Coluzzi 2025 — Microglial activation in nociplastic pain (TSPO-PET → therapy)

One-paragraph summary

Narrative review consolidating the evidence that microglial activation drives nociplastic pain, with FM positioned as the prototype condition. Two strands integrated: (1) preclinical models showing microglial activation produces and sustains the central-sensitization phenotype; (2) TSPO-PET neuroimaging in patients showing strong correlation between widespread microglial activation and nociplastic-pain syndromes — strongest in FM. The review's therapeutic claim: nociplastic pain is currently a diagnosis of exclusion because no specific biomarkers exist, but TSPO-PET-positive patients are a candidate sub-population for glial-targeted therapy. Provides the strongest single piece of evidence in the project for promoting neuroinflammation_glial → central_sensitization toward established.

Claims as triples

• microglia — causes → neuroinflammation_glial [evidence: TSPO-PET + preclinical models; confidence: emerging]
• neuroinflammation_glial — modulates → central_sensitization [evidence: TSPO-PET correlation with nociplastic pain; confidence: emerging]
• tspo_pet — predicts → fm_inflammatory_central [evidence: strong correlation in FM; confidence: emerging]
• fm_inflammatory_central — responds_to → low_dose_naltrexone [inferred: glial-targeted therapy class; confidence: inferred]

Methods note

Narrative review by an Italian/UK group (Coluzzi: Sapienza Rome; Malcangio: King's College London — established preclinical-pain neuroinflammation lab). Reviews preclinical literature and PET imaging studies. Not systematic. Authors are pain researchers, not neuroimmunologists — strengths/weaknesses of that perspective.

Limitations

• Narrative review — selection bias possible. Should be cross-checked against systematic reviews (e.g., Albrecht/Loggia primary work) before tier promotion.
• The diagnostic-of-exclusion framing for nociplastic pain is contested — the IASP framework treats nociplastic as a positive diagnosis, not exclusion.
• The therapeutic-strategy section is hypothesis-generating, not based on RCT evidence specific to TSPO-positive FM patients (because such trials don't exist yet).

Open questions raised

• Are TSPO-PET signal magnitude and central-sensitization severity quantitatively correlated within FM (graded), or is it binary (TSPO-positive = inflammatory subtype)? (Q5 directly addressed.)
• Do TSPO-positive FM patients differ in treatment response to LDN, minocycline, P2X4/P2X7 antagonists vs. TSPO-negative FM patients? (Subtype-stratified trial design question.)
• Is microglial activation the cause of central sensitization or its consequence? (Q2.)

Triangulation notes

• Anchors neuroinflammation_glial as a well-supported emerging-tier mechanism. Combined with the autoimmune-anchor papers, the project's evidence base now has two independent FM mechanistic threads (autoimmune-IgG and central-glial), each well-supported.
• The autoimmune and inflammatory-central subtypes are likely not the same patients: autoantibody-positive FM (Seefried 2025) ≈ 37%, TSPO-positive FM (Coluzzi 2025 narrative) — overlap unknown. Q14, Q5 address this directly.
• Therapeutic implication: TSPO-positive subtype is a candidate for low-dose naltrexone, minocycline, or P2X4/P2X7 antagonist trials.

Bridges

• B5 (Glymphatic ↔ FM via sleep + neuroinflammation) — this review reinforces B5 by establishing that neuroinflammation is real in FM, but doesn't add glymphatic-specific data.
• B4 (ME/CFS ↔ FM via post-viral neuroimmune) — TSPO-PET findings extend to ME/CFS (Younger 2025 reportedly), so glial-activation is plausibly a shared mechanism.