Central amygdala activation of extracellular signal-regulated kinase 1 and age-dependent changes in inflammatory pain sensitivity in mice

Abstract

Aging populations are more sensitive to noxious stimuli as a result of altered somatosensory systems. In these experiments, we examined pain-like behaviors in young, middle-aged, and old mice during peripheral inflammation to determine if the same sensitivity exists in pre-clinical animal models. Immediately following injury, middle-aged and old mice exhibited more spontaneous pain-like behaviors than young mice, matching pain prevalence in clinical populations. Middle-aged and old mice also developed persistent mechanical hypersensitivity in the injured paw. Furthermore, old mice developed mechanical hypersensitivity in the non-injured paw suggesting age-dependent changes in central nociceptive systems. To address this end, pain-related protein expression was examined in the central nucleus of the amygdala (CeA), a limbic brain region that modulates somatic pain. Following injury, increased phosphorylation of extracellular-signal regulated kinase 1 (ERK1), a protein with known nociceptive functions, was observed in the right CeA of old mice and not middle-aged or young animals. These findings suggest that age-dependent changes in supraspinal nociceptive systems may account for increased pain-like behaviors in aging populations.

Effects of Aging on Formalin-Induced Pain Behavior and Analgesic Activity of Gabapentin in C57BL/6 Mice

“…These results are in agreement with the evidence that aged animals develop heightened hypersensitivity in several experimental pain models (Crisp et al, 2003;Bishay et al, 2013) and that formalin test behavioral pattern is influenced by age (Gagliese and Melzack, 1999). Also under different experimental conditions (10 ml of 4% formalin solution (Kolber et al, 2010)), C57BL/6 mice display enhanced nociceptive behavior and increased variability among different ages in the second phase and mechanical allodynia (Sadler et al, 2017). Aged C57BL/6J mice present a mitochondrial impairment (Kadoguchi et al, 2020) and a decrease in oxidative phosphorylation as well as alteration in apoptosis regulation (see (Azzu and Valencak, 2017)).…”

The influence of aging and duration of nerve injury on the antiallodynic efficacy of analgesics in laboratory mice

“…However, other experiments comparing von Frey thresholds across similarly aged mice have reported no differences 16 or reduced sensitivity with increasing age. 24 Most experiments have used inbred C57BL/6 mice, rather than the outbred CD-1 mice used here. In the same manner as sex differences in pain and pain inhibition have been shown to interact thoroughly with genetic background, 10 , 20 aging effects almost certainly do as well.…”

Lateralized kappa opioid receptor signaling from the amygdala central nucleus promotes stress-induced functional pain

“…We found that KOR antagonism in the right CeA, but not the left CeA or RVM, prevented the loss of DNIC measured in either hindpaw in morphine primed animals. A lateralized role of the amygdala has been shown in inflammatory [13,33,63,75] and neuropathic pain [28] models and mGluR5 activation in the right, but not left, CeA is sufficient to produce peripheral hypersensitivity in the absence of injury [39]. Recently, we demonstrated that microinjection of a KOR agonist into the right, but not left, CeA produced allodynia in both hindpaws following priming with sumatriptan to model medication overuse headache [91].…”