Background & Aims

Pre-surgical stress is a well-recognised risk factor for acute and chronic post-surgical pain (Rosenberger and Pogatzki-Zahn, 2022). While the precise underlying neurobiological mechanisms are unknown, neuro-immune interactions are believed to play a key role (Yang et al., 2020). Few preclinical animal studies have examined the effect of chronic stress on the post-surgical nociceptive response in rats (Arora et al., 2018; Meng et al., 2021) and, to our knowledge, none have examined effects on thermal hypersensitivity, latent sensitization or affective response. The aim of this study was to examine the effect of chronic stress on sensory and affective consequences of surgery and determine if these were associated with alterations in neuroimmune signalling in the spinal cord and anterior cingulate cortex.

Methods

Male 8-week-old Sprague-Dawley rats were exposed to repeated restraint stress (RRS, 6h/day for 21 days) or no restraint stress (handling). Fecal corticosterone levels, and behavioural despair assessed using the Forced Swim Test, were examined at the end of the restraint period, after which animals underwent paw incision or sham surgery. Mechanical and thermal hypersensitivity (electronic Von Frey [eVF] and Hargreaves [HG] test, respectively) were assessed prior to and periodically for 17 days post-surgery, while affective behaviour was assessed on day 2 (Place Escape/Avoidance Paradigm), 4 (Open Field Test), 6 (Elevated Plus Maze) and day 10 (Light Dark Box) post-surgery. On post-surgical days 23 and 26, naloxone (s.c. 3 mg/kg) was administered followed by eVF and HG to examine presence of latent sensitization. Expression of microglial and astrocyte activation markers Iba1, Itgam, Gfap, and IL1b was examined using RT-qPCR in the spinal dorsal horn and the anterior 5 days post-surgery.

Results

RRS resulted in increased fecal corticosterone levels, increased immobility in FST and increased anxiety-related behaviour in the OFT and EPM, but did not alter baseline mechanical and thermal sensitivity. RRS exacerbated ipsilateral mechanical and thermal hypersensitivity on post-surgical days 1-5 and prolonged post-surgical hypersensitivity by 6 days. RRS increased the aversion to mechanical stimuli (PEAP) and enhanced anxiety-like behaviour in the EPM and LDB. In contrast, RRS did not affect the surgery-induced increase in anxiety-related behaviour in the OFT. RRS prolonged naloxone-mediated reinstatement of thermal, but not mechanical, hypersensitivity in surgery animals. RRS increased the expression of Iba1, Itgam and IL1b in the ipsilateral dorsal horn of the spinal cord of surgery but not sham animals. No effect of RRS or surgery on microglial and astrocyte activation was observed in the anterior cingulate cortex.

Conclusions

RRS increased despair- and anxiety-like behaviour and corticosterone levels, without altering baseline mechanical and thermal sensory responding. However, RRS is associated with increased magnitude and duration of post-surgical mechanical and thermal hypersensitivity, increased anxiety-like behaviour, as well as prolonged opioid antagonist-mediated reinstatement of hypersensitivity, demonstrating that chronic stress can affect both the sensory and the affective component of post-surgical pain. These behavioural effects were associated with elevated levels of reactive microglia and proinflammatory cytokines in the spinal cord, suggesting that increased spinal neuro-immune signalling may mediate, at least in part, the exacerbation of the post-surgical pain phenotype observed following chronic stress.

References

Arora et al. (2018). Neuroscience 382 35–47
Meng et al. Pain Physician (2021).24:E1099-E1108 • ISSN 1533-315.
Rosenberger and Pogatzki-Zahn (2022)BJA Education, 22(5): 190e196.
Yang et al. (2020). Nat Immunol (11): 1319–1326.

Presenting Author

Ariadni Bella

Poster Authors

Ariadni Bella

MSc

Univeristy of Galway/Univeristy of Strasbourg

Lead Author

David Finn

University of Galway

Lead Author

Ipek Yalcin

UNIVERSITY OF STRASBOURG

Lead Author

Topics

  • Mechanisms: Biological-Molecular and Cell Biology