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bioRxiv · 10.1101/2021.04.30.442126

Long-term sensitization of rat spinal neurons induced by adolescent psychophysical stress is further enhanced by a mild-nociceptive lumbar input

Singaravelu, S. K.·Goitom, A.·Surakka, A. P.·Moerz, H.·Schilder, A.·Hansson, A.·Spanagel, R.·Treede, R.-D.
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Abstract

BackgroundNon-specific low back pain (LBP) is one of the most common chronic pain conditions and adverse childhood experiences (ACEs) are known mediators for chronicity of LBP. Sensitization of dorsal horn neurons (DHNs) is a significant element that contributes to chronic LBP. Repeated restraint stress in adult animals is known to cause manifest DHN sensitization when combined with a short-lasting nociceptive input. ObjectiveIn this study, we investigated whether repeated restraint stress in early adolescence leads to a long-term sensitization of DHNs and if an additional mild-nociceptive input by intramuscular nerve growth factor (NGF) leads to further sensitization. MethodsAdolescent Wistar rats were stressed repeatedly in a narrow plastic restrainer, 1 hour per day for 12 consecutive days. Control animals were handled but not restrained. In adulthood, rats were treated with intramuscular injections of saline or NGF (short-lasting mild-nociceptive input) into the lumbar multifidus muscle (L5). Behavioral tests for pain sensitivity were performed before, after stress and inconjunction with intramuscular injections. Rats were transcardially perfused and immunohistochemistry was performed on lumbar (L2) spinal segments. ResultsAdolescent restraint stress significantly lowered the low back pressure pain threshold (PPT) immediately after the stress (p<0.0001) and was maintained throughout adulthood (p<0.05). Additionally, paw withdrawal threshold (PWT) was significantly lowered by stress (p<0.0001) but normalized towards adulthood. An NGF injection in adulthood in previously stressed animals lowered the PPT (Cohens d=0.87) and increased microglia marker (Iba-1) immunoreactive area in the superficial DHN (p<0.01) with a trend in increased ferets diameter of the immunoreactive cell (p=0.05). ConclusionsOur adolescence stress model induced behavioral signs of sensitization and enhanced sensitivity to further sensitization and dorsal horn microglia activation by subsequent mild nociceptive input (NGF injection). These findings help to understand certain aspects of how adolescent stress might predispose to exacerbation of pain with an additional insult.

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Singaravelu, S. K., Goitom, A., Surakka, A. P., Moerz, H., Schilder, A., Hansson, A., Spanagel, R., Treede, R.-D.. 2021-04-30. Long-term sensitization of rat spinal neurons induced by adolescent psychophysical stress is further enhanced by a mild-nociceptive lumbar input. https://doi.org/10.1101/2021.04.30.442126

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