Age-related gene expression changes in lumbar spinal cord: Implications for neuropathic pain

Abstract

Clinically, pain has an uneven incidence throughout lifespan and impacts more on the elderly. In contrast, preclinical models of pathological pain have typically used juvenile or young adult animals to highlight the involvement of glial populations, proinflammatory cytokines, and chemokines in the onset and maintenance of pathological signalling in the spinal dorsal horn. The potential impact of this mismatch is also complicated by the growing appreciation that the aged central nervous system exists in a state of chronic inflammation because of enhanced proinflammatory cytokine/chemokine signalling and glial activation. To address this issue, we investigated the impact of aging on the expression of genes that have been associated with neuropathic pain, glial signalling, neurotransmission and neuroinflammation. We used qRT-PCR to quantify gene expression and focussed on the dorsal horn of the spinal cord as this is an important perturbation site in neuropathic pain. To control for global vs region-specific age-related changes in gene expression, the ventral half of the spinal cord was examined. Our results show that expression of proinflammatory chemokines, pattern recognition receptors, and neurotransmitter system components was significantly altered in aged (24–32 months) versus young mice (2–4 months). Notably, the magnitude and direction of these changes were spinal-cord region dependent. For example, expression of the chemokine, Cxcl13, increased 119-fold in dorsal spinal cord, but only 2-fold in the ventral spinal cord of old versus young mice. Therefore, we propose the dorsal spinal cord of old animals is subject to region-specific alterations that prime circuits for the development of pathological pain, potentially in the absence of the peripheral triggers normally associated with these conditions.

Chronic Pain in the Elderly: Mechanisms and Distinctive Features

“…Cxcl13 also shows a pronounced increase in gene expression with age alone, displaying critical changes in pain signaling in the elderly [56]. A decrease of myelin proteins has been reported to correlate with increased glial activation because of the production of pro-inflammatory cytokines that can compromise white matter integrity [56]. These results are consistent with observations relating to age-dependent changes of myelinated Aδ type fibers as well as unmyelinated C-type fibers [29,30].…”

“…C-X-C motif chemokine 13 (Cxcl13), for example, is highly upregulated following nerve injury, and is largely involved in inflammatory responses and glial function in spinal dorsal cord. Cxcl13 also shows a pronounced increase in gene expression with age alone, displaying critical changes in pain signaling in the elderly [56]. A decrease of myelin proteins has been reported to correlate with increased glial activation because of the production of pro-inflammatory cytokines that can compromise white matter integrity [56].…”

Molecular and Cellular Mechanisms of Neuropathic Pain in Aging

“…Past research has documented the emergence of pro-inflammatory and activating characteristics of microglia as a consequence of increased age . CSF1 is increased in the aged spinal dorsal cord and leads to the activation of microglia . In the context of brain aging, a comprehensive transcriptomic analysis of microglia has been performed using specific RNA sequencing, which has revealed the differential expression of 511 genes associated with aging, such as major histocompatibility complex (MHC) class II proteins, CD68, and IL-1β, and a distinct morphological feature characterized by thicker protrusions. − In comparison to normal adult brains, stimulation with lipopolysaccharides exacerbates and prolongs neuroinflammation caused by activated microglia in the aging brain .…”

“…142 Alzheimer's disease (AD) is the most prevalent form of dementia among elderly individuals and has a significant impact on the pain processing system in brain. 143 AD patients demonstrate decline in opioid receptor abundance and opioidmediated analgesia 161,163 pro-inflammatory and activating features appear in microglia 174,175 inducing long-lasting neuroinflammation 180,181 brain decline in brain volume 141 presence of senile neuroinflammatory plaques 142 Alzheimer's disease exerts notable effects on the pain, cognition, and endocrine system 145 long-term chronic pain may lead to changes in brain morphology 147−149 reduced number of serotonin receptors in the prefrontal cortex and noradrenergic terminals in the spinal dorsal horn 154 dysregulation of the hypothalamic−pituitary−adrenal axis 104 decline in the concentration and turnover rates of catecholamines, GABA, and opioid receptors in the limbic system 155 more pronounced facial expressions during invasive clinical examinations, compared to their healthy counterparts. 144 The disease exerts notable effects on the pain, cognition, and endocrine system of the cingulate cortex, insular cortex, and frontal lobe regions.…”

Altered Intrinsic Properties and Inhibitory Connectivity in Aged Parvalbumin-Expressing Dorsal Horn Neurons

“…Thus, their increased capacity for sustained repetitive discharge and potential enhancement of their presynaptic inhibitory function would maintain the capacity of PVINs to prevent touch induced pain with advancing age. The stimulus that drives these agerelated changes in PVIN function is unclear, however, it is now well established that the aged CNS exists in a chronic neuroinflammatory state (Simen et al, 2011;Abdel-Aziz et al, 2014;Mayhew et al, 2020). Thus, any change to PVIN function may simply be a compensatory mechanism to stabilize spinal sensory processing and maintain the segregation of tactile and nociceptive circuits.…”