# [¹⁸F]Fluspidine PET/CT imaging to assess postoperative pain-associated σ1 receptor expression in female rats under analgesia

## TL;DR

[¹⁸F]Fluspidine PET/CT imaging can detect postoperative pain in rats even when they are under analgesia, offering a more reliable method for pain assessment.

## Contribution

This study introduces [¹⁸F]fluspidine PET/CT as a novel method for detecting σ1 receptor expression associated with postoperative pain in analgesia-treated rats.

## Key findings

- PET/CT imaging revealed elevated σ1R expression at the incision site on day 1 after surgery, despite analgesia.
- σ1R expression normalized by day 4, and no behavioral signs of pain were observed.
- Imaging with [¹⁸F]fluspidine is sensitive to peripheral σ1R upregulation even under non-steroidal anti-inflammatory drug treatment.

## Abstract

Pain assessment in animal models is challenging, as behavioral tests often lack sensitivity. Particularly under analgesia, it is unclear whether pain occurs without medication. Imaging of pain-associated pathways, such as σ1 receptor (σ1R) expression, offers a promising approach to better understand underlying mechanisms. Therefore, this study evaluated [¹⁸F]fluspidine positron emission tomography/computed tomography (PET/CT) imaging for detecting σ1R-mediated pain after partial liver resection in rats.

Postoperative pain was assessed in eighteen female Wistar rats undergoing skin incision or partial liver resection. Nine untreated rats served as controls. Carprofen was administered for three consecutive days after surgery. PET/CT imaging was performed on postoperative days 1, 4, and 7. At each time point, organs and incision sites of three animals were harvested for histological analysis. Postoperative pain and welfare were monitored by observational score sheets, the Open Field test, Rat Grimace Scale, Von Frey test, fecal corticosterone metabolites, and hemograms.

Despite analgesic treatment, PET/CT and immunohistochemistry revealed elevated σ1R expression at the abdominal incision site on day 1 after partial liver resection in comparison to the other groups, likely due to the additional peritoneal opening. σ1R expression normalized by day 4. No behavioral indicators of pain or distress were observed, though mechanical hypersensitivity was detected on day 4 in all groups, likely due to carprofen side effects.

[18F]Fluspidine PET/CT imaging sensitively detected postoperative pain-associated σ1R expression independent of analgesia. This imaging modality could remarkably refine pain monitoring, opening to further studies using different pain and analgesia models.

[¹⁸F]Fluspidine PET/CT imaging demonstrates high sensitivity in detecting pain-associated σ1R upregulation despite non-steroidal anti-inflammatory drug administration. This approach offers valuable insights for refining pain assessment, improving severity grading, and enhancing the reliability and translational value of preclinical pain models.

PET/CT imaging with [18F]fluspidine sensitively detects pain-associated σ1R expression post-liver resection.Necessary analgesia interferes with some behavioral tests, limiting their reliability for pain assessment.[18F]Fluspidine detects peripheral σ1R upregulation despite non-steroidal anti-inflammatory drug analgesia.Imaging pain-associated receptors provides valuable insights for refining preclinical pain monitoring.

PET/CT imaging with [18F]fluspidine sensitively detects pain-associated σ1R expression post-liver resection.

Necessary analgesia interferes with some behavioral tests, limiting their reliability for pain assessment.

[18F]Fluspidine detects peripheral σ1R upregulation despite non-steroidal anti-inflammatory drug analgesia.

Imaging pain-associated receptors provides valuable insights for refining preclinical pain monitoring.