Australia.
Sydney Pain Consortium, Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales 2006, Australia.
eNeuro. 2023 Jun 12;10(6). doi: 10.1523/ENEURO.0069-23.2023. Print 2023 Jun.
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.
中脑导水管周围灰质（PAG），特别是其腹外侧柱（vlPAG），是调节人类和啮齿动物痛觉、恐惧和焦虑行为的关键下行途径的一部分。先前的研究表明，vlPAG 内的抑制性 GABA 能神经元在这种痛觉调制中起着主要作用。然而，PAG 包含多种神经元亚型，不同亚型的抑制性神经元对痛觉控制的贡献尚未得到研究。在这里，我们在表达甘氨酸转运体 2（GlyT2::cre）启动子下表达 Cre 重组酶的小鼠中采用了一种化学遗传学策略，以调节 vlPAG 内的一组新型甘氨酸能神经元，并研究它们在痛觉控制中的作用。我们发现，激活 GlyT2-PAG 神经元会增强雄性和雌性小鼠对冷和有害热的反应，并增加运动活动（LMA）。相比之下，抑制 GlyT2-PAG 神经元会降低痛觉反应，而运动行为不受影响。我们的研究结果表明，vlPAG 中的 GlyT2 神经元调节痛觉，并表明靶向 GlyT2-PAG 神经元的策略可用于设计新型镇痛疗法。
