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

At a Glance

Category	Detail
Condition	Chronic inflammatory and neuropathic pain
Key Mechanisms	mTORC2 signaling modulates spinal nocioceptive plasticity via actin-dependent structural changes and mTORC1-dependent mRNA translation; phosphorylation of Akt at serine 473 indicates mTORC2 activity
Target Population	Patients with chronic inflammatory or neuropathic pain involving spinal nocioceptive pathways
Care Setting	Neurological and pain management clinical settings

Key Highlights

Pharmacological activation of spinal mTORC2 induces mechanical and thermal pain hypersensitivity.
Inhibition or genetic ablation of mTORC2 component Rictor in spinal cord alleviates inflammatory and neuropathic pain symptoms.
Cell type-specific deletion of Rictor reveals distinct roles of mTORC2 in excitatory and inhibitory spinal neurons in mediating pain hypersensitivity.

Guideline-Based Recommendations

Diagnosis

Consider assessment of spinal mTORC2 activity via biomarkers such as phosphorylated Akt (serine 473) in research settings to understand chronic pain mechanisms.

Management

Target spinal mTORC2 signaling for therapeutic intervention to reduce inflammatory and neuropathic pain.
Use of antisense oligonucleotides (ASOs) targeting Rictor or selective inhibition of mTORC2 in spinal neurons may alleviate pain hypersensitivity.

Monitoring & Follow-up

Monitor pain hypersensitivity symptoms (mechanical and thermal) following interventions targeting mTORC2.
Evaluate functional changes in spinal synaptic potentiation as a correlate of treatment efficacy.

Risks

Potential off-target effects of mTORC2 modulation need consideration due to its role in synaptic plasticity and memory formation.
Cell type-specific targeting is important to minimize adverse effects on inhibitory or excitatory neuronal functions.

Patient & Prescribing Data

Adult male and female mice models of inflammatory and neuropathic pain; translational relevance to human chronic pain patients

Intrathecal administration of mTORC2 activators induces pain hypersensitivity; antisense oligonucleotides targeting Rictor reduce pain symptoms; genetic ablation studies support cell-specific therapeutic targeting.

Clinical Best Practices

Consider spinal mTORC2 as a novel therapeutic target in chronic pain management.
Employ cell type-specific strategies to inhibit mTORC2 in excitatory or inhibitory spinal neurons depending on pain etiology.
Use behavioral and molecular assays to evaluate treatment response and spinal synaptic plasticity changes.
Incorporate both male and female subjects in preclinical studies to ensure generalizability of findings.