Chronic stress-induced mechanical hyperalgesia is controlled by capsaicin-sensitive neurones in the mouse

Eur J Pain. 2017 Sep;21(8):1417-1431. doi: 10.1002/ejp.1043. Epub 2017 Apr 25.


Background: Clinical studies demonstrated peripheral nociceptor deficit in stress-related chronic pain states, such as fibromyalgia. The interactions of stress and nociceptive systems have special relevance in chronic pain, but the underlying mechanisms including the role of specific nociceptor populations remain unknown. We investigated the role of capsaicin-sensitive neurones in chronic stress-related nociceptive changes.

Method: Capsaicin-sensitive neurones were desensitized by the capsaicin analogue resiniferatoxin (RTX) in CD1 mice. The effects of desensitization on chronic restraint stress (CRS)-induced responses were analysed using behavioural tests, chronic neuronal activity assessment in the central nervous system with FosB immunohistochemistry and peripheral cytokine concentration measurements.

Results: Chronic restraint stress induced mechanical and cold hypersensitivity and increased light preference in the light-dark box test. Open-field and tail suspension test activities were not altered. Adrenal weight increased, whereas thymus and body weights decreased in response to CRS. FosB immunopositivity increased in the insular cortex, dorsomedial hypothalamic and dorsal raphe nuclei, but not in the spinal cord dorsal horn after the CRS. CRS did not affect the cytokine concentrations of hindpaw tissues. Surprisingly, RTX pretreatment augmented stress-induced mechanical hyperalgesia, abolished light preference and selectively decreased the CRS-induced neuronal activation in the insular cortex. RTX pretreatment alone increased the basal noxious heat threshold without influencing the CRS-evoked cold hyperalgesia and augmented neuronal activation in the somatosensory cortex and interleukin-1α and RANTES production.

Conclusions: Chronic restraint stress induces hyperalgesia without major anxiety, depression-like behaviour or peripheral inflammatory changes. Increased stress-induced mechanical hypersensitivity in RTX-pretreated mice is presumably mediated by central mechanisms including cortical plastic changes.

Significance: These are the first data demonstrating the complex interactions between capsaicin-sensitive neurones and chronic stress and their impact on nociception. Capsaicin-sensitive neurones are protective against stress-induced mechanical hyperalgesia by influencing neuronal plasticity in the brain.

MeSH terms

  • Animals
  • Capsaicin / analogs & derivatives
  • Capsaicin / pharmacology*
  • Cold Temperature
  • Disease Models, Animal
  • Diterpenes / pharmacology*
  • Hot Temperature
  • Hyperalgesia / etiology*
  • Hyperalgesia / psychology
  • Male
  • Mice
  • Nociception / drug effects*
  • Nociceptive Pain / etiology*
  • Nociceptive Pain / prevention & control
  • Nociceptive Pain / psychology
  • Nociceptors / drug effects
  • Nociceptors / physiology
  • Restraint, Physical
  • Stress, Psychological / complications*


  • Diterpenes
  • resiniferatoxin
  • Capsaicin