CD3 + T cells are critical for the resolution of comorbid inflammatory pain and depression-like behavior

Neurobiol Pain. 2020 Jan 21;7:100043. doi: 10.1016/j.ynpai.2020.100043. eCollection Jan-Jul 2020.

Abstract

Background: Chronic pain and depression often co-occur. The mechanisms underlying this comorbidity are incompletely understood. Here, we investigated the role of CD3+ T cells in an inflammatory model of comorbid persistent mechanical allodynia, spontaneous pain, and depression-like behavior in mice.

Methods: C57Bl/6 wt and Rag2 -/- mice were compared in their response to intraplantar administration of complete Freund's adjuvant (CFA). Mechanical allodynia, spontaneous pain and depression-like behavior were assessed by von Frey, conditioned place preference and forced swim test respectively.

Results: Resolution of mechanical allodynia, spontaneous pain, and depression-like behavior was markedly delayed in Rag2 -/- mice that are devoid of adaptive immune cells. Reconstitution of Rag2 -/- mice with CD3+ T cells from WT mice before CFA injection normalized the resolution of indicators of pain and depression-like behavior. T cells did not contribute to onset or severity of indicators of pain and depression-like behavior. The lack of T cells did not affect cytokine expression in the paw, spinal cord and brain, indicating that the delayed resolution was not resulting from prolonged (neuro)inflammation.

Conclusions: Our findings show that T cells are critical for the natural resolution of mechanical allodynia, spontaneous pain, and depression-like behavior after an inflammatory challenge. Dysregulation of this T cell-mediated resolution pathway could contribute to the comorbidity of chronic pain and depression.

Significance: Chronic pain and depression are frequently associated with signs of inflammation. However, general immunosuppression is not sufficient to resolve comorbid pain and depression. Here we demonstrate that T cells are required for resolution of comorbid persistent mechanical allodynia, spontaneous pain, and depression in a model of peripheral inflammation, indicating the immune system can contribute to both onset and resolution of these comorbidities. Enhancing pro-resolution effects of T cells may have a major impact to treat patients with comorbid persistent pain and depression.

Keywords: CFA; Comorbidity; Depression-like behavior; Inflammatory pain; Recovery; T cells.