Effects of acute and chronic sleep loss on immune modulation of rats

Sleep deprivation is now recognized as an increasingly common condition inherent to modern society, and one that in many ways, is detrimental to certain physiological systems, namely, immune function. Although sleep is now viewed by a significant body of researchers as being essential for the proper working of a host of defense systems, the consequences of a lack of sleep on immune function remains to be fully comprehended. The aim of the current study was to investigate how paradoxical sleep deprivation (PSD) for 24 and 96 h and sleep restriction (SR) for 21 days by the modified multiple-platform method, and their respective 24-h recovery periods, affect immune activation in rats. To this end, we assessed circulating white blood cell counts, lymphocyte count within immune organs, as well as Ig and complement production. The data revealed that PSD for 96 h increased complement C3 and corticosterone concentration in relation to the control group. In contrast, the spleen weight, total leukocytes, and lymphocytes decreased during SR for 21 days when compared with the control group, although production of a certain class of immunoglobulin, the IgM, did increase. After recovery sleep, lymphocyte count in axillary lymph nodes grew when rats had rebound sleep after PSD for 24 h, neutrophils increased after PSD 96 h and lymphocytes numbers were higher after SR 21 days. Such alterations during sleep deprivation suggest only minor alterations of nonspecific immune parameters during acute PSD, and a significant impairment in cellular response during chronic SR.     

Impact of sex on hyperalgesia induced by sleep loss

This study evaluated the impact of sex on the short term consequences of different periods of sleep deprivation and the effect of the respective sleep recovery periods on nociceptive responses. Male and female C57BL/6J mice were assigned to the following groups: paradoxical sleep deprived (PSD) for 72 h, sleep restricted (SR) for 15 days, exposed to respective recovery periods for 24 h, or untreated home-cage controls (CTRL). Mice were submitted to a noxious thermal stimulus to evaluate their nociceptive response after PSD, SR, or recovery periods. Blood was collected for hormonal analysis. The nociceptive response was significantly lower in PSD and SR mice compared to CTRL animals, regardless of the sex. However, SR females had a lower paw withdrawal threshold than males. Sleep recovery was able to restore normal nociceptive sensitivity after PSD in both sexes. The hyperalgesia induced by SR was not reversed by sleep rebound. In females, low concentrations of estradiol were found after SR, and these concentrations continued to decrease after 24 hours of sleep recovery. The PSD male mice exhibited higher concentrations of corticosterone than the CTRL and SR male mice. Corticosterone levels were not affected by SR. Our study revealed that PSD and SR induce hyperalgesia in mice. The SR groups showed marked changes in the nociceptive response, and the females were more sensitive to these alterations. This finding indicates that, although different periods of sleep deprivation change the nociceptive sensitivity in male and female mice, sex could influence hyperalgesia induced by chronic sleep loss.     

Stress-Induced Changes in the Activity of Angiotensin-Converting Enzyme in Structures of the Hypothalamo-Hypophyseal-Adrenocortical System of Adrenalectomized Rats

We studied the effects of stress induced by different influences (immobilization and compulsory swimming) on the activity of angiotensin-converting enzyme (ACE, an enzyme of the proteolytic conversion of angiotensin II) in structures of the hypothalamo-hypophyseal-adrenocortical system (HHAS) of unilaterally adrenalectomized (hemiadrenalectomized, HAE) rats. The pattern of stress-induced changes in the activity of ACE depended on the type of stress; rigid daily immobilization of rats for 1 h resulted in more significant shifts. Post-immobilization stress changes in the activity of ACE in the HHAS structures of HAE rats (with a lower basal activity of the endogenous angiotensin system in their hypothalamus) differed from the stress-induced reaction of the enzyme in intact rats. In HAE rats, we also observed inhibition of the activity of a glucocorticoid link of the stress system, as compared with that in intact animals. An inhibitor of ACE, captopril, and a stable analog of leucine-enkephalin, dalargin, when injected before stressing, were capable of decreasing the stress-induced ACE reaction in the hypothalamus and adenohypophysis and of limiting manifestations of the reaction of the adrenals to immobilization. This is interpreted as a proof of the involvement of the components of the angiotensin and enkephalin systems in the formation of the HHAS system to stressing of HAE rats.     

Sleep deprivation under sustained hypoxia protects against oxidative stress

We previously showed that total sleep deprivation increased antioxidant responses in several rat brain regions. We also reported that chronic hypoxia enhanced antioxidant responses and increased oxidative stress in rat cerebellum and pons, relative to normoxic conditions. In the current study, we examined the interaction between these two parameters (sleep and hypoxia). We exposed rats to total sleep deprivation under sustained hypoxia (SDSH) and compared changes in antioxidant responses and oxidative stress markers in the neocortex, hippocampus, brainstem, and cerebellum to those in control animals left undisturbed under either sustained hypoxia (UCSH) or normoxia (UCN). We measured changes in total nitrite levels as an indicator of nitric oxide (NO) production, superoxide dismutase (SOD) activity and total glutathione (GSHt) levels as markers of antioxidant responses, and levels of thiobarbituric acid-reactive substances (TBARS) and protein carbonyls as signs of lipid and protein oxidation products, respectively. We found that acute (6h) SDSH increased NO production in the hippocampus and increased GSHt levels in the neocortex, brainstem, and cerebellum while decreasing hippocampal lipid oxidation. Additionally, we observed increased hexokinase activity in the neocortex of SDSH rats compared to UCSH rats, suggesting that elevated glucose metabolism may be one potential source of the enhanced free radicals produced in this brain region. We conclude that short-term insomnia under hypoxia may serve as an adaptive response to prevent oxidative stress.     

Antioxidant responses to chronic hypoxia in the rat cerebellum and pons

Obstructive sleep apnea (OSA) is characterized by chronic intermittent hypoxia (CIH) and sleep fragmentation and deprivation. Exposure to CIH results in oxidative stress in the cortex, hippocampus and basal forebrain of rats and mice. We show that sustained and intermittent hypoxia induces antioxidant responses, an indicator of oxidative stress, in the rat cerebellum and pons. Increased glutathione reductase (GR) activity and thiobarbituric acid reactive substance (TBARS) levels were observed in the pons and cerebellum of rats exposed to CIH or chronic sustained hypoxia (CSH) compared with room air (RA) controls. Exposure to CIH or CSH increased GR activity in the pons, while exposure to CSH increased the level of TBARS in the cerebellum. The level of TBARS was increased to a greater extent after exposure to CSH than to CIH in the cerebellum and pons. Increased superoxide dismutase activity (SOD) and decreased total glutathione (GSHt) levels were observed after exposure to CIH compared with CSH only in the pons. We have previously shown that prolonged sleep deprivation decreased SOD activity in the rat hippocampus and brainstem, without affecting the cerebellum, cortex or hypothalamus. We therefore conclude that sleep deprivation and hypoxia differentially affect antioxidant responses in different brain regions.     

Serotonin Turnover in Discrete Regions of Young Rat Brain After 24 h REM Sleep Deprivation

The present study has attempted to elucidate the alteration of serotonin turnover after 24 h REM sleep deprivation in different regions in brain of young rat. Sleep deprivation was induced by the inverted flowerpot technique. Results of this study show increased serotonin turnover after 24 h REM sleep deprivation in all the brain regions except in the hypothalamus. The decreased 5-HT ratio shows increased serotonin in the hypothalamus after 24 h sleep deprivation. This study indicates increased activity of serotonergic neurons in the hypothalamus after 24 h sleep deprivation. This also indicates that the hypothalamus plays a role in the immediate compensatory mechanism during 24 h REM sleep deprivation in young rats.     

Sex-related effects of sleep deprivation on depressive- and anxiety-like behaviors in mice

Anxiety and depressive symptoms are generated after paradoxical sleep deprivation (PSD). However, it is not clear whether PSD produces differential effects between females and males. The aim of this study was to assess the effect of PSD on anxiety- and depressive-like behaviors between sexes. Male and female BALB/c mice were divided in three groups: the control group, the 48-h PSD group and the 96-h PSD group. Immediately after PSD protocols, the forced swimming and open field test were applied. Sucrose consumption test was used to evaluate the middle-term effect of PSD. We found that corticosterone serum levels showed significant differences in the 96-h PSD females as compared to 96-h PSD males. In the open-field test, the 48-h and 96-h PSD females spent more time at the periphery of the field, and showed high locomotion as compared to males. In the elevated plus maze, the 48-h PSD females spent more time in closed arms than males, which is compatible with anxiety-like behavior. The forced swim test indicated that the 96-h PSD males spent more time swimming as compared to the 96-h PSD females. Remarkably, the 96-h PSD males had lower sucrose intake than the 96-h PSD females, which suggest that male mice have proclivity to develop a persistent depressive-like behavior late after PSD. In conclusion, male mice showed a significant trend to depressive-like behaviors late after sleep deprivation. Conversely, female have a strong tendency to display anxiety- and depressive-like behaviors immediately after sleep deprivation.     

Adenosine kinase and 5'-nucleotidase activity after prolonged wakefulness in the cortex and the basal forebrain of rat

The effect of prolonged wakefulness on adenosine kinase (AK), ecto-5'-nucleotidase and endo-5'-nucleotidase activity was assessed in the present study. Rats were sleep deprived for 3 or 6h, and one group was allowed to sleep 2h of recovery sleep after the 6h deprivation. The cortex and the basal forebrain were dissected, and frozen rapidly on dry ice. The enzyme activity of adenosine kinase was measured by monitoring the conversion of [2-3H]-adenosine into [3H]-adenosine monophosphate (AMP) and the ecto-5'-nucleotidase and endo-5'-nucleotidase activities by monitoring the conversion of [2-3H]-AMP into [3H]-adenosine. The enzyme activities did not change during deprivation or recovery sleep in either cortex or basal forebrain when compared to unhandled controls. Significant diurnal variation in enzyme activities was noted in both brain areas. In the basal forebrain adenosine kinase and both nucleotidases showed their lowest activity in the middle of the rest phase, 6h after lights on, suggesting a low level of adenosine metabolism, both production and degradation at this time point. In the cortex adenosine kinase had a diurnal activity pattern similar to the basal forebrain and the ecto-5'-nucleotidase activity was low already early in the rest phase, 3h after lights on, and remained low until the end part of the rest phase, 8h after lights on. Endo-5'-nucleotidase lacked diurnal variation. These activity patterns may be associated with the lower level of energy metabolism during sleep compared to wakefulness.     

Angiotensin converting enzyme (kininase II) mRNA production and enzymatic activity in human peripheral blood monocytes are induced by GM-CSF but not other cytokines

Peripheral blood monocytes (PBM) do not possess angiotensin converting enzyme (ACE) activity in the inactive state. However, measurable PBM ACE activity is found in patients with certain inflammatory disease. We have examined the effect of cytokines likely to be present during granulomatous inflammation on the regulation of ACE mRNA in PBM. The presence of ACE mRNA in human PBM cultured in vitri with various cytokines for up to 6 days was analyzed using polymerase chain reaction. PBM not exposed to cytokines did not express ACE mRNA, while incubation of PBM with recombinant human GM-CSF resulted in high levels of ACE mRNA expression after 72 h of cell culture, which persisted through day six. Increased ACE mRNA expression occurred concommitantly with phenotypic changes in cell size and shape consistent with cell activation. A 5-fold increase in ACE enzymatic activity also occurred. Incubation of PBM with all other cytokines tested failed to induce ACE mRNA expression. Alveolar macrophages expressed ACE mRNA immediately following their isolation, but mRNA expression decreased markedly during a 24-h period of incubation and was only partially reversed with exogenous GM-CSF. We conclude that GM-CSF enhances ACE mRNA levels in human PBM, but not in alveolar macrophages.     

Induction of PGHS-2 mRNA in response to cerebral hypoperfusion in late-gestation fetal sheep

Previous studies have demonstrated that cerebral ischemia stimulated the increased abundance of immunoreactive PGHS-2, but not PGHS-1, in brain tissue homogenates in late-gestation fetal sheep. The goal of the present study was to detect PGHS-1 and PGHS-2 mRNA in specific fetal brain regions, and to semi-quantitatively detect changes in the abundance of the respective mRNA's in response to cerebral hypoperfusion. Fetal brain tissues were collected from control fetuses and from fetuses 30 min and 2 h after cerebral hypoperfusion (produced by brachiocephalic occlusion). Messenger RNA was studied by RT-PCR, and expressed semiquantitatively as a ratio of PGHS-1 or PGHS-2 mRNA abundance to beta-actin mRNA abundance. PGHS-2 mRNA was only detected in the fetal hippocampus, hypothalamus, and brain stem and it was induced by cerebral hypoperfusion. In contrast, PGHS-1 mRNA was detected in all fetal brain tissues but was not induced. We conclude that cerebral hypoperfusion induced PGHS-2 gene expression in hippocampus, hypothalamus, and brainstem, and we speculate that the increased abundance of the enzyme is likely to be important for control of reflex responses to hypotension in the fetus.     

MCH levels in the CSF,brain preproMCH and MCHR1 gene expression during paradoxical sleep deprivation,sleep rebound and chronic sleep restriction

Neurons that utilize melanin-concentrating hormone (MCH) as neuromodulator are located in the lateral hypothalamus and incerto-hypothalamic area. These neurons project throughout the central nervous system and play a role in sleep regulation. With the hypothesis that the MCHergic system function would be modified by the time of the day as well as by disruptions of the sleep-wake cycle, we quantified in rats the concentration of MCH in the cerebrospinal fluid (CSF), the expression of the MCH precursor (Pmch) gene in the hypothalamus, and the expression of the MCH receptor 1 (Mchr1) gene in the frontal cortex and hippocampus. These analyses were performed during paradoxical sleep deprivation (by a modified multiple platform technique), paradoxical sleep rebound and chronic sleep restriction, both at the end of the active (dark) phase (lights were turned on at Zeitgeber time zero, ZT0) and during the inactive (light) phase (ZT8).We observed that in control condition (waking and sleep ad libitum), Mchr1 gene expression was larger at ZT8 (when sleep predominates) than at ZT0, both in frontal cortex and hippocampus.In addition, compared to control, disturbances of the sleep–wake cycle produced the following effects: paradoxical sleep deprivation for 96 and 120 h reduced the expression of Mchr1 gene in frontal cortex at ZT0. Sleep rebound that followed 96 h of paradoxical sleep deprivation increased the MCH concentration in the CSF also at ZT0. Twenty-one days of sleep restriction produced a significant increment in MCH CSF levels at ZT8. Finally, sleep disruptions unveiled day/night differences in MCH CSF levels and in Pmch gene expression that were not observed in control (undisturbed) conditions.In conclusion, the time of the day and sleep disruptions produced subtle modifications in the physiology of the MCHergic system.     

Conditions that affect sleep alter the expression of molecules associated with synaptic plasticity

Many theories propose that sleep serves a purpose in synaptic plasticity. We tested the hypothesis, therefore, that manipulation of sleep would affect the expression of molecules known to be involved in synaptic plasticity. mRNA expression of four molecules [brain-derived neurotrophic factor (BDNF), activity-regulated cytoskeleton-associated protein (Arc), matrix metalloproteinase-9 (MMP-9), and tissue plasminogen activator (tPA)] was determined after 8 h of sleep deprivation and after 6 h of a mild increase in ambient temperature, a condition that enhances sleep in rats. After sleep deprivation, BDNF, Arc, and tPA mRNAs in the cerebral cortex increased while MMP-9 mRNA levels decreased. Conversely, after enhanced ambient temperature, BDNF, Arc, and tPA mRNAs decreased while MMP-9 mRNA increased. In the hippocampus, sleep deprivation did not significantly affect BDNF and tPA expression, although Arc mRNA increased and MMP-9 mRNA decreased. Brain temperature enhancement decreased Arc mRNA levels in the hippocampus but did not affect BDNF, MMP-9, or tPA in this area. Results are consistent with the notion that sleep plays a role in synaptic plasticity.     

Human plasma DSIP decreases at the initiation of sleep at different circadian times

Nocturnal plasma delta sleep-inducing peptide-like immunoreactivity (DSIP-LI) was determined serially in seven healthy male subjects. Time courses during nocturnal sleep (2300-0800 h), nocturnal sleep deprivation (2300-0500 h), and morning recovery sleep (0500–0800 h) after sleep deprivation were compared. A significant decrease in plasma DSIP-LI was found at the transition from wakefulness to sleep in both evening sleep (2300 h) and morning recovery sleep (0500 h). Time courses were accompanied by physiological changes in sleep electroencephalographic slow-wave activity, and in plasma concentrations of cortisol and human growth hormone. No sleep stage specificity was found. It is concluded that DSIP is influenced by the initiation of sleep.     

An ameliorative effect of recovery sleep on total sleep deprivation-induced neurodegeneration

Neurodegenerative changes following sleep deprivation (SD) result in debilitating behavioral and cognitive dysfunction. SD causes gradual cognitive impairment and later results in neurodegeneration. These changes are thought to be the consequences of cellular disorganization and degeneration in selected brain areas – the hippocampus, prefrontal cortex, amygdala, and hypothalamus. We investigated the histological changes in mice exposed to 6 days SD and to the effects of 2 days of recovery sleep in the brain regions listed above. Cytological changes, total viable cell count in hippocampal subregions, Bcl-2 expression, and degenerative changes like cell morphology and membrane integrity of neurons were evaluated. Results demonstrated that prolonged SD decreased the count of viable and healthy cells and caused a decrease in Bcl-2 positive cells and an increase in degenerated cells with pyknotic morphology, chromatolysis and darkly stained cytoplasm. Degenerative changes were ameliorated by 2 days of recovery sleep or rehabilitation after SD. Data suggest that chronic SD constitutes a severe threat to the brain and leads to neurodegeneration, while rehabilitation or recovery sleep ameliorates or protects the brain from neurodegenerative challenges.     

The effects of paradoxical sleep deprivation on estrous cycles of the female rats

The present purpose was to examine how sleep deprivation affects the estrous cycle of the female rat. Paradoxical sleep-deprived (PSD) adult female Wistar rats were compared to home-cage control (CTRL) on their estrous cyclicity. Forty-four PSD and forty-four CTRL female rats were distributed into 4 subgroups of 11 animals each according to the phase of estrous cycle and were subjected to sleep deprivation for 96 h by the multiple platform technique. After PSD period, vaginal estrous cycles were taken for an additional 9 days. Animals that were submitted to PSD in diestrus phase (PSD-diestrus) had their estrous cycles disrupted during the recovery period by showing a constant diestrus during the first week. As for hormone alterations, progesterone concentrations were statistically higher in PSD-diestrus compared to respective phase control and to PSD-proestrus and PSD-estrus rats while CTRL-metestrus had higher levels than CTRL-proestrus and estrus groups. Testosterone was significantly decreased in PSD-estrus in relation to PSD-proestrus and PSD-diestrus groups and was lower in CTRL-diestrus rats than in home-cage rats in proestrus. In addition, PSD-diestrus phase exhibited higher concentrations of corticosterone and lower estrogen than the respective control rats. These data indicate that PSD may modulate the ovarian hormone release through alterations in hormonal-neurochemical mechanisms.     

Bone marrow and peripheral white blood cells number is affected by sleep deprivation in a murine experimental model

Sleep deficit and related disorders are becoming increasingly prevalent in modern life and an extensive literature has documented that acute or chronic sleep deprivation can lead to several physiological consequences. Here, we evaluated the effects of sleep deprivation on hematopoietic composition of either bone marrow or peripheral blood. Mice were subjected to paradoxical sleep deprivation (PSD) for 72 h by modified multiple platform method, with or without an additional sleep recovery (SR) period of 10 days. PSD decreased total cellularity of the bone marrow and peripheral blood concomitantly. Subsequent analysis of cell composition showed that absolute number of hematopoietic stem/progenitor cells and colony-forming units was decreased. Moreover, the absolute number of granulocytes and monocytes in bone marrow was reduced in PSD group. These alterations were paralleled by an accumulation of neutrophils and monocytes in peripheral blood. PSD also induced lymphopenia in the circulation. To the best of our knowledge, this is the first study that demonstrates the importance of sleep on the hematopoietic microenvironment and provides new insights into the relationship between sleep and the immune system.     

抗体应答期间大鼠脑和胸腺中儿茶酚胺含量的变化

目的：探讨在抗体应答期间,脑和淋巴器官中儿茶酚胺（ＣＡｓ）含量的动态变化,籍以了解免疫状态对中枢和外周ＣＡｓ神经活动的影响。方法：用绵羊红细胞（ＳＲＢＣ）免疫大鼠,在免疫后第２￣７ｄ应用高效液相色谱－电化学检测法（ＨＰＬＣ－ＥＣＤ）测定大鼠下丘脑、海马、脑干和胸腺中云甲肾上腺素（ＮＡ）、肾上腺素（Ａ）、多巴胺（ＤＡ）和高香草酸（ＨＶＡ）的含量。结果：①下且脑和海马内ＮＡ在抗体应答期间升高,而胸腺中     

Proteomic analysis of the effects and interactions of sleep deprivation and aging in mouse cerebral cortex

The cellular and molecular processes that underlie the drives and functions of sleep have been the topic of many studies in the last few decades. Discovery-based techniques, such as cDNA microarrays, have increasingly been utilized in conjunction with sleep deprivation paradigms to examine the molecular mechanisms and functions of sleep. These studies have helped to validate and expand existing hypotheses, such as those on the roles of sleep in synaptic plasticity and in energy metabolism. The mechanisms underlying the highly prevalent changes in sleep architecture with age are not known, but likely reflect fundamental changes in the molecular basis of circadian timing and sleep homeostatic processes. We decided to explore the effects and interactions of sleep deprivation and aging utilizing the proteomic technique of difference in gel electrophoresis (DIGE). DIGE, which utilizes cyanine dye labeling of samples, allows for the comparison of multiple experimental groups within and across gels. In this study, we compared cerebral cortex tissue from young (2.5 months) and old (24 months) mice that had been sleep deprived for 6 h to tissue from undisturbed young and old control animals. Following DIGE, automatic image matching and spot identification, and statistical analysis, 43 unique proteins were identified. The proteins were grouped into seven functional classes based on published characteristics: cell signaling, cytoskeletal, energy metabolism, exocytosis, heat shock proteins, mRNA processing/trafficking, and serum proteins. The identity and characteristics of these proteins relevant to sleep and aging are discussed.     

Angiotensinase and vasopressinase activities in hypothalamus, plasma, and kidney after inhibition of angiotensin-converting enzyme: basis for a new working hypothesis

Reducing angiotensin II (Ang II) production via angiotensin-converting enzyme (ACE) inhibitors is a key approach for the treatment of hypertension. However, these inhibitors may also affect other enzymes, such as angiotensinases and vasopressinase, responsible for the metabolism of other peptides also involved in blood pressure control, such as Ang 2-10, Ang III, Ang IV, and vasopressin. We analyzed the activity of these enzymes in the hypothalamus, plasma, and kidney of normotensive adult male rats after inhibition of ACE with captopril. Aspartyl- (AspAP), glutamyl- (GluAP), alanyl- (AlaAP) and cystinyl-aminopeptidase (CysAP) activities were measured fluorimetrically using arylamides as substrates. Systolic blood pressure (SBP), water intake, and urine flow were also measured. Captopril reduced SBP and increased urine flow. In the hypothalamus, GluAP and AspAP increased, without significant changes in either AlaAP or CysAP. In contrast with effects in plasma, GluAP was unaffected, AspAP decreased, while AlaAP and CysAP increased. In the kidney, enzymatic activities did not change in the cortex, but decreased in the medulla. These data suggest that after ACE inhibition, the metabolism of Ang I in hypothalamus may lead mainly to Ang 2-10 formation. In plasma, the results suggest an increased formation of Ang IV together with increased vasopressinase activity. In the kidney, there is a reduction of vasopressinase activity in the medulla, suggesting a functional reduction of vasopressin in this location. The present data suggest the existence of alternative pathways in addition to ACE inhibition that might be involved in reducing BP after captopril treatment.     

Paradoxical Sleep Deprivation Aggravates and Prolongs Incision-Induced Pain Hypersensitivity via BDNF Signaling-Mediated Descending Facilitation in Rats

The mechanisms underlying the pronociceptive effect of paradoxical sleep deprivation (PSD) are not fully established. The modulation of BDNF signaling-mediated descending facilitation from the rostral ventromedial medulla (RVM) of brain stem has been demonstrated in persistent pain models of inflammatory pain, but not in incisional pain model. Recent study has shown that PSD increases the expression of brain-derived neurotrophic factor (BDNF) in the brainstem structure. Therefore, in the current study, we asked whether the BDNF signaling-mediated descending facilitation was involved in the PSD-induced pronociceptive effect on incisional pain and delay the recovery period of postoperative pain in rats. Our results found that a preoperative 24 h PSD significantly aggravated the pain hypersensitivity after incision and prolonged the duration of postoperative pain. The lesions of ipsilateral dorsolateral funiculus partly reversed the PSD-induced pronociceptive effect on incisional pain. Interestingly, the 24 h PSD, but not incision significantly enhanced the levels of BDNF protein expression in the RVM areas of rats. Furthermore, at 1 day or 4 days after incision, intra-RVM microinjection of a BDNF antibody partly reversed the PSD-induced pronociceptive effects in incisional rats, while it did not change the cumulative pain scores and paw withdrawal thresholds in rats receiving only plantar incision. These findings suggest that the preoperative PSD may aggravate and prolong the incision-induced pain hypersensitivity via BDNF signaling-mediated descending facilitation.