Background & Aims

Background & Aims: The clinical impact of pain is greatest in women, who are more likely to report chronic pain. However, the majority of preclinical pain studies are performed on male animals, leading to a significant knowledge gap.
Treatments for chronic pain conditions such as osteoarthritis (OA) have limited efficacy, and many people are still prescribed opioids, despite mounting evidence that they provide limited longterm benefit and often have severe side effects. Recent evidence suggests that prior opioid-exposure can worsen outcomes to subsequent painful injury, but the underlying mechanisms are unknown.
Aims: 1) Develop a preclinical mode of opioid pre-exposure and OA pain in female rats. 2) Probe the underlying mechanisms using in vivo spinal electrophysiology and ex vivo molecular and anatomical approaches

Methods

Methods: Female Sprague-Dawley rats (~8 weeks) received bi-daily systemic doses of saline (1mL/kg) or morphine (3mg/kg, s.c) for one week, then a single intra-articular injection of saline (50µL) or monosodium iodoacetate (MIA, 2mg), creating 4 experimental groups (n=12/group)
1.Saline/saline – opioid naïve, pain-free
2.Saline/MIA – opioid naïve, with OA-like pain
3.Morphine saline – sustained opioid exposure, pain-free
4.Morphine/MIA – sustained opioid exposure, with OA-like pain
Dosing continued for a further 3 weeks, with changes in withdrawal thresholds (PWT) and weight-bearing asymmetry assessed. Spinal cord protein expression was analysed via Western blotting (n=6/group), or spinal multi-electrode array (MEA) recordings were performed to assess sensory network responses to mechanical and electrical stimuli (n=6/group). Knee joint pathology was scored via macroscopic or microscopic analyses.

Results

Sustained morphine treatment exacerbated OA-like pain in female rats, with greater change in weight-bearing asymmetry (-24% vs -12%, p<0.01) and markedly lower PWTs (change of -2.56 vs -0.28 hairs, p<0.01) observed compared to MIA alone. Histological analyses revealed comparable joint pathology between the two MIA groups. Spinal MEA recordings in rats revealed a significant increase in C fibre latency responses in morphine/MIA treated rats in the intermediate dorsal horn when compared to saline/MIA (0.31 vs 0.13 threshold crossings/ms, p<0.01). Wind up (a marker of spinal sensitization) in the intermediate and deep dorsal horn also occurs earlier and is significantly greater in the morphine/MIA group compared to saline/MIA. These data demonstrate regionally specific alterations in the sensory network activity following sustained morphine treatment in the model of OA pain. Ongoing anatomical investigations are exploring the mechanisms underlying these functional changes.

Conclusions

Sustained morphine exposure increased OA-like pain behaviour in female rats, modelling the clinical situation. MEA recordings revealed regional specific change in spinal network activity, indicating a locus in the intermediate and deep dorsal horn. Complementary anatomical (immunohistochemistry & super-resolution microscopy) approaches are being employed to investigate the cellular mechanisms.

References

This work was supported by MRC (grant MR/W019663/1).
The authors state no conflicts of interest.

Presenting Author

Victoria Chapman

Poster Authors

Victoria Chapman

BSc

School of Life Sciences, University of Nottingham

Lead Author

Stephen Woodhams

PhD

University of Nottingham

Lead Author

Gareth Hathway

PhD

University of Nottingham

Lead Author

Topics

  • Models: Musculoskeletal