Background & Aims

Pain is a multidimensional phenomenon, comprised of affective-motivational, cognitive-evaluative, and sensory-discriminative domains (1). In the presence of pain with no single determinable etiology, such as fibromyalgia (FM), understanding the affective and cognitive dimensions of the disorder is crucial for adequate diagnosis and pain management. However, there is little empirical support for many of the primary animal models of FM in fully replicating this disorder. The current study sought to evaluate two primary preclinical models of FM – the reserpine (2) and subchronic swim stress (3) models – across all three pain dimensions and determine their predictive validity with an FDA-approved fibromyalgia pharmacologic, duloxetine (Cymbalta®). Further, this study sought to combine these two preclinical models to determine if their compounded effect better replicates reported clinical manifestations and management profiles across the affective, cognitive, and sensory domains.

Methods

Female Sprague-Dawley rats (N = 96) were randomized to a pain condition (reserpine, subchronic swim, or reserpinized subchronic swim) or their respective controls alongside a treatment condition (Duloxetine; 30 mg/kg) or a saline control treatment. Animals underwent behavioral sensory measures of mechanical paw withdrawal thresholds (MPWTs) and thermal withdrawal latencies (TWLs), affective measures of sucrose splash test (ST), thigmotaxis/locomotion, and elevated plus maze (EPM), and a cognitive assessment with an olfactory discrimination (OD) task. All sensory assessments were recorded at baseline (BL), pre-treatment (PT), and post-treatment (PoT), while all affective and cognitive measures were compared post-treatment.

Results

For MPWTs, a significant time by pain condition interaction was found from BL to PT (p < .001) and a significant main effect of pain condition/treatment was found PoT (p < .001). Similarly for TWLs, a significant time by pain condition interaction was identified from BL to PT (p = .027), but no effects of pain/treatment condition were found at PoT. No significant differences were identified in thigmotaxis behavior. In locomotion, a significant main effect of pain/treatment condition was identified (p < .001), where duloxetine decreased locomotive behaviors. Evaluation of anxiety-like behavior with EPM revealed an effect of pain/treatment condition on entries into the open arms (p = .012), time in the closed arms (p = .001), and time in the open arms of the chambers (p = .033). There were also trends identified in ST as a result of pain/treatment condition (p = .078), implicative of depression-like behavior. However, assessments of OD revealed no differences in cognition between groups.

Conclusions

Overall, reserpine was effective in producing mechanical hyperalgesia, and potentially time-dependent thermal hyperalgesia, but ineffective in replicating anxiety- and depression-like behavior. Subchronic swim stress was effective in producing mechanical hyperalgesia, and time-dependent thermal sensitivity, as well as trending effects of depression-like behavior, but no changes in anxiety-like behavior. The combination model produced mechanical sensitivity, and potentially time-dependent thermal sensitivity, alongside anxiety-like behaviors and trending depression-like behaviors. However, all models failed to produce changes in cognitive function. Duloxetine treatment selectively alleviated mechanical sensitivity and depression-like behaviors but may have offered adverse effects for anxiety-like behavior and locomotion. Future research should aim to identify the contexts within which these individual models and their combination best replicate the clinical multidimensionality of FM.

References

1. Melzack, R., & Casey, K. (1968). Sensory, Motivational, and Central Control Determinants of Pain: A New Conceptual Model. https://www.researchgate.net/publication/285016812
2. Nagakura, Y., Oe, T., Aoki, T., & Matsuoka, N. (2009). Biogenic amine depletion causes chronic muscular pain and tactile allodynia accompanied by depression: A putative animal model of fibromyalgia. Pain, 146(1–2), 26–33. https://doi.org/10.1016/j.pain.2009.05.024
3. Quintero, L., Moreno, M., Avila, C., Arcaya, J., Maixner, W., & Suarez-Roca, H. (2000). Long-lasting delayed hyperalgesia after subchronic swim stress. Pharmacology Biochemistry and Behavior, 67(3), 449-458.

Presenting Author

Cassie M. Argenbright

Poster Authors

Cassie Argenbright

PhD

St. Jude Children's Research Hospital

Lead Author

Tara M. Brinkman

PhD

St. Jude Children's Research Hospital

Lead Author

Perry N. Fuchs

PhD

The University of Texas Rio Grande Valley

Lead Author

Topics

  • Specific Pain Conditions/Pain in Specific Populations: Fibromyalgia