Neural correlates of hyperalgesia in the monosodium iodoacetate model of osteoarthritis pain

Maryam Abaei, Devi R Sagar, Elizabeth G Stockley, Clare H Spicer, Malcolm Prior, Victoria Chapman, Dorothee P Auer, Maryam Abaei, Devi R Sagar, Elizabeth G Stockley, Clare H Spicer, Malcolm Prior, Victoria Chapman, Dorothee P Auer

Abstract

Background: The mechanisms driving osteoarthritic pain remain poorly understood, but there is increasing evidence for a role of the central nervous system in the chronification of pain. We used functional magnetic resonance imaging to investigate the influence of a model of unilateral knee osteoarthritis on nociceptive processing.

Results: Four to five weeks post intra-articular injection of monosodium iodoacetate (MIA, 1 mg) into the left knee, Sprague Dawley rats were anesthetized for functional magnetic resonance imaging studies to characterize the neural response to a noxious stimulus (intra-articular capsaicin injection). In a two-arm cross-over design, 5 µM/50 µl capsaicin was injected into either the left knee (n = 8, CAPS-MIA) or right control knee (n = 8, CAPS-CON), preceded by contralateral vehicle (SAL) injection. To assess neural correlates of mechanical hyperalgesia, hindpaws were stimulated with von Frey hairs (8 g: MIA; 15 g: control knee, based on behavioral withdrawal responses). The CAPS-MIA group exhibited significant activation of the periaqueductal gray, unilateral thalamus and bilateral mensencephalon, superior-colliculus, and hippocampus, with no significant activation in the other groups/conditions. Capsaicin injection increased functional connectivity in the mid-brain network and mediodorsal thalamic nucleus, hippocampus, and globus pallidus, which was significantly stronger in CAPS-MIA compared to CAPS-CON groups. Mechanical stimulation of the hyperalgesic (ipsilateral to MIA knee) and normalgesic (contralateral) hindpaws evoked qualitatively different brain activation with more widespread brainstem and anterior cingulate (ACC) activation when stimulating the hyperalgesic paw, and clearer frontal sensory activation from the normalgesic paw.

Conclusions: We provide evidence for modulation of nociceptive processing in a chronic knee osteoarthritis pain model with stronger brain activation and alteration of brain networks induced by the pro-nociceptive stimulus. We also report a shift to a medial pain activation pattern following stimulation of the hyperalgesic hindpaw. Taken together, our data support altered neural pain processing as a result of peripheral and central pain sensitization in this model.

Keywords: Hyperalgesia; osteoarthritis model; pain fMRI.

© The Author(s) 2016.

Figures

Figure 1.
Figure 1.
Study design: (a) across 32 day time period; (b) stimulation protocol during fMRI: 10 min block design (20 s on/20 s off) mechanical pain stimulation using 8 (or 15) g von Frey to the left (or right [L/R]) hindpaw and then 60 min single cross-over fMRI consisting of baseline, at 10 min, intra-articular (i.a.) injection of 50 µl saline (SAL) to MIA or control knee (CON), and at 25 min contralateral intra-articular injection of CAPS (50 µl CAPS).
Figure 2.
Figure 2.
Intra-articular injection of MIA significantly increased weight bearing asymmetry and decreased hind paw withdrawal thresholds on the ipsilateral side compared to baseline. Data are expressed as mean ± SEM (n = 16 rats). Statistical analysis was performed using a Kruskall Wallis test with a Dunn’s multiple comparison test. *p < 0.05, **p < 0.01, *** p < 0.001 compared to baseline.
Figure 3.
Figure 3.
Group mean fMRI activation (red–yellow, p < 0.05 corrected) for MIA-CAPS (CAPS injection into MIA knee, n = 8), overlaid on average T2-structural image. Blue lines indicate the borders for: (a) PAG, (b) Superior-Colliculus, (c) Mesencephalic region, (d) Thalamus, (e) Hypothalamus, and (f) Hippocampus.
Figure 4.
Figure 4.
CAPS-induced increased functional connectivity map in MIA-CAPS group (red–yellow) and in CON-CAPS group (blue-light) in axial view, overlaid on T2-weighted template (p < 0.05 corrected). The blue line indicates the structural borders of (a) Mesencephalic Region, (b) Cortex Insular, (c) Primary Motor Cortex, (d) Caudate-Putamen, (e, f) Cortex Parietal Association, (g) Cortex Somatosensory, and (h) Hippocampus Anterior Dorsal.
Figure 5.
Figure 5.
Intra-articular injection of CAPS induced an increase of functional connectivity in the mediodorsal thalamic nucleus (a), Hippocampus (b), and Globus Pallidus (c) in MIA-CAPS group compared to CON-CAPS group; corrected P < 0.05.
Figure 6.
Figure 6.
Activation maps (False discovery rate corrected, p < 0.05) evoked by von Frey pain stimulation of the hindpaw with a threshold hair: (a) ipsilateral to the control (left) knee (15 g von Frey hair) and (b) ipsilateral to the MIA (right) knee (8 g von Frey hair). Von Frey weights were chosen as the respective minimum force needed to elicit withdrawal in awake rats.

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