Original Research Article
mTOR activation by constitutively active serotonin6 receptors as new paradigm in neuropathic pain and its treatment

https://doi.org/10.1016/j.pneurobio.2020.101846Get rights and content
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Highlights

  • Constitutively active spinal 5-HT6 receptors activate mTOR in neuropathic pain.

  • 5-HT6 receptor inverse agonists prevent allodynia and co-morbid cognitive deficits.

  • Disrupting 5-HT6 receptor/mTOR complex prevents allodynia and cognitive deficits.

  • Blocking the 5-HT6/mTOR pathway is a new avenue for neuropathic pain treatment.

Abstract

Chronic neuropathic pain is a highly disabling syndrome that is poorly controlled by currently available analgesics. Here, we show that painful symptoms and associated cognitive deficits induced by spinal nerve ligation in the rat are prevented by the administration of serotonin 5-HT6 receptor inverse agonists or by the mTOR inhibitor rapamycin. In contrast, they are not alleviated by the administration of 5-HT6 receptor neutral antagonists. Likewise, activation of mTOR by constitutively active 5-HT6 receptors mediates allodynia in oxaliplatin-induced peripheral neuropathy in rats but not mechanical nociception in healthy rats. Furthermore, both painful and co-morbid cognitive symptoms in neuropathic rats are strongly reduced by intrathecal delivery of a cell-penetrating peptide that disrupts 5-HT6 receptor/mTOR physical interaction. Collectively, these findings demonstrate a deleterious influence of non-physiological mTOR activation by constitutively active spinal 5-HT6 receptors upon painful and cognitive symptoms in neuropathic pains of different etiologies. They suggest that targeting the constitutive activity of 5-HT6 receptors with inverse agonists or disrupting the 5-HT6 receptor/mTOR interaction might be valuable strategies for the alleviation of neuropathic pain and cognitive co-morbidities.

Abbreviations

AUC
area under the curve
CIPN
chemotherapy-induced peripheral neuropathy
CPPQ
(S)-1-[(3-chlorophenyl)sulfonyl]-4-(pyrrolidine-3-yl-amino)-1H-pyrrolo[3,2-c]quinoline dihydrochloride
IIQ
4-{[5-methoxy-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-1-yl]sulfonyl}isoquinoline dihydrochloride
MPE
maximal possible effect
NNT
number needed to treat
NOR
novel object recognition
OXA
oxaliplatin
PZ-1388
2-(3-fluorophenyl)-1-[(3-chlorophenyl)sulfonyl]-N-(piperidin-4-yl)-1H-pyrrole-3-carboxamide hydrochloride
RM
repeated measure
SNL
spinal nerve ligation
SNRI
serotonin-noradrenaline reuptake inhibitor
SSRI
selective serotonin reuptake inhibitor
TCA
tricyclic antidepressant

Keywords

Neuropathic pain
Cognitive deficit
5-HT6 receptor
Constitutive activity
mTOR
Inverse agonist

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