Nociceptor Sensitization Depends on Age and Pain Chronicity

Acute inflammation sensitizes C-fiber nociceptors to mechanical force only in young animals. A, Trace examples from young animals injected with either PBS (top left) or CFA (bottom left) and aged animals injected with either PBS (top right) or CFA (bottom right). B, C-fiber nociceptors from acutely inflamed (2 day) young animals respond with significantly higher action potential firing rates in response to increasing mechanical forces. C, C-fiber nociceptors from acutely inflamed aged animals trend toward responding with increased action potential firing in response to increasing mechanical forces, but this relationship is not significant. D, At baseline, C fibers from aged animals are more sensitive to mechanical stimuli than C fibers from young animals. E, von Frey thresholds for individual C fibers were not different between the four cohorts. Each point on the graph represents the von Frey threshold of an individual C fiber, and the black bars are indicative of the group mean. F, More C fibers from acutely inflamed animals tend to have ongoing, nonevoked activity (>0.05 Hz), although this relationship is not significant.

Chronic inflammation results in a desensitization of C fibers to mechanical force in young, but not aged animals. A, Trace examples from young animals injected with either PBS (top left) or CFA (bottom left) and aged animals injected with either PBS (top right) or CFA (bottom right). B, After 8 weeks of inflammation, C fibers from young animals respond with significantly lower action potential firing rates in response to increasing mechanical forces. C, After 8 weeks of inflammation, C fibers from aged animals trend toward lower firing rates in response to increasing mechanical forces. D, The firing rates of C fibers from inflamed young animals are significantly lower after 8 weeks of chronic inflammation compared with 2 days of acute inflammation. E, The firing rates of C fibers from inflamed aged animals are significantly lower after 8 weeks of chronic inflammation compared with 2 days of acute inflammation. F, G, Plots of the firing rates of individual C fibers at different forces for each cohort for young (F) and aged (G) animals. Note that after 2 days of acute inflammation the entire population of C fibers in both young and aged animals shifts toward elevated firing rates, rather than only a subpopulation of increased responders. H, von Frey thresholds for individual C fibers are elevated in both young and aged animals after 8 weeks of chronic inflammation. Each point on the graph represents the von Frey threshold of an individual C fiber, and the black bars are indicative of the group mean. I, Chronic inflammation results in an increased percentage of C fibers demonstrating ongoing, nonevoked activity in young animals, but not in aged animals.

C-fiber action potential firing patterns do not explain the significant behavioral sensitization, but reduction in action potential firing rates during chronic inflammation. A–D, Grouped instantaneous firing rates over the 12 s mechanical stimulus binned into 200 ms intervals for fibers from young acutely inflamed animals (A), aged acutely inflamed animals (B), young chronically inflamed animals (C), and aged chronically inflamed animals (D). E, C fibers from acutely inflamed young and aged animals fired with a significantly higher percentage of interspike intervals between 0 and 99 ms. F, The CV₂ for a 140 mN stimulus were significantly different for C fibers from acutely inflamed young and aged animals, and chronically inflamed young animals, but these relationships do not consistently demonstrate that variability may underlie the increased behavioral sensitization seen acutely and chronically. G, The time to first action potential after the onset of the mechanical stimulus is not different for any of the cohorts.

C-fiber responses to capsaicin are reduced during chronic inflammation, while behavioral sensitization to capsaicin remains intact. A, C-fiber responses to capsaicin are similar under naïve and acutely inflamed conditions in young animals, but responses are strongly attenuated during chronic inflammation. B, The number of action potentials fired by capsaicin-sensitive C fibers is also reduced after 8 weeks of chronic inflammation in young animals (although this is not statistically significant). C, In aged animals, C-fiber responses to capsaicin are similar across the naïve, acute inflamed, and chronic inflamed states. Note the low numbers that are due to the lack of aged animal availability. D, Number of action potentials fired by aged C fibers in response to capsaicin. E, Young animals exhibit sensitized pain behaviors in response to capsaicin injection during both acute inflammatory and chronic inflammatory states, despite the reduced afferent responses to capsaicin at 8 weeks.

AM fibers from young animals exhibit reduced mechanical firing rates following inflammation. A, Following both 2 day acute and 8 week chronic inflammation, AM fibers from young animals exhibit reduced firing rates in response to mechanical stimuli. B, Plots of the firing rates of individual AM fibers at different forces for each cohort of young animals. Note the loss of a population of high-responding AM fibers at the 2 day and 8 week time points. C, von Frey thresholds of individual AM fibers from young animals are elevated after 8 weeks of chronic inflammation compared with fibers from naïve animals.