Abstract
Management of time and circadian disruption is an extremely important factor in basic research on pain and analgesia. Although pain is known to vary throughout the day, the mechanism underlying this circadian variation remains largely unknown. In this study, we hypothesized that the process of pain transmission to the central nervous system (after receiving nociceptive stimuli from outside the body) would show day-night differences. Ten-week-old male mice were kept under a strict 12/12-h light/dark cycle for at least 10 days. Formalin was then injected into the second branch region of the trigeminal nerve and the duration of pain-related behaviors (PRBs) was assessed. Immunohistochemical staining was then performed, and the c-Fos-immunopositive cells in the trigeminal spinal tract subnucleus caudalis (Sp5C) were counted. The results showed that the duration of PRBs was longer and the number of c-Fos immunopositive cells in the Sp5C was higher at nighttime than during the day. In addition, the trigeminal ganglia (TG) were extracted from the mice and examined by quantitative real-time PCR to evaluate the daytime and nighttime expression of nociceptive receptors. The results showed that the mRNA expression of transient receptor potential ankyrin 1 in the TG was significantly higher at night than during the day. These results suggest that pain in the trigeminal nerve region is more intense at nighttime, when rodents are active, than during the daytime, partly due to differences in nociceptor expression.
Highlights
In mammals, physiological functions and behaviors such as sleep, wakefulness, body temperature, and endocrine secretion are regulated by circadian rhythms to ensure that these functions are maximized throughout the day (Ruben et al, 2018; Rijo-Ferreira and Takahashi, 2019)
Ten-week-old male C57BL/6J mice were purchased from Japan SLC, Inc. (Shizuoka, Japan) and housed in a temperaturecontrolled (24–25◦C) quiet room under a 12/12-h light/dark cycle [i.e., light on was defined as Zeitgeber time (ZT) 0, light off was defined as ZT12] for at least 10 days, with food and water available ad libitum
We reproduced a model of acute, persistent pain by injecting formalin into the right upper lip of mice (Figure 1A) and examined whether pain-related behaviors (PRBs) showed day-night differences at the behavioral level
Summary
Physiological functions and behaviors such as sleep, wakefulness, body temperature, and endocrine secretion are regulated by circadian rhythms to ensure that these functions are maximized throughout the day (Ruben et al, 2018; Rijo-Ferreira and Takahashi, 2019). As for pain research, Diurnal Variation in Pain Sensitivity chronobiological studies have revealed the circadian variability of pain. These studies have mainly focused on behavioral findings when animals are subjected to nociceptive stimuli (Rosenfeld and Rice, 1979; Pickard, 1987; Konecka and Sroczynska, 1998), and only a few studies have attempted to elucidate the related molecular mechanisms (Koyanagi et al, 2016). The concept of time is one of the most important factors in basic research on pain and analgesia, and the identification of the circadian variation of pain and underlying molecular mechanisms is expected to lead to more effective methods of pain control
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