Calretinin-expressing islet cells: a source of pre- and post-synaptic inhibition of non-peptidergic nociceptor input to the mouse spinal cord
Calretinin-expressing islet cells: a source of pre- and post-synaptic inhibition of non-peptidergic nociceptor input to the mouse spinal cord
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DOI：
10.1101/2023.06.01.543241
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发表时间：
2023-06
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通讯作者：
Olivia C Davis;A. Dickie;M. Mustapa;K. Boyle;Tyler J. Browne;M. Gradwell;Kelly M. Smith;E. Polgár;Andrew M. Bell;Éva Kókai;Masahiko Watanabe;H. Wildner;H. Zeilhofer;D. Ginty;R. Callister;B. Graham;A. Todd;D. Hughes
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作者：
Olivia C Davis;A. Dickie;M. Mustapa;K. Boyle;Tyler J. Browne;M. Gradwell;Kelly M. Smith;E. Polgár;Andrew M. Bell;Éva Kókai;Masahiko Watanabe;H. Wildner;H. Zeilhofer;D. Ginty;R. Callister;B. Graham;A. Todd;D. Hughes
无髓鞘的非肽能伤害感受器（NP传入）分支于脊髓的层II中并接收GABA能轴轴突触，其介导突触前抑制。然而，到目前为止，这种轴-轴突触输入的来源还不清楚。在这里，我们提供的证据表明，它起源于一个人口的抑制性钙视网膜蛋白表达的中间神经元（iCRs），这对应于板II胰岛细胞。NP传入神经元可分为3个功能不同的类别（NP 1 - 3）。NP1传入与病理性疼痛状态有关，而NP2和NP3传入也起着神经感受器的作用。我们的研究结果表明，所有这3种传入类型支配iCRs，并从他们接受轴轴突触，提供反馈抑制NP输入。iCR还形成轴-树突触，并且它们的靶包括自身受NP传入神经支配的细胞，从而允许前馈抑制。因此，理想地放置iCR以控制从非肽能伤害感受器和神经刺激感受器到其他背角神经元的输入，并且因此代表用于治疗慢性疼痛和瘙痒的潜在治疗靶标。
Unmyelinated non-peptidergic nociceptors (NP afferents) arborise in lamina II of the spinal cord and receive GABAergic axoaxonic synapses, which mediate presynaptic inhibition. However, until now the source of this axoaxonic synaptic input was not known. Here we provide evidence that it originates from a population of inhibitory calretinin-expressing interneurons (iCRs), which correspond to lamina II islet cells. The NP afferents can be assigned to 3 functionally distinct classes (NP1-3). NP1 afferents have been implicated in pathological pain states, while NP2 and NP3 afferents also function as pruritoceptors. Our findings suggest that all 3 of these afferent types innervate iCRs and receive axoaxonic synapses from them, providing feedback inhibition of NP input. The iCRs also form axodendritic synapses, and their targets include cells that are themselves innervated by the NP afferents, thus allowing for feedforward inhibition. The iCRs are therefore ideally placed to control the input from non-peptidergic nociceptors and pruritoceptors to other dorsal horn neurons, and thus represent a potential therapeutic target for the treatment of chronic pain and itch.