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<p>Parkinson’s disease (PD)-associated pain, linked to locus coeruleus noradrenergic (LC-NE) degeneration, involves spinal dorsal horn (SDH) nociceptive dysregulation. Using a unilateral 6-OHDA rat PD model combined with DSP-4-induced NE depletion, this study investigated the potential linkage between α<sub>2</sub> adrenergic receptor dysfunction and Cav2.2 channel dysregulation in pain pathogenesis. 6-OHDA-induced rats exhibited mechanical/thermal hypersensitivity, exacerbated by DSP-4 co-administration, alongside SDH neuronal hyperactivity (c-FOS), gliosis (GFAP + astrocytes, IBA1 + microglia), inflammatory cytokine elevation, and Cav2.2 upregulation. Clonidine (α<sub>2</sub> agonist) concomitantly restored spinal NE levels, reversed nociceptive thresholds, suppressed glial activation, normalized glutamate/GABA imbalance, and downregulated Cav2.2 expression. Notably, Ω-conotoxin GVIA (Cav2.2 antagonist) similarly produced alleviated hypersensitivity, attenuated neuroinflammation, and rebalanced excitatory-inhibitory synaptic transmission. LC-NE degeneration exacerbates PD pain through α<sub>2</sub> receptor–associated Cav2.2 hyperactivity in the SDH, potentially driving neuro-glial crosstalk, excitatory-inhibitory dysregulation, and inflammatory signaling.</p>

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Noradrenergic α2 Receptor Modulates Cav2.2-Mediated Nociception in Parkinson’s Disease Through Spinal Neuro-glial Network

  • 期刊论文

  • 发表日期：

    2025年11月19日

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  • Shouye Cui,
  • Yuan He,
  • Yueting Gu,
  • Hanjing Wu,
  • Dequan Guo,
  • Limei Zhang

摘要

Parkinson’s disease (PD)-associated pain, linked to locus coeruleus noradrenergic (LC-NE) degeneration, involves spinal dorsal horn (SDH) nociceptive dysregulation. Using a unilateral 6-OHDA rat PD model combined with DSP-4-induced NE depletion, this study investigated the potential linkage between α2 adrenergic receptor dysfunction and Cav2.2 channel dysregulation in pain pathogenesis. 6-OHDA-induced rats exhibited mechanical/thermal hypersensitivity, exacerbated by DSP-4 co-administration, alongside SDH neuronal hyperactivity (c-FOS), gliosis (GFAP + astrocytes, IBA1 + microglia), inflammatory cytokine elevation, and Cav2.2 upregulation. Clonidine (α2 agonist) concomitantly restored spinal NE levels, reversed nociceptive thresholds, suppressed glial activation, normalized glutamate/GABA imbalance, and downregulated Cav2.2 expression. Notably, Ω-conotoxin GVIA (Cav2.2 antagonist) similarly produced alleviated hypersensitivity, attenuated neuroinflammation, and rebalanced excitatory-inhibitory synaptic transmission. LC-NE degeneration exacerbates PD pain through α2 receptor–associated Cav2.2 hyperactivity in the SDH, potentially driving neuro-glial crosstalk, excitatory-inhibitory dysregulation, and inflammatory signaling.