A subset of spinal dorsal horn inhibitory interneurons crucial for analgesic effect associated with spinal noradrenaline

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  • Daichi Sueto
    Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University
  • Ishibashi Tadayuki
    Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University Department of Anesthesiology and Critical Care Medicine, Graduate School of Medicine, Kyushu University
  • Yoshikawa Yu
    Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University
  • Yamaura Ken
    Department of Anesthesiology and Critical Care Medicine, Graduate School of Medicine, Kyushu University
  • Tsuda Makoto
    Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University

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Other Title
  • 脊髄後角ノルアドレナリンに関連した鎮痛効果に重要な脊髄後角抑制性神経サブセット

Description

<p>Pain information transmission/processing in the spinal dorsal horn (SDH) is strongly controlled by descending neurons from the brain. One of the major neurotransmitters of descending pathways is noradrenaline (NA). Descending NAergic neurons from the locus coeruleus (LC) is known to produce analgesic effects via activation of inhibitory interneurons in the SDH. However, the identity of the inhibitory interneuron subset in the SDH is poorly understood. Recently, we have found a subset of the SDH inhibitory interneurons captured by adeno-associated viral (AAV) vectors incorporating a neuropeptide Y promoter (AAV-NpyP+) that is crucial for neuropathic allodynia. Here, we showed that this neuronal subset is a major target of spinal NA to inhibit pain information transmission/processing. Whole-cell patch-clamp recordings using spinal cord slices revealed that NA predominantly depolarizes AAV-NpyP+ neurons. This effect was suppressed by a pharmacological blockade and genetic knockdown of α1B-adrenoceptor (AR) in AAV-NpyP+ neurons in the SDH. Furthermore, we found that the analgesic effect of duloxetine on neuropathic pain which is associated with an increase in the spinal NA level by inhibiting NA reuptake into presynaptic terminals is reduced by AAV-NpyP+ neuron-selective knockdown of α1B-ARs. These results indicate that α1B-ARs expressed in AAV-NpyP+ neurons would be a target of spinal NA presumably from descending LC neurons and contribute to the analgesic effect of duloxetine. Thus, spinal α1B-ARs could be a new therapeutic target.</p>

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