(L-477) Chronic Pain Leads to Modality-Specific Sleep Changes

Introduction:: Up to 80% of patients with chronic pain conditions report disrupted sleep patterns (e.g. insomnia, premature arousals, fragmentation)^1,2. Sleep and pain are negatively reinforcing: pain can disrupt sleep while poor sleep can exacerbate pain experience and alter pain pathway thresholds. Furthermore, the type of sleep disruption resulting from chronic pain is unpredictable and variable. This is especially problematic in joint pain conditions where few studies have explored sleep and pain relationships. Understanding how sleep and pain relate will remove this knowledge barrier and improve daily clinical management of chronic pain patients.

Unpredictable sleep disruptions in chronic pain conditions may be due to different pain modalities. The objective of this work is to leverage preclinical models to better understand how pain modalities may alter sleep in differently. Different pain modalities can affect different tissue with unique physical and psychological experiences. For example, nociceptive pain, such as inflammatory pain caused by an injury, follows established neural pathways serving as functionally informative or protective. Conversely, neuropathic pain derives from damaged neural pathways sending unpredictable and variable signals to the brain without helpful functional or protective information. We hypothesize that these two different modalities of pain (neuropathic vs inflammatory) will associate with different sleep measures of fragmentation (microarousal index, sleep fragmentation index, duration of sleep event) and sleep quality (% time sleeping, rapid eye movement (REM) sleep measures). This work will enable comparative associations between pain modality and sleep dysfunction phenotypes, putting joint-pain-related sleep disruptions within the larger context of chronic pain-sleep research.


Materials and Methods:: Adult C57b/6 mice (n=27, female) were pair-housed under standard 12:12 hour light-dark cycles with ad libitum food and water. All animals were anesthetized (2-3% isoflurane) and prepared for aseptic surgery. To model neuropathic pain, animals then received either a T10 contusion (50 kdyne, IH-400 Infinite Horizon Impactor) spinal cord injury (SCI, n=7), a T10 laminectomy sham (LAMX, n=6), or no procedure (NAÏVE, n=6). To model inflammatory knee pain, animals then received either a 10 ul intra-articular knee injection of monoiodoacetate (MIA, n=4, 0.2 mg/ul) or phosphate buffered saline (SALINE, n=4). SCI and LAMX animals received 48 hours of post-operative meloxicam (2 mg/kg, twice daily), Baytril (2.5 mg/kg, daily), and supplemental hydration (0.5 ml sterile saline daily). Bladders were expressed twice daily until animals voided independently.

Animals were acclimated to experimenters and equipment prior to behavioral studies and surgery. Baseline 3-stage sleep (wake, REM sleep, and non-REM sleep) and hind paw mechanical pain sensitivity were recorded before surgery and weekly for 6 weeks post-procedure to model chronic timelines. Sleep was noninvasively measured in animal homecages during the 12-hour dark cycle using electric field (EF) sensors developed by our group and previously validated against gold standard electroencephalogram (EEG) + electromyograph (EMG). EF sensors are able to translate animal movement into a voltage trace passively from outside a homecage which can then be scored for 3-stage sleep comparable to EEG/EMG. Data means were analyzed using multifactorial ANOVAs with Tukey’s HSD post-hoc test and correlations made using general linear regression models.


Results, Conclusions, and Discussions:: At 6 weeks post-procedure, both the SCI (p< 0.001) and MIA (p< 0.001) groups exhibited heightened mechanical hypersensitivity relative to their respective baseline values consistent with previous findings (Figure 1). 6-week SCI and MIA mechanical sensitivity were not different from each other, suggesting similar intensity of evoked pain is experienced by both groups.

Although they both experienced evoked mechanical sensitivity, the different injury models experienced different changes in sleep quality metrics. Compared to respective baseline values, SCI animals at 6 weeks post-procedure showed increased micro-arousals per hour (p<0.001), a higher sleep fragmentation index (SFI, p<0.001), and reduced changes in sleep event duration (p<0.002) and REM latency (p<0.037) indicating REM sleep. MIA animals did not exhibit cohesive group sleep changes, and only showed a subtle trend between mechanical sensitivity and percent of time spent in REM. SCI animal mechanical sensitivity correlated with many sleep measures associated with sleep fragmentation: micro-arousal index (p<0.001, R2=0.89), SFI (p<0.001, R2=0.82), and average sleep event duration (p<0.001, R2=0.76). This suggests that SCI-induced pain may cause or exacerbate more pervasive sleep dysfunction through premature arousal mechanisms.

These findings indicate neuropathic and inflammatory pain modalities, regardless of evoked response intensity, affect sleep in different ways. SCI-induced neuropathic pain leads to more severe fragmented sleep while MIA-induced inflammatory knee pain leads to more subtle REM sleep disruptions. This may be partially explained by previous work indicating bilateral injuries (like SCI) result in more severe sleep disruptions than unilateral injuries (like the unilateral knee injection here). REM sleep is associated with maintaining neural health, so altered REM sleep seen in both SCI and MIA animals may indicate important initial pathways for further temporal study of pain-related sleep dysfunction.

Understanding how different pain experiences and modalities alter sleep will enable development of better clinical management of chronic pain conditions specific to pain experience, including potential new therapeutic methods such as chronotherapy to manage joint pain.


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References (Optional):
1. Perry G. Fine, MD, Long-Term Consequences of Chronic Pain: Mounting Evidence for Pain as a Neurological Disease and Parallels with Other Chronic Disease States, Pain Medicine, Volume 12, Issue 7, July 2011, Pages 996–1004, https://doi.org/10.1111/j.1526-4637.2011.01187.x



2. Melikoglu MA, Celik A. Does Neuropathic Pain Affect the Quality of Sleep? Eurasian J Med. 2017 Feb;49(1):40-43. doi: 10.5152/eurasianjmed.2017.16261. PMID: 28416931; PMCID: PMC5389492.
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