Aging and miR-155 in mice influence survival and neuropathic pain after spinal cord injury

Abstract

Spinal cord injury (SCI) elicits chronic pain in 65% of individuals. In addition, SCI afflicts an increasing number of aged individuals, and those with SCI are predisposed to shorter lifespan. Our group previously identified that deletion of the microRNA miR-155 reduced neuroinflammation and locomotor deficits after SCI. Here, we hypothesized that aged mice would be more susceptible to pain symptoms and death soon after SCI, and that miR-155 deletion would reduce pain symptoms in adult and aged mice and improve survival. Adult (2 month-old) and aged (20 month-old) female wildtype (WT) and miR-155 knockout (KO) mice received T9 contusion SCI. Aged WT mice displayed reduced survival and increased autotomy - a symptom of spontaneous pain. In contrast, aged miR-155 KO mice after SCI were less susceptible to death or spontaneous pain. Evoked pain symptoms were tested using heat (Hargreaves test) and mechanical (von Frey) stimuli. At baseline, aged mice showed heightened heat sensitivity. After SCI, adult and aged WT and miR-155 KO mice all exhibited heat and mechanical hypersensitivity at all timepoints. miR-155 deletion in adult (but not aged) mice reduced mechanical hypersensitivity at 7 and 14 d post-SCI. Therefore, aging predisposes mice to SCI-elicited spontaneous pain and expedited mortality. miR-155 deletion in adult mice reduces evoked pain symptoms, and miR-155 deletion in aged mice reduces spontaneous pain and expedited mortality post-SCI. This study highlights the importance of studying geriatric models of SCI, and that inflammatory mediators such as miR-155 are promising targets after SCI for improving pain relief and longevity.

Keywords: Aging; Chronic pain; Longevity; Mechanical allodynia; Neuroinflammation; Neuropathic pain; Spinal cord injury; Thermal hyperalgesia; microRNA.

Figure 1.

Aged WT mice with SCI had increased 6-week mortality and spontaneous pain, whereas miR-155 KO aged mice were protected from these post-SCI detriments. a. Adult WT and miR-155 KO mice and aged miR-155 KO mice had high post-SCI survival, whereas most aged WT mice died within 42 d after SCI. b. Fewer aged WT (33%, vs. 100% of adult WT) mice survived to 42 dpo; aged miR-155 KO mice had enhanced 6-week survival (70%). c. Timecourse of spontaneous pain after SCI in adult and aged WT and KO mice. Aged WT mice had higher pain incidence than adult WT mice. d. At 42 d post-SCI, aged mice had increased spontaneous pain vs. adult mice; miR-155 KO mice had reduced incidence of pain vs. WT mice (aged WT: 78%, aged KO: 30%). e. Horizontal plot of all individual aged WT and miR-155 KO mice showing onset and timing of autotomy (yellow circles and lines) and premature endpoints (red triangles). † indicates p<0.05 between adult and aged mice; * indicates p<0.05 between WT and KO mice; ANOVA with Holm-Sidak post-hoc test.

Figure 2.

Effects of aging and miR-155 deletion on sensory thresholds at baseline and after SCI (Hargreaves heat – a-c; von Frey mechanical – d-f). a. At baseline, aged mice had reduced response latency to heat. There was no significant effect of miR-155 deletion. b-c. Both adult (b) and aged (c) mice after SCI displayed heat hyperalgesia at all times tested (7–28 dpo). miR-155 deletion did not modify SCI-elicited heat hypersensitivity. d. Baseline mechanical thresholds were not significantly altered in aged or miR-155 KO mice. e,f. Both adult and aged WT mice exhibited mechanical allodynia from 7–28 d after SCI. Adult miR-155 KO mice had ameliorated mechanical hypersensitivity at 7 and 14 dpo. † indicates p<0.05 group difference between adult and aged mice; colored + indicates p<0.05 within-genotype between pre- and post-SCI thresholds; * indicates p<0.05 between WT and KO mice.