Targeting spinal mechanistic target of rapamycin complex 2 alleviates inflammatory and neuropathic pain

By
Calvin Wong
Luis David Rodriguez-Hernandez
Kevin C Lister
Ning Gu
Weihua Cai
Mehdi Hooshmandi
Jonathan Fan
Nicole Brown
Vivienne Nguyen
Alfredo Ribeiro-da-Silva
Robert P Bonin
Arkady Khoutorsky
August 21, 2024
0 min

Brain

Overview

This study demonstrates that spinal mTORC2 plays a critical role in the development and maintenance of inflammatory and neuropathic pain. Pharmacological activation of mTORC2 induces pain hypersensitivity, while its inhibition via Rictor downregulation alleviates pain symptoms in mouse models.

Background

Chronic pain involves plastic changes in spinal nociceptive circuits. The mechanistic target of rapamycin (mTOR) exists in two complexes: mTORC1, well-known for regulating mRNA translation in pain sensitization, and mTORC2, which modulates actin dynamics and synaptic plasticity but whose role in spinal pain pathways is less understood. Previous evidence shows increased mTORC2 activity in spinal cord during pain states, but specific functional roles and therapeutic potential remained unclear. This study investigates spinal mTORC2's contribution to inflammatory and neuropathic pain using genetic and pharmacological approaches.

Data Highlights

Intervention	Effect on Pain Hypersensitivity
Intrathecal mTORC2 activator (A-443654)	Induced long-lasting mechanical and thermal hypersensitivity
Rictor antisense oligonucleotides (ASOs)	Alleviated inflammatory and neuropathic pain hypersensitivity
Rictor deletion in Tac1+ and TacR1+ excitatory neurons	Reduced inflammation-induced mechanical and thermal hypersensitivity; reduced nerve injury-induced heat hyperalgesia
Rictor deletion in inhibitory interneurons	Strongly alleviated nerve injury-induced mechanical hypersensitivity

Key Findings

Activation of spinal mTORC2 induces mechanical and thermal pain hypersensitivity.
Inhibition of mTORC2 via Rictor downregulation alleviates both inflammatory and neuropathic pain symptoms.
Selective deletion of Rictor in excitatory neurons impairs spinal synaptic potentiation and reduces inflammation- and nerve injury-induced pain hypersensitivity.
Deletion of Rictor in inhibitory neurons specifically reduces nerve injury-induced mechanical allodynia without affecting inflammatory pain.
mTORC2 activity, measured by Akt phosphorylation at serine 473, is increased in spinal cord during pain states.
Cell type-specific roles of mTORC2 highlight distinct mechanisms in mediating pain hypersensitivity.

Clinical Implications

Targeting spinal mTORC2 signaling, particularly through modulation of Rictor, represents a promising therapeutic strategy for chronic inflammatory and neuropathic pain. Cell type-specific interventions may allow tailored approaches to alleviate distinct pain modalities, potentially improving efficacy and reducing side effects.

Conclusion

Spinal mTORC2 is a key mediator of chronic pain hypersensitivity with distinct roles in excitatory and inhibitory neurons. Its inhibition offers a novel avenue for therapeutic intervention in inflammatory and neuropathic pain conditions.