Differential aging-related changes in neurophysiology and gene expression in IB4-positive and IB4-negative nociceptive neurons.

Despite 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.