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Deficient Inhibitory Endogenous Pain Modulation Correlates With Periaqueductal Gray Matter Metabolites During Chronic Whiplash Injury

Serrano-Muñoz, Diego PhD*; Galán-Arriero, Iriana PhD*,†; Ávila-Martín, Gerardo PhD*,‡; Gómez-Soriano, Julio PhD§; Florensa, José PhD; García-Peris, Antonio MD; Romero-Muñoz, Luis M. PhD§; Barriga-Martín, Andrés PhD¶,#; Taylor, Julian PhD*,**,††

doi: 10.1097/AJP.0000000000000722
Original Articles

Objectives: This study examined predictive correlations between periaqueductal gray (PAG) and anterior cingulate cortex (ACC) metabolite levels with deficient inhibitory endogenous pain modulation (EPM), including sensory and affective measures of pain during chronic whiplash injury (WHI).

Materials and Methods: Healthy patients, and participants with chronic WHI, without (WHI-noP) or with pain (WHI-P), were screened with the Douleur Neuropathique 4 tool (DN4). EPM was assessed with C6 tonic heat pain stimuli with a Conditioned Pain Modulation (CPM) protocol. Magnetic resonance spectroscopy quantified ACC and PAG metabolite levels.

Results: WHI-P participants were characterized with high pain intensity and interference, and lower quality of life scores, compared with WHI-noP. Inhibitory CPM at 30 seconds was identified in the healthy noninjured (−45±16%; P<0.001) and WHI-noP groups (−36±8%; P<0.001). However, inhibitory EPM was not detected in the WHI-P group (−25±15%; P=0.06). Best fit and stepwise multiple regression revealed that the PAG glutamate/myoinositol metabolite ratio (P=0.01) and total creatine levels (P=0.02) predicted loss of EPM in the WHI-P group (r2=0.71, α=0.97). Although myoinositol predicted loss of EPM in the ACC (P=0.04), this was below statistical power (r2=0.31; α=0.56). The ACC N-acetyl-aspartate/myoinositol ratio (P=0.006) predicted chronic pain (DN4, r2=0.53; α=0.87).

Discussion: The results of this study demonstrate deficient EPM at 30 seconds during tonic heat pain stimulation in WHI-P participants, compared with noninjured healthy volunteers or individuals with WHI-noP. In addition, quantification of PAG and ACC metabolites related to glutamate and glia predicted central chronic pain mechanisms related to loss of inhibitory EPM, while ACC metabolites characterized chronic pain described by descriptors and sensory changes.

*Sensorimotor Function Group, National Hospital of Paraplegics, SESCAM

ITAS Group, Faculty of Health Sciences, University of Castilla La Mancha, Talavera de la Reina

Integrated Management Health Area, SESCAM, Talavera de la Reina

§Toledan Physiotherapy Research Group, Faculty of Nurse and Physiotherapy, University of Castilla La Mancha

Radiodiagnosis Service, National Hospital of Paraplegics, SESCAM

Research Group in Spine Pathology, Orthopedic Surgery and Traumathology Unit, National Hospital of Paraplegics, SESCAM

#Faculty of Medicine, University of Castilla La Mancha, Toledo, Spain

**Harris Manchester College, University of Oxford, Oxford

††Stoke Mandeville Spinal Research, National Spinal Injuries Centre, Buckinghamshire Healthcare NHS Trust, Aylesbury, UK

Present address: Iriana Galán-Arriero, PhD, ITAS Group, Faculty of Health Sciences, University of Castilla La Mancha, Avda. Real Fábrica de Sedas, s/n, Talavera de la Reina, 45600, Toledo, Spain.

Supported by the “Fundación Mutua Madrileña-Adeslas 2015-2018,” which included a maintenance grant for DSM and the DolSCI Special Emphasis Network Capital Grant from Spinal Research UK. The funders were not involved in the study design. The authors declare no conflict of interest.

Reprints: Iriana Galán-Arriero, PhD, Sensorimotor Function Group, Hospital Nacional de Parapléjicos, Finca La Peraleda s/n, Toledo 45071, Spain (e-mail:

Received August 1, 2018

Received in revised form March 19, 2019

Accepted April 14, 2019

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