In vivo evidence for metabotropic glutamate receptor 5 dysregulation in chronic pain

Neuropsychopharmacology. 2025 Dec 19. doi: 10.1038/s41386-025-02296-9. Online ahead of print.

ABSTRACT

Chronic pain (CP) is a significant source of personal and public health burden with high prevalence (up to one in five in the United States) and few safe, effective treatment options. This study examined relationships between metabotropic glutamate receptor 5 (mGlu5) availability and CP in vivo for the first time. A transdiagnostic sample of individuals (major depressive disorder; bipolar disorder; healthy controls; N = 112) with and without CP or acute pain completed clinical assessments and participated in an [¹⁸F]FPEB positron emission tomography (PET) scan. Results indicated that mGlu5 availability was 13.5-15.7% lower in individuals with pain relative to those with no pain (p’s = -0.002-0.029) in brain regions implicated in the neurophysiology of pain. Results did not change when controlling for demographics or psychiatric diagnosis. Exploratory analyses demonstrated lower mGlu5 availability in individuals with CP (10.3-14.2% difference) or both acute and CP (15.9-21.1% difference) than those with acute pain only, suggesting specific associations between mGlu5 and CP. Individuals with pain reported more severe depression (p’s = 0.008-0.022) and anxiety (p = 0.009), sleep disturbances (p < 0.001), and worse cognitive functioning (p’s = 0.009-0.025). Across various regions, mGlu5 availability was negatively associated with depression (r’s = -0.24-0.33), anxiety (r = -0.27), and executive dysfunction (r’s = -0.24-0.33); mGlu5 was not related to sleep disturbance. This study demonstrated lower mGlu5 availability in individuals with pain across psychiatric groups and presents mGlu5 as a promising treatment target for pain with low abuse potential, warranting future research examining mGlu5 for pain reduction.

PMID:41413678 | DOI:10.1038/s41386-025-02296-9