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


Santello, Mirko; Bisco, Alberto; Nevian, Natalie Elisabeth; Lacivita, Enza; Leopoldo, Marcello; Nevian, Thomas (2017). The brain-penetrant 5-HT7 receptor agonist LP-211 reduces the sensory and affective components of neuropathic pain. Neurobiology of Disease, 106:214-221.

Abstract

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.

Abstract

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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Pharmacology and Toxicology
07 Faculty of Science > Institute of Pharmacology and Toxicology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Uncontrolled Keywords:Neuropathic pain, Anterior cingulate cortex, HCN channels, Pyramidal neuron
Language:English
Date:6 July 2017
Deposited On:03 Aug 2017 14:29
Last Modified:28 Aug 2017 13:08
Publisher:Elsevier
ISSN:0969-9961
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1016/j.nbd.2017.07.005
PubMed ID:28690143

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