2. Spinal cord. Nociceptive afferents terminate in the spinal dorsal horn, where they form synapses with second-order neurons through the secretion of glutamate, substance P, and calcitonin gene-related peptide (CGRP; Basbaum et al., 2009). Ascending tracts, which transmit noxious stimuli, project through the ventrolateral spinal cord to reach some nuclei of the thalamus (Gore, 2022).

3. From thalamus to brain (ascending tract). The thalamus plays a fundamental role in processing somatosensory information, including pain signals. Third-order neurons, emanating from thalamic nuclei, project to the somatosensory cortex (primary -S1- and secondary -S2-), anterior cingulate cortex (ACC), prefrontal cortex (PFC), periaqueductal grey (PAG), nucleus accumbens (NAc), and hippocampus (HP; Gore, 2022).

4. From brain to spinal cord (descending tract). The descending pain pathway is composed of some supraspinal elements, including the rostral ventromedial medulla (RVM) and PAG (Bourne et al., 2014). Noradrenaline (NA) and serotonin (5-HT) are the key neurotransmitters involved in the descending inhibition (Bourne et al., 2014). The PAG receives inputs from the prefrontal cortex and ACC, and activates some neurons located in the nucleus raphe magnus (NRM), which contain 5-HT. Serotoninergic neurons, along with noradrenergic projections (originating from the locus coeruleus -LC-), establish synapses with spinal interneurons (Ossipov et al., 2014). These interneurons, located in the spinal dorsal horn, release several inhibitory neurotransmitters such as glycine, γ-aminobutyric acid (GABA), nitric oxide (NO), opioid peptides, and endocannabinoids. In accordance with the gate control theory, proposed by Ronald Melzack and Patrick Wall in 1965 (Melzack and Wall, 1965), non-noxious sensory afferents (mechanorreceptors) activate spinal interneurons, thereby modulating pain signals within the spinal cord. The analgesic effects mediated by inhibitory neurotransmitters are as follows: (i) activation of the respective receptors, located on nociceptive afferents, induces the influx of Cl⁻ ions or efflux of K⁺ ions, leading to hyperpolarization and a subsequent reduction in the secretion of glutamate, substance P, or CGRP onto the spinal dorsal horn; (ii) the inhibition of second-order neurons due to their hyperpolarization, a process that occurs in a similar manner (Hughes and Todd, 2020).

2. Changes in fiber composition. In the elderly, there is a profound reduction in both the conduction velocity and density of specific Aδ nociceptive nerve fibers (Chakour et al., 1996). This alteration in fiber composition results in chronic pain (Gibson and Farrell, 2004).

3. Changes in ion channels and receptors. Aging causes significant modifications in nociceptor ion channels, affecting both their quantity and type, which contributes to the increased prevalence of chronic pain in the elderly. Moreover, aging alters the functionality of transient receptor potential channels (TRP; e.g., TRPV1) as well as K⁺ channels (e.g., K_Ca2.1), causing increased nociceptor activity and release of substance P and CGRP onto the spinal dorsal horn, thereby intensifying pain sensation (Strickland et al., 2019; Xiao et al., 2023).

4. Decreased local blood flow. Recent research, conducted by Devanne et al. (2024), has revealed that diminished local blood flow in older adults induces chronic inflammation and amplified pain sensitivity. This situation arises from reduced nutrient bioavailability, as well as the accumulation of toxicants (like reactive oxygen species -ROS-) and cell debris (Sanada et al., 2018; Chaudhary et al., 2023).

5. Chronic inflammation. In the elderly, chronic inflammation is usually observed in many tissues. Pro-inflammatory cytokines (e.g., IL-1β, IL-6, and TNF-α), regulated by many microRNAs (e.g., miR-155, let-7c, and miR-181a), are known to disrupt many anabolic signaling pathways, which can lead to development of sarcopenia (Fan et al., 2016). The factors which contribute to the chronic inflammation are as follows (Sanada et al., 2018): (i) cell debris and/or immunoglobulin accumulation (this fact results in the sustained activation of the immune system); (ii) impaired microbiota (evokes the infiltration of microorganisms and the stimulation of the immune system); (iii) cell senescence (senescent cells -generated by several mechanisms, like telomere shortening, which culminate in the activation of p16 and p53-release several pro-inflammatory cytokines, resulting in low-grade inflammation); (iv) immunosenescence (age-related reduction in immune responses; Liu et al., 2023); (v) altered coagulation and fibrinolysis systems (recent studies have observed an increase in inflammatory processes among older adults). Chronic inflammation in the periphery evokes peripheral sensitization, defined by elevated responsiveness of nociceptors (Puja et al., 2021).

6. Epigenetic influences. Research on biological aging identifies nine potential hallmarks, including epigenetic alterations (López-Otín et al., 2013). These variations are distinguished by anomalous DNA methylation patterns, histone modifications, and the participation of ncRNAs, particularly microRNAs (Wang et al., 2022). Although the specific genes influenced by epigenetic alterations in the PNS of older adults with chronic pain are not yet identified, genes influenced by epigenetic mechanisms have been identified in several experimental chronic pain murine models, making it a promising research area. In the spinal nerve ligation (SNL) experimental model, which induces chronic neuropathic pain, the activation of histone methyltransferase G9a (dimethylates histone H3 at lysine 9; H3K9me2) causes transcriptional repression of the Oprm1 gene (encodes μ-opioid receptor -MOR-) in the DRG (Zhang et al., 2016). Moreover, this model alters DNA methylation patterns in the DRG, influencing genes that encode voltage-gated and ligand-gated ion channels, all of which are involved in pain processing (Garriga et al., 2018). The role of microRNAs should also be considered, due to the detection of 63 microRNAs whose level of expression was altered in the DRG following SNL (von Schack et al., 2011).

2. Structural and functional brain changes. Significant structural alterations in the brain have been documented in older adults with chronic pain. These variations mainly affect regions involved in pain processing, suggesting a complex interaction between aging and pain (Mackey and Maeda, 2004). Gray matter volume reductions have been reported in many areas of the brain in the elderly (such as, PFC, PAG, HP, and corpus callosum; Zimmerman et al., 2009; Buckalew et al., 2010; Luo et al., 2022). Moreover, several studies show that older adults with chronic pain have altered cortical connectivity within the descending pain pathway (Cruz-Almeida and Cole, 2020).

3. Changes in neurotransmitter activity. Multiple inhibitory neurotransmitters (GABA, 5-HT, NA, glycine, and opioid peptides) are diminished in brains of older patients with chronic pain (Bruehl et al., 2012; Yang and Chang, 2019). The absence of these neurotransmitters in the CNS allows nociceptors to release increased amounts of glutamate and/or substance P onto the spinal dorsal horn, due to the lack of presynaptic inhibition mechanisms (Hughes and Todd, 2020).

4. Chronic inflammation. Persistent inflammation in the CNS is fundamental in the maintenance of chronic pain in the elderly. This process is characterized by the activation of glial cells, especially microglia and astroglia, in both the spinal cord and brain (Paladini et al., 2015). Glial cells secrete numerous pro-inflammatory cytokines (e.g., IL-1β and TNF-α) and chemokines (e.g., CCL2 and CX3CL1), which lead to central sensitization by increasing neuronal excitability and synaptic plasticity (Puja et al., 2021). This mechanism is driven by the NF-κB transcription factor (Shih et al., 2015). The release of pro-inflammatory mediators enhances pain intensity through various mechanisms: (i) upregulation of pain-related receptors (e.g., IL-1β increases the activity of N-methyl-D-aspartate -NMDA-receptors; Viviani et al., 2003); (ii) downregulation of GABA receptors (induced by TNF-α; Stellwagen et al., 2005); (iii) neuroplasticity (numerous cytokines trigger the long-term potentiation -LTP- process and allow continuous pain signal transmission; Gonçalves Dos Santos et al., 2020).

5. Epigenetic influences. Consistent with the previous section, the epigenetic mechanisms involved in chronic pain in the CNS of the elderly must be elucidated. However, the impact of epigenetics on chronic pain is recognized, providing a starting point for studying chronic pain in the elderly. DNA methylation has a considerable effect on chronic pain in the CNS, as evidenced by studies in rodent models of chronic neuropathic pain that show modifications in global DNA methylation within the PFC and thalamus. These alterations are associated with decreased expression of DNA methyltransferases DNMT1 and DNMT3a, along with changes in TET enzyme levels (Alvarado et al., 2015; Rodrigues et al., 2023). In relation to histone modifications, trimethylation of histone H3 (H3K27me3) and increased activity of histone deacetylases (HDACs) contribute to sustained production of pro-inflammatory cytokines in the CNS of rodents with chronic inflammatory pain (Jiang et al., 2023). In many experimental models of chronic pain, various microRNAs (including miR-101, miR-132, miR-155, and miR-223) have been identified as modulators of chronic pain through their effects on neuronal excitability and/or synaptic plasticity (Kovanur Sampath et al., 2023; Zhang et al., 2023).