Diurnal Variation in Trigeminal Pain Sensitivity in Mice

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.

Circadian rhythm of PERIOD2::LUCIFERASE expression in the trigeminal ganglion of mice

“…In the clinic, the trigeminal-innervated area is where complaints of glossodynia, hypersensitivity, and insensitivity are localized, even in the absence of an organic oral cavity abnormality ( Scala et al, 2003 ). Recently, we described a diurnal variation in pain in the trigeminal-innervated area in mice, with greater sensitivity to pain during the dark than during the light period; this may be due in part to diurnal variation in TRPA1 mRNA expression in the trigeminal ganglia ( Niiro et al, 2021 ). However, the rhythm of the trigeminal ganglion itself, which produces the day-night difference, is not known.…”

The disruptive relationship among circadian rhythms, pain, and opioids

“…It is possible that this discrepancy in behavior is a result of genetic differences between the two strains, as differences in underlying circadian biology between C57BL/6 and Swiss (CF1) mice have been previously noted ( Pilz et al, 2015 ). A recent study examined time-of-day differences in mouse orofacial pain, reporting that peak behavioral pain responses were observed during the middle of the light (rest) phase ( Niiro et al, 2021 ). The additional behavioral discrepancy between this study and the above studies may be a result of the different pain behavioral paradigms implemented.…”

“…There is growing evidence of the clock gene-driven rhythmic expression of various proteins involved in nociception and pain signal processing ( Chu et al, 2022 ). For example, rhythmic expression of pain-related proteins in mice observations include substance P ( Zhang et al, 2012 ) and the α2δ-1 voltage-gated calcium channel in the dorsal root ganglia ( Kusunose et al, 2010 ), Trpa1 in the trigeminal ganglia ( Niiro et al, 2021 ), and the NR2B NDMA glutamate receptor subunit and two of its response elements in the spinal cord ( Xia et al, 2016 ). Lastly, and of critical relevance, rhythmic expression of the μ-opioid receptor transcript has been observed in the periaqueductal gray of mice ( Takada et al, 2013 ).…”

Circadian rhythms and glial cells of the central nervous system

“…Recent studies have unravelled a daily rhythm of pain sensitivity in humans (Hagenauer et al ., 2017; Daguet et al ., 2022) and mice (Niiro et al ., 2021), suggesting a circadian control of nociception. While sensory neurons may be involved in this mechanism (Niiro et al ., 2021), astrocytes also play a key role in nociception (Segal et al ., 2018).…”

“…Recent studies have unravelled a daily rhythm of pain sensitivity in humans (Hagenauer et al ., 2017; Daguet et al ., 2022) and mice (Niiro et al ., 2021), suggesting a circadian control of nociception. While sensory neurons may be involved in this mechanism (Niiro et al ., 2021), astrocytes also play a key role in nociception (Segal et al ., 2018). Disruption of astrocyte activity induced by intrathecal injection of fluorocitrate significantly reduces circadian clock gene expression in the mouse lumbar spinal cord, a key processing site for sensory stimuli.…”