The Constitutive Activity of Spinal 5-HT₆ Receptors Contributes to Diabetic Neuropathic Pain in Rats

Area of Science:

• Neuroscience
• Pharmacology
• Diabetology

Background:

• Diabetic neuropathy frequently causes chronic pain and cognitive impairments.
• Serotonin type 6 (5-HT₆) receptor inverse agonists show promise for pain relief.
• Constitutive activity of 5-HT₆ receptors and mTOR signaling are implicated in neuropathic pain.

Purpose of the Study:

• To investigate the role of 5-HT₆ receptor constitutive activity and mTOR signaling in a rat model of diabetic neuropathic pain.
• To evaluate the therapeutic potential of 5-HT₆ receptor inverse agonists and mTOR inhibitors for neuropathic pain and cognitive deficits.

Main Methods:

• Induction of diabetic neuropathic pain in rats using streptozocin (STZ).
• Administration of 5-HT₆ receptor inverse agonists, rapamycin, or a cell-penetrating peptide.
• Assessment of mechanical hyperalgesia, tactile allodynia, and cognitive function.
• Investigation of 5-HT₆ receptor-mTOR interaction.

Main Results:

• 5-HT₆ receptor inverse agonists and rapamycin significantly reduced mechanical hyperalgesia and cognitive deficits in diabetic rats.
• These treatments also alleviated tactile allodynia in other neuropathic pain models (spinal nerve ligation, oxaliplatin).
• Intrathecal delivery of a peptide disrupting 5-HT₆ receptor-mTOR interaction ameliorated both pain and cognitive symptoms in diabetic rats.

Conclusions:

• Constitutive activity of spinal 5-HT₆ receptors contributes to painful and cognitive symptoms in diabetic neuropathic pain.
• Targeting 5-HT₆ receptor constitutive activity with inverse agonists is a potential strategy for managing diabetic neuropathic pain.
• Disrupting the 5-HT₆ receptor-mTOR interaction offers a novel therapeutic approach for diabetic neuropathic pain and associated cognitive comorbidities.