Abstract
SummaryDespite pain prevalence altering with age, the effects of aging on the properties of nociceptors are not well understood. Nociceptors, whose somas are located in dorsal root ganglia, are frequently divided into two groups based on their ability to bind isolectin B4 (IB4). Here, using cultured neurons from 1‐, 3‐, 5‐, 8‐, 12‐, and 18‐month‐old mice, we investigate age‐dependent changes in IB4‐positive and IB4‐negative neurons. Current‐clamp experiments at physiological temperature revealed nonlinear changes in firing frequency of IB4‐positive, but not IB4‐negative neurons, with a peak at 8 months. This was likely due to the presence of proexcitatory conductances activated at depolarized membrane potentials and significantly higher input resistances found in IB4‐positive neurons from 8‐month‐old mice. Repetitive firing in nociceptors is driven primarily by the TTX‐resistant sodium current, and indeed, IB4‐positive neurons from 8‐month‐old mice were found to receive larger contributions from the TTX‐resistant window current around the resting membrane potential. To further address the mechanisms behind these differences, we performed RNA‐seq experiments on IB4‐positive and IB4‐negative neurons from 1‐, 8‐, and 18‐month‐old mice. We found a larger number of genes significantly affected by age within the IB4‐positive than IB4‐negative neurons from 8‐month‐old mice, including known determinants of nociceptor excitability. The above pronounced age‐dependent changes at the cellular and molecular levels in IB4‐positive neurons point to potential mechanisms behind the reported increase in pain sensitivity in middle‐aged rodents and humans, and highlight the possibility of targeting a particular group of neurons in the development of age‐tailored pain treatments.
Highlights
According to the United Nations Population Division, the number of people aged 60 or over is expected to increase by 56% by 2030 (UN, 2015)
We studied age dependence of the firing rate of isolectin B4 (IB4)+ and IB4À dorsal root ganglia (DRG) neurons, by inducing action potentials (APs) with 500 ms depolarizing current steps at 35°C
To decipher the mechanisms behind these differences in firing rate, we studied the effect of aging on two major determinants of neuronal excitability: resting membrane potential (RMP) and input resistance (Ri)
Summary
According to the United Nations Population Division, the number of people aged 60 or over is expected to increase by 56% by 2030 (UN, 2015). Middle-aged and older people are more likely to both report painful conditions and receive analgesic treatments, with the prevalence of certain types of pain peaking at midlife (Buskila, Abramov, Biton, & Neumann, 2000; Rustoen et al, 2005; Schopflocher, Taenzer, & Jovey, 2011; Yeo & Tay, 2009). While this is partly due to the higher prevalence within these groups of age-related diseases, such as diabetes, cancer, arthritis, and stroke (Ayis, Gooberman-Hill, & Ebrahim, 2003; Denton & Spencer, 2010), healthy aging affects pain mechanisms at both peripheral and central levels (Farrell, 2012; Yezierski, 2012) and is likely to contribute to the reported statistics on age dependence of pain prevalence. While the excitability of IB4À neurons was found to be relatively age-independent, the excitability of IB4+ neurons followed an inverted “U” pattern with a peak in firing rate at 8 months, suggesting that IB4+ neurons may contribute to higher susceptibility to pain around middle age, and pointing to the possibility of targeting this subset of nociceptors in treatments of age-dependent chronic and neuropathic pain
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