Research ArticleDim Light at Night Exposure Induces Cold Hyperalgesia and Mechanical Allodynia in Male Mice
Introduction
Artificial lighting is an indispensable feature of the 21st-century that provides abundant benefits for human society. Nonetheless, a growing body of evidence has elucidated the detrimental effects of exposure to artificial light at night (LAN), a nearly ubiquitous form of artificial lighting. Most organisms on earth evolved with endogenous circadian systems that rely on light days and dark nights for circadian system coordination (Reppert and Weaver, 2002). As such, LAN can disrupt a range of behavioral and physiological processes that interact with the circadian system, including sleep-wake cycles, metabolism, and immune function (Cho et al., 2015, Russart and Nelson, 2018). Disruption of circadian rhythms is provoked by atypical light signaling from retinal photoreceptors to the suprachiasmatic nucleus (SCN) during the dark phase; the SCN is known as the ‘master clock’ of the mammalian circadian system, (Lucas et al., 2012).
LAN exposure has been linked to health issues in both biomedical and ecological contexts. In humans, LAN exposure is correlated with an increased risk for breast and prostate cancers, depression in the elderly population, and obesity (Davis et al., 2001, Kloog et al., 2009, Obayashi et al., 2013, McFadden et al., 2014). Animal studies have demonstrated that dim LAN (∼5 lx; dLAN) exposure can result in increased body mass, altered metabolism, disrupted immune function, and disrupted inflammatory signaling in the brain (Bedrosian et al., 2011a, Bedrosian et al., 2011b, Fonken et al., 2013a, Borniger et al., 2014, Hogan et al., 2015). Notably, dLAN augments the central expression of Il-1β in female mice and induces depressive like behavior in both sexes in as few as four nights of exposure (Walker et al., 2019).
dLAN-induced inflammation may play a role in the induction of hyperalgesia or other similar chronic pain states, as pain sensitivity is influenced by the central and peripheral expression of cytokines. For example, pro-inflammatory cytokines heighten pain sensitivity through peripheral and central sensitization (Zhang et al., 2012). Peripherally, inflammation in the dorsal root ganglia (DRG) can lead to sensitization (Martin et al., 2019) and ultimately hyperalgesia (i.e., increased sensitivity of noxious stimuli) and allodynia (i.e., painful reactions to innocuous stimuli). Centrally, inflammation can lead to sensitization and reduced inhibitory signaling in the dorsal horn of the spinal cord (Kawasaki et al., 2008) and in regions of the midbrain or brainstem, such as the periaqueductal grey (PAG) or the rostral ventral medulla (RVM), respectively (Wei et al., 2008, Xu et al., 2018). Typically, the PAG-RVM axis plays a role in the regulation of descending facilitatory and inhibitory nociceptive signaling (Bodnar and Heinricher 2013).
Additionally, dLAN exposure can be characterized as a disruptor of circadian rhythms. Other forms of circadian rhythm disruption, such as night-shift work or sleep disruption have been correlated with altered pain thresholds (Onen et al., 2001, Matre et al., 2017). Pain sensitivity follows circadian patterns in both humans and mice; pain sensitivity is often highest following the end of the active period, likely reflecting rhythmic expression of inflammatory markers and/or opioid receptors in the brain (Kavaliers and Hirst, 1983, Takada et al., 2013). Disruption of these patterns could lead to altered pain sensitivity.
In the present study, we investigated the effects of acute (3–4 nights) dLAN exposure on pain responsiveness and the effects of chronic dLAN exposure (27–28 nights) of dLAN exposure on pain responsiveness and expression of pronociceptive transcripts in male mice. Specifically, we hypothesized that dLAN-mediated circadian rhythm disruption heightens pain responsiveness and perturbs the expression of central and peripheral nociception-related peptides and receptors. Thus, we predicted that dLAN would induce thermal hyperalgesia and mechanical allodynia through increased expression of inflammatory factors.
Section snippets
Mice
Forty adult male CFW mice (∼8 weeks old) were ordered from Charles River Laboratories. Upon arrival at the WVU vivarium, mice were given one week to acclimate to light–dark (LD) (14:10 h, ∼125:0 lux or ∼33.2:0.0 μW/cm2 @ 550 nm) housing conditions. Lights went on/off in the vivarium at 05:00 h and 19:00 h EST, respectively. Throughout the study, mice were individually housed in polypropylene cages (30 × 18 × 14 cm) on corn cob bedding (Envigo 7092; Wisconsin, USA) at a temperature of 22 ± 2 °C
dLAN alters body mass and timing of food consumption
dLAN exposure increased the percent change in body mass relative to baseline (t37 = 2.686, p < 0.05; Fig. 1A). dLAN altered the timing of food consumption, driving decreased dLAN group food consumption during the active phase (Fig. 1B) and increased consumption during the inactive phase (Fig. 1C). A main effect of lighting condition was present in active phase consumption (F1,38 = 58.66, p < 0.0001; Fig. 1B) and in inactive phase consumption (F1,38 = 65.16, p < 0.0001; Fig. 1C). Food
Discussion
In this experiment, we examined the effects of acute (3–4 nights) and chronic (28–29 nights) dLAN exposure on both pain responsiveness and the gene expression of several pronociceptive peptides. We observed that male mice exposed to dLAN experienced cold hyperalgesia and mechanical allodynia at acute and chronic time points. In contrast, mice did not exhibit heat hyperalgesia at either assessed time point. Further, dLAN exposure upregulated levels of Il-6 and Ngf in the medulla and increased
Declarations of interest
None.
Acknowledgements
Research reported in this publication was supported by the National Institute of General Medical Sciences of the National Institutes of Health under Award Number 5U54GM104942-04. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We thank Terri Poling for her excellent care of the animals during this study. Special appreciation is given to Alexandra Richmond and Jordan Pascoe for their valuable
Data availability
Data related to this article are available upon reasonable request to the corresponding author.
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2023, Experimental GerontologyCitation Excerpt :ALAN causes a higher risk of breast cancer and obesity in women (Park et al., 2019; Urbano et al., 2021). Under the exposure to 5 lux intensity of ALAN, increased expression of hippocampus TNF and Il-6 levels (Hogan et al., 2015) and medulla Il-6 (Bumgarner et al., 2020) were demonstrated in male mice. In an extreme case, female mice exposed to only three nights of 5 lx of light reported an increase in hippocampus Il-1β, proving that ALAN can have both immediate and long-lasting impacts on inflammation (Walker et al., 2020).
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2021, Journal of PainCitation Excerpt :Although the mechanism has not been fully elucidated, there are some animal studies that might provide a mechanistic explanation. Bumgarner et al reported that dim light exposure at night in male mice induced cold hyperalgesia and mechanical allodynia.9 Specifically, 28 days of dim light exposure caused increased expression of mu-opioid receptors in the periaqueductal gray and increased IL-6 and NGF expression in the medulla.