Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Department of Anatomy and Neurobiology, Program in Neuroscience, University of Maryland, School of Medicine, Baltimore, MD 21201, USA.
Brain. 2022 Jul 29;145(7):2586-2601. doi: 10.1093/brain/awac189.
In perilous and stressful situations, the ability to suppress pain can be critical for survival. The rostral ventromedial medulla contains neurons that robustly inhibit nocioception at the level of the spinal cord through a top-down modulatory pathway. Although much is known about the role of the rostral ventromedial medulla in the inhibition of pain, the precise ability to directly manipulate pain-inhibitory neurons in the rostral ventromedial medulla has never been achieved. We now expose a cellular circuit that inhibits nocioception and itch in mice. Through a combination of molecular, tracing and behavioural approaches, we found that rostral ventromedial medulla neurons containing the kappa-opioid receptor inhibit itch and nocioception. With chemogenetic inhibition, we uncovered that these neurons are required for stress-induced analgesia. Using intersectional chemogenetic and pharmacological approaches, we determined that rostral ventromedial medulla kappa-opioid receptor neurons inhibit nocioception and itch through a descending circuit. Lastly, we identified a dynorphinergic pathway arising from the periaqueductal grey that modulates nociception within the rostral ventromedial medulla. These discoveries highlight a distinct population of rostral ventromedial medulla neurons capable of broadly and robustly inhibiting itch and nocioception.
在危险和紧张的情况下，抑制疼痛的能力对于生存至关重要。延髓头端腹内侧含有神经元，通过自上而下的调制途径，在脊髓水平上强烈抑制伤害感受。尽管人们对延髓头端腹内侧在抑制疼痛中的作用了解很多，但从未实现过直接操纵延髓头端腹内侧的疼痛抑制神经元的精确能力。我们现在揭示了一种抑制小鼠伤害感受和瘙痒的细胞回路。通过分子、追踪和行为方法的结合，我们发现含有κ-阿片受体的延髓头端腹内侧神经元抑制瘙痒和伤害感受。通过化学遗传抑制，我们发现这些神经元是应激诱导镇痛所必需的。使用交岔化学遗传和药理学方法，我们确定延髓头端腹内侧κ-阿片受体神经元通过下行回路抑制伤害感受和瘙痒。最后，我们确定了来自导水管周围灰质的强啡肽能通路，该通路调节延髓头端腹内侧的伤害感受。这些发现突出了延髓头端腹内侧中能够广泛而强烈地抑制瘙痒和伤害感受的一个独特神经元群体。
