The brain-penetrant 5-HT7 receptor agonist LP-211 reduces the sensory and affective components of neuropathic pain

NEUROBIOLOGY OF DISEASE

卷:106

Article

Santello, Mirko^1,3,4,5  Bisco, Alberto¹  Nevian, Natalie Elisabeth¹  Lacivita, Enza⁶  Leopoldo, Marcello⁶  Nevian, Thomas^1,2 

[1] Univ Bern, Dept Physiol, Buhlpl 5, CH-3012 Bern, Switzerland

[2] Univ Bern, Ctr Cognit Learning & Memory, Bern, Switzerland

[3] Univ Zurich, Inst Pharmacol & Toxicol, Winterthurerstr 190, CH-8057 Zurich, Switzerland

[4] Univ Zurich, Neurosci Ctr Zurich, CH-8057 Zurich, Switzerland

[5] Swiss Fed Inst Technol, CH-8057 Zurich, Switzerland

[6] Univ Bari Aldo Moro, Dept Pharm Drug Sci, Via Orabona 4, I-70125 Bari, Italy

关键词: Neuropathic pain;    Anterior cingulate cortex;    HCN channels;    Pyramidal neuron;   

DOI  :  10.1016/j.nbd.2017.07.005

来源: Elsevier

【 摘 要 】

Neuropathic pain is a debilitating pathological condition of high clinical relevance. Changes in neuronal excitability in the anterior cingulate cortex (ACC) play a central role in the negative emotional and affective aspects of chronic pain. We evaluated the effects of LP-211, a new serotonin-receptor-type-7 (5-HT7R) agonist that crosses the blood-brain barrier, on ACC neurons in a mouse model of neuropathic pain. LP-211 reduced synaptic integration in layer 5 pyramidal neurons, which was enhanced in neuropathic pain due to a dysfunction of dendritic hyperpolarization-activated-and-cyclic-nucleotide-regulated (HCN) channels. Acute injection of LP-211 had an analgesic effect, increasing the mechanical withdrawal threshold in neuropathic animals, which was partially mediated by an action in the ACC. Additionally, the acute application of LP-211 blocked the switch in the place escape/avoidance behavior induced by noxious stimuli. Thus systemic treatment with a 5-HT7R agonist leads to modulation of the ACC, which dampens sensory and affective aspects of chronic pain. (C) 2017 The Authors. Published by Elsevier Inc.

【 授权许可】

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