Misaligned Feeding May Aggravate Pain by Disruption of Sleep–Awake Rhythm

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Increasing evidence suggests that patients with eating disorders are more likely to develop chronic pain. A misaligned diet has been reported to disrupt the sleep–awake rhythms. Combined with our previous investigation on circadian pain, we aimed to investigate the role of misaligned diet in the pain sensitivity and the underlying mechanisms.


Two-month-old C57BL/6J male mice were administered chronic constriction injury (CCI) surgery to establish neuropathic pain models. CCI mice were randomized to scheduled food access throughout the whole day (CCI-free), during the daytime (CCI-misaligned), and at night (CCI-aligned), respectively. The paw withdrawal mechanical threshold, indicating pain behavior, was measured by Von Frey. The gross motor activity pattern indicating the sleep–awake rhythm was monitored by Mini-Mitter. Melatonin (Mel) was administered to ameliorate the sleep–awake rhythm (CCI-free + Mel and CCI-misaligned + Mel). The expressions of circadian pain–related proteins were detected by quantitative polymerase chain reaction and western blot. The primary outcome is the pain threshold and the secondary outcome is the sleep–awake rhythm.


Misaligned diet during the peri-CCI surgery period significantly decreased the paw withdrawal mechanical threshold compared with the CCI-free mice (day 14: 0.40 ± 0.09 vs 0.64 ± 0.15; P = .03;) and altered the sleep–awake rhythm. Mel pretreatment alleviated the increased pain (day 14, CCI-misaligned + Mel versus CCI-misaligned: day 14: 0.60 ± 0.13 vs 0.35 ± 0.12; P = .022) and the disrupted sleep–awake rhythm caused by misaligned feeding. The mRNA levels of N-methyl-D-aspartate receptor subtype 2B (NR2B), Ca2+/calmodulin-dependent protein kinase II (CaMKII), and cyclic adenosine monophosphate-response element binding protein (CREB) in the spinal dorsal horn increased in CCI-misaligned mice compared with the CCI-free mice. The phosphor-NR2B, phosphor-CaMKII, and phosphor-CREB also increased in CCI-misaligned mice compared with the CCI-free mice. However, the expressions of NR2B, CaMKII, and CREB were decreased in CCI-misaligned + Mel mice compared to CCI-misaligned mice at both transcriptional and translational levels.


Misaligned diet might aggravate pain sensitivity through the disruption of the sleep–awake cycle, which could be recovered by Mel. NR2B-CaMKII-CREB may participate in the disruption of sleep–awake rhythm–mediated pain aggravation.

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