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

•Anterior cingulate cortex contributes to the emotional/affective distress in chronic pain.•Dysfunction of HCN channels increase cellular excitability in chronic pain.•LP-211 is a brain-penetrant 5-HT7 receptor agonist that enhances HCN channel function.•LP-211 alleviates the sensory and affective/emotional pain behavior in neuropathic animals.

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.