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. 2016 Sep;41(10):2463-72.
doi: 10.1038/npp.2016.44. Epub 2016 Mar 25.

Traumatic Stress Promotes Hyperalgesia via Corticotropin-Releasing Factor-1 Receptor (CRFR1) Signaling in Central Amygdala

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Free PMC article

Traumatic Stress Promotes Hyperalgesia via Corticotropin-Releasing Factor-1 Receptor (CRFR1) Signaling in Central Amygdala

Christy A Itoga et al. Neuropsychopharmacology. .
Free PMC article

Abstract

Hyperalgesia is an exaggerated response to noxious stimuli produced by peripheral or central plasticity. Stress modifies nociception, and humans with post-traumatic stress disorder (PTSD) exhibit co-morbid chronic pain and amygdala dysregulation. Predator odor stress produces hyperalgesia in rodents. Systemic blockade of corticotropin-releasing factor (CRF) type 1 receptors (CRFR1s) reduces stress-induced thermal hyperalgesia. We hypothesized that CRF-CRFR1 signaling in central amygdala (CeA) mediates stress-induced hyperalgesia in rats with high stress reactivity. Adult male Wistar rats were exposed to predator odor stress in a conditioned place avoidance paradigm and indexed for high (Avoiders) and low (Non-Avoiders) avoidance of predator odor-paired context, or were unstressed Controls. Rats were tested for the latency to withdraw hindpaws from thermal stimuli (Hargreaves test). We used pharmacological, molecular, and immunohistochemical techniques to assess the role of CRF-CRFR1 signaling in CeA in stress-induced hyperalgesia. Avoiders exhibited higher CRF peptide levels in CeA that did not appear to be locally synthesized. Intra-CeA CRF infusion mimicked stress-induced hyperalgesia. Avoiders exhibited thermal hyperalgesia that was reversed by systemic or intra-CeA injection of a CRFR1 antagonist. Finally, intra-CeA infusion of tetrodotoxin produced thermal hyperalgesia in unstressed rats and blocked the anti-hyperalgesic effect of systemic CRFR1 antagonist in stressed rats. These data suggest that rats with high stress reactivity exhibit hyperalgesia that is mediated by CRF-CRFR1 signaling in CeA.

Figures

Figure 1
Figure 1
Repeated testing does not alter thermal nociception, and predator odor increases thermal nociception in avoiders. (a) Mean±SEM paw withdrawal latency for experimentally naive rats. Latency remained stable over 32 days, indicating that repeated testing does not lead to sensitization nor habituation. (b) Mean±SEM paw withdrawal latency of Control (open triangles, solid line), Non-Avoider (open circles, dotted line), and Avoider (solid circle, solid line) rats at baseline and 48 h after odor (Avoider and Non-Avoider) or air (Control) exposure. Scatter plots denote (c) individual rat baseline paw withdrawal latency before odor exposure vs avoidance of predator paired chamber 24 h after odor exposure, (d) avoidance of predator paired chamber 24 h after odor exposure vs paw withdrawal latency 48 h after odor exposure, (e) avoidance of predator paired chamber 24 h after odor exposure vs avoidance of predator odor paired chamber 8 days after odor exposure. *Denotes p<0.05 when compared with pre-odor baseline. #Denotes p<0.05 when compared with Control and Non-Avoider 48 h after odor exposure.
Figure 2
Figure 2
Predator odor increases CRF in CeA of Avoiders, and Intra-CeA CRF produces CPA and hyperalgesia. (a) Mean±SEM pg CRF/mg total protein in CeA of CeA of Control (white bar), Non-Avoider (gray bar), and Avoider (black bar) rats. *Denotes p<0.05 when compared with Control and Non-Avoider. (b) Mean±SEM change in time spent in the Intra-CeA CRF-paired chamber. *Denotes p<0.05 trend analysis of CRF dose. (c) Mean±SEM paw withdrawal latency in rats infused in CeA with vehicle or CRF (0.5 μg). *Denotes p<0.05 when compared with vehicle infusion.
Figure 3
Figure 3
Predator odor does not increase CRF mRNA, CRFR1 mRNA, or CRF-positive cell counts. (a) Mean±SEM fold change of CRF mRNA level in CeA of Control (white bar), Non-Avoider (gray bar), and Avoider (black bar) rats. (b) Mean±SEM fold change of CRFR1 mRNA level in CeA of Control (white bar), Non-Avoider (gray bar), and Avoider (black bar) rats. (c) Photomicrograph shows representative CRF labeling in CeA under × 5 objective. Scale bar, 200 μm. White box indicates area of inset figure. The inset shows the individual CRF-ir cells under × 100 objective. Scale bar, 20 μm. (d) Mean±SEM CRF cell count per CeA section in Control (white bar), Non-Avoider (gray bar), and Avoider (black bar) rats. (e) Mean±SEM CRF cell count per CeL section in Control (white bar), Non-Avoider (gray bar), and Avoider (black bar) rats. (f) Mean±SEM CRF cell count per CeM section in Control (white bar), Non-Avoider (gray bar), and Avoider (black bar) rats.
Figure 4
Figure 4
Intra-CeA tetrodotoxin blocks anti-hyperalgesia effects of systemic R121919. Mean±SEM percent baseline paw withdrawal latency of Control (white bars), Non-Avoider (gray bars), and Avoider (black bars) rats with vehicle or R121919 systemic treatment and vehicle or tetrodotoxin infusion into CeA. *Denotes p<0.05 when compared with Control and Non-Avoider at the same treatment. #Denotes p<0.05 when compared with vehicle/vehicle treatment within a group. $Denotes p<0.05 when compared with R121919/vehicle treatment within a group.
Figure 5
Figure 5
Inhibition of CRFR1s in CeA blocks predator odor-induced increases in thermal nociception in avoiders. Mean±SEM paw withdrawal latency of Control (white bars), Non-Avoider (gray bars), and Avoider (black bars) rats infused in CeA with vehicle or one of three R121919 doses (0.0625, 0.125, and 0.25 μg). *Denotes p<0.05 when compared with Controls and Non-Avoider rats. #Denotes p<0.05 when compared with all other drug doses within Avoider rats.

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