Short-Term Sleep Disturbance-Induced Stress Does not Affect Basal Pain Perception, but Does Delay Postsurgical Pain Recovery

Abstract

Chronic sleep disturbance-induced stress is known to increase basal pain sensitivity. However, most surgical patients frequently report short-term sleep disturbance/deprivation during the pre- and postoperation periods and have normal pain perception presurgery. Whether this short-term sleep disturbance affects postsurgical pain is elusive. Here, we report that pre- or postexposure to rapid eye movement sleep disturbance (REMSD) for 6 hours daily for 3 consecutive days did not alter basal responses to mechanical, heat, and cold stimuli, but did delay recovery in incision-induced reductions in paw withdrawal threshold to mechanical stimulation and paw withdrawal latencies to heat and cold stimuli on the ipsilateral side of male or female rats. This short-term REMSD led to stress shown by an increase in swim immobility time, a decrease in sucrose consumption, and an increase in the level of corticosterone in serum. Blocking this stress via intrathecal RU38486 or bilateral adrenalectomy abolished REMSD-caused delay in recovery of incision-induced reductions in behavioral responses to mechanical, heat, and cold stimuli. Moreover, this short-term REMSD produced significant reductions in the levels of mu opioid receptor and kappa opioid receptor, but not Kv1.2, in the ipsilateral L4/5 spinal cord and dorsal root ganglia on day 9 after incision (but not after sham surgery).

Perspective: Our findings show that short-term sleep disturbance either pre- or postsurgery does not alter basal pain perception, but does exacerbate postsurgical pain hypersensitivity. The latter may be related to the reductions of mu and kappa opioid receptors in the spinal cord and dorsal root ganglia caused by REMSD plus incision. Prevention of short-term sleep disturbance may help recovery from postsurgical pain in patients.

Keywords: Short-term sleep disturbance; postoperative pain; stress; surgery.

Conflict of interest statement

Disclosures: The authors do not have any conflicts of interest.

Copyright © 2015 American Pain Society. Published by Elsevier Inc. All rights reserved.

Figures

Fig. 1

Time-dependent changes in basal paw withdrawal responses to mechanical, heat, and cold stimuli after rapid eye movement sleep disturbance (REMSD) 6 h daily for consecutive days as indicated in male rats. Significant reductions were seen in bilateral paw withdrawal thresholds in response to mechanical stimulation on day 5 post-REMSD (1a, 1b), in left hind paw withdrawal latencies in response to heat stimulation on day 5 post-REMSD (1c) and on day 4 and 5 post-REMSD on right hind paw (1d), and in paw withdrawal latency in response to cold stimulation on day 4 and 5 post-REMSD (1e) in REMSD group. * P < 0.05, ** P < 0.01 vs the corresponding time points in control group. N = 5/group.

Fig. 2

Effect of pre-surgical exposure to short-term rapid eye movement sleep disturbance (REMSD) on postsurgical pain in male rats. REMSD 6 h daily for 3 consecutive days did not alter basal paw withdrawal responses to mechanical (2a, 2d), heat (2b, 2e), and cold (2c) stimuli on the ipsilateral (2a, 2b, 2c) and contralateral (2d, 2e) sides in the sham plus REMSD group, but markedly delayed recovery in incision-induced reductions in paw withdrawal threshold to mechanical stimulation (2a) and paw withdrawal latencies to heat (2b) and cold (2c) stimuli on the ipsilateral side on day 7 and 9 post-REMSD in the incision plus REMSD group, compared to the incision plus control group. No changes in paw withdrawal responses were seen during the observation period in the sham plus control group. * P < 0.05, ** P < 0.01 vs the corresponding time points in the incision plus control group. N = 5/group.

Fig. 3

Effect of post-surgical exposure to short-term rapid eye movement sleep disturbance (REMSD) on postsurgical pain in male rats. REMSD 6 h daily for 3 consecutive days did not alter basal paw withdrawal responses to mechanical (3a, 3d), heat (3b, 3e), and cold (3c) stimuli on the ipsilateral (3a, 3b, 3c) and contralateral (3d, 3e) sides in the sham plus REMSD group, but markedly delayed recovery in incision-induced reductions in paw withdrawal threshold to mechanical stimulation on day 7 and 9 post-REMSD (3a) and paw withdrawal latencies to heat (3b) and cold (3c) stimuli on days 4, 7, and 9 post-REMSD on the ipsilateral side in the incision plus REMSD group, compared to the incision plus control group. No changes in paw withdrawal responses were seen during the observation period in the sham plus control. * P < 0.05, ** P < 0.01 vs the corresponding time points in the incision plus control group. N = 5/group.

Fig. 4

Effect of post-surgical exposure to short-term rapid eye movement sleep disturbance (REMSD) on postsurgical pain in female rats. REMSD 6 h daily for 3 consecutive days did not alter basal paw withdrawal responses to mechanical (4a, 4d), heat (4b, 4e), and cold (4c) stimuli on the ipsilateral (4a, 4b, 4c) and contralateral (4d, 4e) sides in sham plus REMSD group, but markedly delayed recovery in incision-induced reductions in paw withdrawal threshold to mechanical stimulation (4a) and paw withdrawal latency to heat stimulation (4b) on days 7 and 9 post-REMSD and paw withdrawal latency to cold stimulation (4c) on days 4, 7, and 9 post-REMSD on the ipsilateral side in the incision plus REMSD group, compared to the incision plus control group. No changes in paw withdrawal responses were seen during the observation period in the sham plus control group. * P < 0.05, ** P < 0.01 vs the corresponding time points in the incision plus control group. N = 5/group.

Fig. 5

Existence of stress after short-term rapid eye movement sleep disturbance (REMSD) in male rats. REMSD 6 h daily for 3 consecutive days significantly increased immobility time in a forced swim test (5a), decreased sucrose consumption in a sucrose preference test (5b), and elevated the level of corticosterone in blood serum (5c) in both the sham plus REMSD group and the incision plus REMSD group, compared to the sham plus control group. These changes were not observed in the incision plus control group (5a, 5b, 5c). No significant differences in changes in body weight before and day 9 post-REMSD were seen among the four groups (5d). ** P < 0.01 vs the corresponding sham plus control group. N = 5/group.

Fig. 6

Effect of intrathecal pre-administration of RU38486 (Ru) on exacerbated postsurgical pain induced by short-term rapid eye movement sleep disturbance (REMSD) in male rats. In the incision plus REMSD group, intrathecal vehicle (10 μl of 10% ethanol) 1 h before REMSD daily for 3 days did not affect marked reductions in paw withdrawal threshold to mechanical stimulation (6a) and paw withdrawal latencies to heat (6b) and cold (6c) stimuli on the ipsilateral side on day 9 post-incision. However, RU38486 (2 μg/10μl) 1 h before REMSD daily for 3 days completely abolished these reductions (6a, 6b, and 6c). RU38486 did not alter basal paw withdrawal responses to mechanical, heat, and cold stimuli on the contralateral side of the incision plus REMSD group (6d and 6e) and on either ipsilateral (6a, 6b, and 6c) or contralateral (6d and 6e) side of the incision plus control group and the sham plus control or REMSD group. Intrathecal vehicle did not affect all basal paw withdrawal responses on the contralateral side of the incision plus REMSD group (6d and 6e) and on either ipsilateral (6a, 6b, and 6c) or contralateral (6d and 6e) side of the sham plus control group. ** P < 0.01 vs the corresponding sham plus control group with intrathecal vehicle. N = 5/group.

Fig. 7

Effect of bilateral adrenalectomy (ADX) on exacerbated postsurgical pain induced by short-term rapid eye movement sleep disturbance (REMSD) in male rats. In the incision plus REMSD group, sham surgery of ADX (sham-ADX) before REMSD did not affect marked reductions in paw withdrawal threshold to mechanical stimulation (7a) and paw withdrawal latencies to heat (7b) and cold (7c) stimuli on the ipsilateral side on day 9 post-incision. However, bilateral ADX before REMSD entirely reversed these reductions (7a, 7b, and 7c). ADX did not alter basal paw withdrawal responses to mechanical, heat, and cold stimuli on the contralateral sides of the incision plus REMSD group (7d and 7e) and on either ipsilateral (7a, 7b, and 7c) or contralateral (7d and 7e) sides of the incision plus control group and the sham-incision (sham surgery of incision) plus control or REMSD group. Sham-ADX did not affect all basal paw withdrawal responses on the contralateral side of the incision plus REMSD group (7d and 7e) and on either the ipsilateral (7a, 7b, and 7c) or contralateral (7d and 7e) side of the sham plus control group. ** P < 0.01 vs the corresponding sham-incision plus control group with sham-ADX. N = 5/group.

Fig. 8

Effect of pre-surgical exposure to short-term rapid eye movement sleep disturbance (REMSD) on the expression of MOR, KOR, and Kv1.2 proteins in the ipsilateral L4/5 dorsal horn (8a) and L4/5 DRGs (8b) on day 9 post-incision from the sham plus control group, incision plus control group, sham plus REMSD group, and incision plus REMSD group. Top panels: examples of Western blots that show the expression of MOR, KOR, and Kv1.2 proteins. GAPDH is used as a loading control. Bottom: statistical summary of MOR, KOR, and Kv1.2 protein expression. Data are presented as mean ± SEM. N = 4–5/group. * P < 0.05 compared to the corresponding sham plus control group.