The periaqueductal gray in chronic low back pain: dysregulated neurotransmitters and function

Pain. 2025 May 15. doi: 10.1097/j.pain.0000000000003617. Online ahead of print.

ABSTRACT

Mechanisms underlying chronic pain are insufficiently understood, hampering effective treatment approaches. Preclinical evidence suggests a potential contribution of decreased excitatory (glutamatergic) and increased inhibitory (γ-aminobutyric acid [GABA]ergic) neurotransmission in the periaqueductal gray (PAG), a key descending pain modulatory brainstem area. This magnetic resonance spectroscopy (MRS) study investigated (1) whether a lower excitatory/inhibitory balance is also observed in the PAG of patients with nonspecific chronic low back pain (CLBP) and (2) whether the excitatory/inhibitory balance relates to psychophysical measures of descending pain modulation and pain sensitivity. Magnetic resonance spectroscopy was acquired on a 3T MR system in 41 patients with CLBP and 29 age- and sex-matched controls. Descending pain modulation and pain sensitivity were evaluated using conditioned pain modulation and pressure pain stimuli, respectively, which were both assessed at the lower back as the most painful area and the nondominant hand as a pain-free, remote area. Patients with CLBP presented with a lower glutamate + glutamine (Glx)/GABA ratio compared with controls (P = 0.002), driven by both decreased Glx (P = 0.012) and increased GABA (P = 0.038). Controls with lower Glx/GABA were more sensitive to pressure pain in both areas, but this association was missing in the patients (lower back: P = 0.004; hand: P = 0.002). Patients with more severe clinical pain showed impaired descending pain modulation at the hand (P = 0.003). In line with preclinical evidence, these findings support a dysregulated PAG in patients with CLBP that might be associated with dysfunctional descending pain inhibition.

PMID:40372313 | DOI:10.1097/j.pain.0000000000003617