Abstract
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Objectives To establish a metabolic signature of pain using micropositron emission tomography, 18FDG, and two animals models: the acetic acid writhing and the formalin pain assays. To clarify sex-linked divergence in pain (Mogil 2012), we analyzed male vs. female behavioral and metabolic differences using the formalin assay.
Methods Rodents first received baseline 18FDG scans. Formalin paw animals received 50µl of 5% formalin in the left rear paw 10 minutes prior to 18FDG to capture the inflammatory phase. Pain scoring used the Dubuisson and Dennis method. Acetic acid animals received 0.9% acetic acid (10ml/kg, IP) 15 minutes after 18FDG injection. Behavior was recorded for 30 minutes. Images were reconstructed using OSEM-MAP algorithms and co-registered to a standard rat atlas (Paxinos and Watson) using PMOD. Statistical comparisons were done using SPM5.
Results The acetic acid group averaged 12.65 ± 1.69 writhes and increases in 18FDG uptake occurred in the dorsolateral periaqueductal grey, retrosplenial granular cortex, and the intermediate reticular nucleus. The formalin group expressed a pain score of 2.15 ± 0.19. Increases in 18FDG uptake also occurred in the dorsolateral periaqueductal grey, striatum, hippocampus, cerebellum, and thalamus. Males and females had similar activations in the periaqueductal grey and thalamus, but females have significant decreases in the caudate putamen and decreased uptake in the nucleus accumbens shell. Behaviorally, females express a higher pain score (1.5 vs. 0.5) than males at the start of the inflammatory phase, and a slightly higher behavioral expression of pain overall.
Conclusions Regions associated with addiction (i.e., striatum and thalamus) are activated in peripheral but not in visceral pain. A pharmacologic strategy targeted at blocking brain activations in regions associated with addiction may block opioid's abuse potential while not affecting their analgesic properties. We have shown that regions associated with dopaminergic neurons, pain and memory are different and may be responsible for the behavioral differences we observed in males and females.
Research Support Funded by Department of Defense (DOD) Grant PR 094020 WKS.