Abstract
Back-translating the clinical manifestations of human disease burden into animal models is increasingly recognized as an important facet of preclinical drug discovery. We hypothesized that inbred rat strains possessing stress hyper-reactive-, depressive- or anxiety-like phenotypes may possess more translational value than common outbred strains for modeling neuropathic pain. Rats (inbred: LEW, WKY, F344/ICO and F344/DU, outbred: Crl:SD) were exposed to Spared Nerve Injury (SNI) and evaluated routinely for 6 months on behaviours related to pain (von Frey stimulation and CatWalk-gait analysis), anxiety (elevated plus maze, EPM) and depression (sucrose preference test, SPT). Markers of stress reactivity together with spinal/brain opioid receptor expression were also measured. All strains variously developed mechanical allodynia after SNI with the exception of stress-hyporesponsive LEW rats, despite all strains displaying similar functional gait-deficits after injury. However, affective changes reflective of anxiety- and depressive-like behaviour were only observed for F344/DU in the EPM, and for Crl:SD in SPT. Although differences in stress reactivity and opioid receptor expression occurred, overall they were relatively unaffected by SNI. Thus, anxio-depressive behaviours did not develop in all strains after nerve injury, and correlated only modestly with degree of pain sensitivity or with genetic predisposition to stress and/or affective disturbances.
Highlights
Back-translating the clinical manifestations of human disease burden into animal models is increasingly recognized as an important facet of preclinical drug discovery
We reported that the μ-opioid receptor agonist morphine possessed distinct analgesic profiles across various inbred and outbred rat strains both in the absence and presence of tissue injury26
We performed two-way repeated measures (RM) ANOVA for each individual strain, and found the effect of surgery to be significant for all strains, except for the Lewis strain ( FF344/ICO[1,330] = 94.24, P < 0.0001. FF344/DU[1,330] = 11.57, P = 0.0039. FWKY[1,352] = 134.7, P < 0.0001. FSD[1,286] = 25.98, P = 0.0002)
Summary
Back-translating the clinical manifestations of human disease burden into animal models is increasingly recognized as an important facet of preclinical drug discovery. We reported that the μ-opioid receptor agonist morphine possessed distinct analgesic profiles across various inbred and outbred rat strains both in the absence and presence of tissue injury26 Taken together, these observations suggest that strains with genetic predisposition to stress hyper-reactivity, depressive- or anxiety-like phenotypes could possess a higher translational value when assessing emotional comorbid burden as experienced by human pain patients. These observations suggest that strains with genetic predisposition to stress hyper-reactivity, depressive- or anxiety-like phenotypes could possess a higher translational value when assessing emotional comorbid burden as experienced by human pain patients We decided to investigate plasticity within the opioid pain modulatory systems in the current study based on our knowledge of strain-dependent opioid-mediated a nalgesia
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