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

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


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.

MeSH terms

  • Analysis of Variance
  • Animals
  • Avoidance Learning / drug effects
  • Central Amygdaloid Nucleus / metabolism*
  • Central Amygdaloid Nucleus / pathology
  • Conditioning, Psychological / drug effects
  • Corticotropin-Releasing Hormone / genetics
  • Corticotropin-Releasing Hormone / metabolism
  • Corticotropin-Releasing Hormone / pharmacology
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Hyperalgesia / pathology*
  • Hyperalgesia / physiopathology
  • Male
  • Neurons / drug effects
  • Neurons / pathology
  • Odorants
  • Pain Measurement
  • Pain Threshold / drug effects
  • Pyrimidines / pharmacology
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Wistar
  • Receptors, Corticotropin-Releasing Hormone / antagonists & inhibitors
  • Receptors, Corticotropin-Releasing Hormone / genetics
  • Receptors, Corticotropin-Releasing Hormone / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Stress, Psychological / physiopathology*


  • Pyrimidines
  • R 121919
  • RNA, Messenger
  • Receptors, Corticotropin-Releasing Hormone
  • CRF receptor type 1
  • Corticotropin-Releasing Hormone