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Link to original content: http://pubmed.ncbi.nlm.nih.gov/37985842/
Antinociceptive effect of intermittent fasting via the orexin pathway on formalin-induced acute pain in mice - PubMed Skip to main page content
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. 2023 Nov 20;13(1):20245.
doi: 10.1038/s41598-023-47278-3.

Antinociceptive effect of intermittent fasting via the orexin pathway on formalin-induced acute pain in mice

Hyunjin Shin #  1 , Jaehyuk Kim #  1   2 , Sheu-Ran Choi #  3 , Dong-Wook Kang  1 , Ji-Young Moon  4 , Dae-Hyun Roh  5 , Miok Bae  6 , Jungmo Hwang  7 , Hyun-Woo Kim  8
Affiliations

Antinociceptive effect of intermittent fasting via the orexin pathway on formalin-induced acute pain in mice

Hyunjin Shin et al. Sci Rep. .

Abstract

It has been suggested that stress responses induced by fasting have analgesic effects on nociception by elevating the levels of stress-related hormones, while there is limited understanding of pain control mechanisms. Here, we investigated whether acute or intermittent fasting alleviates formalin-induced pain in mice and whether spinal orexin A (OXA) plays a role in this process. 6, 12, or 24 h acute fasting (AF) and 12 or 24 h intermittent fasting (IF) decreased the second phase of pain after intraplantar formalin administration. There was no difference in walking time in the rota-rod test and distance traveld in the open field test in all groups. Plasma corticosterone level and immobility time in the forced swim test were increased after 12 h AF, but not after 12 h IF. 12 h AF and IF increased not only the activation of OXA neurons in the lateral hypothalamus but also the expression of OXA in the lateral hypothalamus and spinal cord. Blockade of spinal orexin 1 receptor with SB334867 restored formalin-induced pain and spinal c-Fos immunoreactivity that were decreased after 12 h IF. These results suggest that 12 h IF produces antinociceptive effects on formalin-induced pain not by corticosterone elevation but by OXA-mediated pathway.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Effects of acute and intermittent fasting on formalin-induced pain behaviors. (a) Formalin-induced pain behaviors were measured for 40 min at 5-min intervals after 6 h acute fasting (AF 6 h), 12 h acute fasting (AF 12 h), 24 h acute fasting (AF 24 h), 12 h intermittent fasting (IF 12 h), and 24 h intermittent fasting (IF 24 h). Licking behaviors were classified as 1st phase (0–10 min) and 2nd phase (10-40 min). (b) Area under curve (AUC) in the 2nd phase of pain was analyzed in control and fasting groups. Data were expressed as the mean ± SEM. *p < 0.05 and ***p < 0.0001 vs. Control. n = 7 mice/group.
Figure 2
Figure 2
Effects of acute and intermittent fasting on motor function. (a) Rota-rod test was performed after 6 h acute fasting (AF 6 h), 12 h acute fasting (AF 12 h), 24 h acute fasting (AF 24 h), 12 h intermittent fasting (IF 12 h), 24 h intermittent fasting (IF 24 h), and alfaxan administration (positive control). Area under curve (AUC) was analyzed in control, fasting, and alfaxan-treated groups. (b) Open field test was performed in control and fasting groups and the distance traveled for 5 min was analyzed and plotted in a graph. Data were expressed as the mean ± SEM. *p < 0.05 and ***p < 0.0001 vs. Control. n = 5 mice/group.
Figure 3
Figure 3
Effects of acute and intermittent fasting on the corticosterone levels in blood and the immobility time in forced swim test. (a) Corticosterone levels were measured after 6 h acute fasting (AF 6 h), 12 h acute fasting (AF 12 h), 24 h acute fasting (AF 24 h), 12 h intermittent fasting (IF 12 h), and 24 h intermittent fasting (IF 24 h) using ELISA. n = 4–7 mice/group. (b) Forced swim test was performed and immobility time (sec) was measured in control, 12 h acute fasting, and 12 h intermittent fasting groups. Data were expressed as the mean ± SEM. *p < 0.05 and ***p < 0.0001 vs. Control, ###p < 0.0001 vs. IF 12 h. n = 8–10 mice/group.
Figure 4
Figure 4
Effects of acute and intermittent fasting on the activation of orexin neurons in the lateral hypothalamus of mice. (a) Representative images of co-immunostaining with orexin A (OXA, green) and FosB/ΔFosB (red) in the lateral hypothalamus of control, 12 h acute fasting (AF 12 h), and 12 h intermittent fasting (IF 12 h) groups. White arrows indicate neurons that co-express orexin A and FosB/ΔFosB. (b) The number of cells co-expressing orexin A and FosB/ΔFosB was counted and shown as a graph. Data were expressed as the mean ± SEM. ***p < 0.0001 vs. Control. n = 5 mice/group.
Figure 5
Figure 5
Effects of acute and intermittent fasting on the levels of protein and mRNA of orexin A or orexin 1 receptor in the hypothalamus and spinal cord of mice. (a) and (b) Western blot analysis was used to determine the expression levels of orexin A (OXA; a) and orexin 1 receptor (OR1; b) in the lateral hypothalamus of control, 12 h acute fasting (AF 12 h), and 12 h intermittent fasting (IF 12 h) groups. (c) OXA mRNA level was detected in the spinal cord of control, AF 12 h, and IF 12 h groups through qPCR. (d) Representative images showing OXA immunoreactivity in the spinal cord of control, AF 12 h, and IF 12 h groups. The changes in OXA immunoreactivity caused by fasting were shown as a graph. Data were expressed as mean ± SEM. WB was quantified as actin and qPCR as GAPDH. *p < 0.05 and ***p < 0.0001 vs. Control. n = 4–11 mice/group.
Figure 6
Figure 6
Effect of acute and intermittent fasting on the number of c-Fos-positive neurons after formalin administration. (a) Representative images showing c-Fos-positive neurons number in the dorsal horn lamina 1 and 2 of the L4-6 spinal cord in groups of control, 12 h acute fasting (AF 12 h), and 12 h intermittent fasting (IF 12 h) groups. (b) The c-Fos-positive neurons number in the dorsal horn lamina 1 and 2 shown in (a) was quantified and graphed. Data were expressed as mean ± SEM. **p < 0.01 vs. Control. n = 4–5 mice/group.
Figure 7
Figure 7
Effects of intrathecal SB334867 administration on formalin-induced nociceptive behaviors and spinal c-Fos expression after intermittent fasting of mice. (a) Formalin-induced nociceptive behaviors were measured in groups of vehicle-treated control, SB334867-treated control, vehicle-treated intermittent fasting (IF), and SB334867-treated IF groups. (b) and (c) The spontaneous nociceptive behaviors were divided into 1st phase (0–10 min) and 2nd phase (10–40 min). Intrathecal injection of SB334867 had no effect on licking behaviors during the 1st phase of pain (b), whereas formalin-induced licking behaviors during the 2nd phase of pain were reduced by SB334867 administration (c). (d) and (e) Representative images (d) and a graph (e) showing the effect of SB334867 on the number of c-Fos-positive neurons in the dorsal horn lamina 1 and 2 of the L4-6 spinal cord in control and IF groups. Data were expressed as mean ± SEM. *p < 0.05, **p < 0.01 vs. Control; #p < 0.05, ##p < 0.01 vs. IF 12 h. n = 5–8 mice/group.
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