European Journal of Pain 13 (2009) 146–153

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European Journal of Pain

journal homepage: www.EuropeanJournalPain.com

Effect of acute gouty arthritis on sleep patterns: A preclinical study

Uriah Guevara-López a,b,*, Fructuoso Ayala-Guerrero c, Alfredo Covarrubias-Gómez a,Francisco J. López-Muñoz d, Ruben Torres-González b

a Department of Pain and Palliative Medicine, National Institute for Medical Sciences and Nutrition Salvador Zubirán, Mexico City, Mexicob Medical Unit of High Specialization (UMAE), Magdalena de las Salinas, Mexican Institute for Social Security, Mexico City, Mexicoc Sleep Clinic, School of Psychology, National Autonomous University of Mexico (UNAM), Mexico City, Mexicod Laboratory No. 7 ‘‘Pain and Analgesia”, Department of Pharmacobiology, Cinvestav-Sede Sur, Mexico

a r t i c l e i n f o

Article history:Received 17 December 2007Received in revised form 11 March 2008Accepted 3 April 2008Available online 22 May 2008

Keywords:Articular painSleepSlow wave sleepREMWakefulnessRats

1090-3801/$34.00 � 2008 European Federation of Chdoi:10.1016/j.ejpain.2008.04.002

* Corresponding author. Present address: DepartMedicine, Instituto Nacional de Ciencias Médicas yVasco de Quiroga No. 15, Col. Sección XVI, CP 14000, M55 5487 0900x5008; fax: +52 55 5485 4333.

E-mail addresses: uriahguevara@gmail.com, uriGuevara-López).

a b s t r a c t

Background: It has been demonstrated that the interrelation between pain and sleep produces changesin sleep patterns and pain perception. Although some evidences suggest that sleep and pain may interactin a complex way, polysomnographic studies in animals with acute nociception are limited in number.

Aims: This study was carried out in order to evaluate the effect of intra-articular knee injection of uricacid on sleep-wake patterns.

Methods: Surgical electrode implantation was performed in seven anesthetized Wistar rats to carry out10 h polysomnographic recordings. Acute nociception was induced by the intra-articular administrationof 30% uric acid crystals into the knee joint of the right hind limb. Two recordings before and after intra-articular drug administration were obtained. Sleep-wake parameters were classified as (i) wakefulness(W), (ii) slow wave sleep (SWS), and (iii) rapid eye movement (REM) sleep. Frequency and duration fromeach parameter were evaluated under the two above-mentioned conditions.

Results: Intra-articular administration of uric acid induced: (i) an increased duration of wakefulness(p = 0.014), (ii) a decrement in the duration (p = 0.001) and number of events (p = 0.027) in REM sleep,and (iii) a decrement in the total sleep time (p = 0.001). SWS did not present statistical differencesbetween groups.

Conclusions: These data suggest that a nociceptive stimulus, induced by the intra-articular administra-tion of uric acid, alters the sleep-wake equilibrium with REM sleep being particularly altered. However,further research concerning pain–sleep interaction is needed.� 2008 European Federation of Chapters of the International Association for the Study of Pain. Published

by Elsevier Ltd. All rights reserved.

1. Introduction

Sleep disturbances are observed in patients suffering a painfulcondition (Lamberg, 1999; Moldofsky, 2001; Rohers and Roth,2005; Lautenbacher et al., 2006); these disturbances are reportedas a decrease in sleep duration, and an increase in diurnal sleepi-ness (Wittig et al., 1982; Affleck et al., 1996; McCracken and Iver-son, 2002; Marin et al., 2006). The association of sleep disturbanceswith painful conditions suggests a complex interrelation betweenthese two phenomena (Moldofsky, 2001; Rohers and Roth, 2005).

Sleep is a highly sensitive function that may be altered byintrinsic and extrinsic factors (Foo and Masson, 2003); therefore,It is possible that a painful condition, such as acute articular pain,

apters of the International Associa

ment of Pain and PalliativeNutrición Salvador Zubirán,exico City, Mexico. Tel.: +52

ahguevara@hotmail.com (U.

might disorganize sleep-wake patterns (Hicks et al., 1979; Calvinoet al., 1987; Carli et al., 1987; Landis et al., 1988, 1989a,b; Heppel-mann and Pawlak, 1997; Andersen and Tufik, 2000, 2003; Roveroniet al., 2001; Schutz et al., 2003, 2004, 2007; Andersen et al., 2006;Wolfe et al., 2006; Ranjbaran et al., 2007).

Studies of sleep patterns in arthritic rats have evidenced: an in-crease in wakefulness (W), a decrease in both slow wave sleep(SWS) and rapid eye movement (REM) sleep, and an increase insleep fragmentation (Landis et al., 1988, 1989a,b; Andersen andTufik, 2000; Schutz et al., 2003, 2004). In those studies, a Freund’sadjuvant solution had been injected in the rat’s tail (Landis et al.,1988, 1989a,b), hind limb (Andersen and Tufik, 2000), or temporo-mandibular joint (Schutz et al., 2003, 2004, 2007).

There are several experimental models to study persistent pain;these models use an intra-articular or subcutaneous injection of di-verse substances (Faires and McCarty, 1962; Pardo and Rodriguez,1966; Van Arman et al., 1970; Okuda et al., 1984a; Wheeler-Acetoand Cowan, 1991); and have been useful in the assay of analgesicdrugs, and in the characterization of the inflammatory process.

tion for the Study of Pain. Published by Elsevier Ltd. All rights reserved.

U. Guevara-López et al. / European Journal of Pain 13 (2009) 146–153 147

A well described experimental model is the intra-articular kneeinjection of an uric acid suspension in mineral oil (uric acid intra-articular administration, UAIA). This model produces: an acuteinflammation, nociception, and a reversible dysfunction of the in-jected limb (Van Arman et al., 1970; Okuda et al., 1984b; López-Muñoz et al., 1993). The UAIA have been used to evaluate the anti-nociceptive response of diverse analgesic drugs and the involvementof several pathways in the inflammatory response (Hoyo-Vadilloet al., 1995; Déciga-Campos et al., 2003; Ventura-Martı́nez et al.,2004; Martı́nez-Quiroz et al., 2005; García-Hernández et al., 2007).

Based on these elements, we propose the evaluation of sleeppatterns in an experimental model of acute gouty arthritis, andthe hypothesis that UAIA disrupts sleep architecture of the ratwas tested. The objective of this experimental work was to evalu-ate the sleep patterns in the rat before and after UAIA (rats withacute gouty arthritis).

2. Methods

2.1. General experimental procedures

Male Wistar rats [Crl(WI)BR] weighing an average of 426 g atthe beginning of the study were used in this study. They werehoused in individual acrylic cages inside a soundproof chamber,under standardized conditions in a room maintained at a constanttemperature (20–24 �C) on a 12 h light/dark cycle (lights on at07:00). Food and water available ad libitum, and an adaptationperiod of 72 h to the laboratory conditions was provided beforesurgical intervention. All experimental procedures were approvedby the internal Ethics Committee (Register number: 0077-INC-MNSZ), and followed the Guidelines on Ethical Standards for Inves-tigations of Experimental Pain in Animals (Covino et al., 1980;Zimmermann, 1983). All tests were performed during the lightphase. The number of experimental animals was kept to a mini-mum, and following the end of the study, rats were euthanizedby CO2 overdose.

2.2. Surgical electrode implantation technique

All animals, under general anesthesia, underwent the surgicalimplantation technique in sterile conditions. Anesthesia was ob-tained by the intraperitoneal administration of sodium pentobarbi-tal (50 mg/kg), and maintained by the administration of ethervapor. The head of each anesthetized animal was fixed in a stereo-taxic frame to perform the surgical procedure.

A midline incision on the scalp was made to expose the skull,after that, four small holes were drilled in the exposed skull surgi-cal area under direct microscopy: (i) two anterior holes (located at2.0 mm anterior to bregma and 2.0 mm lateral to the midline), and(ii) two posterior holes (located at 2.0 mm lateral to the midlineand 2.0 mm posterior to sigma).

Four stainless steel wire electrodes were placed on the durathrough each drilled hole in the skull: (i) two electrodes wereplaced through the anterior holes to obtain brain recordings fromthe frontal cortex, and (ii) two electrodes were placed throughthe posterior holes to obtain brain recordings from occipital cortex.The implantation of cortical electrodes was made under direct sur-gical microscopy and its position fixed with dental acrylic.

To record electromyographic (EMG) activity two copper wireelectrodes were inserted into dorsal neck muscles. Ocular activity(EOG) was recorded from a stainless steel wire electrode locatedon the supraorbital bone of the right eye; and another stainlesssteel wire electrode situated in the nasal bone was placed to serveas ground. Once electrodes were positioned as described, thosewere soldered to a connector and fixed on the skull with dental ac-

rylic. Topical chloramphenicol was used to prevent infections(Andersen and Tufik, 2000; Monassi et al., 2003).

After surgical implantation, each animal was placed inside athermoregulated recovery box (maintained between 20� and24 �C) until functional recovery from surgery was observed. Aftersurgical recovery, each animal was returned to the acrylic housingcage and maintained under the same experimental conditionsprior the implantation procedure. A behavioral observation of eachrat was made for the next 7 days, evaluating: (i) mobility, (ii) activ-ity level, (iii) eating, (iv) drinking, and (v) grooming.

2.3. Electrocorticographic recordings

Seven days after the surgical implantation of electrodes, the ani-mals were placed in a Plexiglas recording cage which was located in-side a sound-attenuated chamber with a one-way glass window tofacilitate observation and correlation of animal behavior with elec-trocorticographic recordings. Temperature, of recording cages, wasmaintained between 20 and 24 �C (mean temperature of23 �C ± 2 �C) with scheduled light/dark cycles of 12 h (lights on at07:00). Food and water were available ‘‘ad libitum”, and an adapta-tion period of 24 h to the recording cage and conditions was allowed.

Recordings were made with a Grass Model 7B Polygraph, and pa-per speed was set at 3 mm/sec. To evaluate the animals during thelight period (inactivity period), two 10 h continuous electrocortico-graphic recordings (from 09:00 to 19:00 h) were performed in sep-arate moments (Ayala-Guerrero et al., 2001, 2002) as follows: (i) abasal recording, obtained eight days after the surgical implantationof electrodes, was made before drug administration; (ii) a UAIArecording, obtained the next day, and 2 h after drug administration.

Studies that document sleep patterns had described differentrecording periods, for example: diurnal register periods of 2 h(Andersen and Tufik, 2000), 3 h (Landis et al., 1988, 1989a), and6 h (Landis et al., 1989b); diurnal continuous recordings of 10 h(Ayala-Guerrero et al., 2001, 2002), 12 h (Andersen and Tufik,2003; Schutz et al., 2003), and 24 h (Kontinen et al., 2003; Monassiet al., 2003); and many others. All of those studies convene in thefact that rats have a nyctameral cycle; and for that reason, mostof the sleep recordings are performed during the day. On the otherhand, it has been documented that normal total sleep time (h/day)in rats has an average of 13 h (Jouvet, 1967; Truett and Domenic,1976); for that reason, some authors had performed electrocortico-graphic continuous recordings during 10 or 12 h. In addition, theobserved functional disability after UAIA is only temporal; in time(10–12 h) the animal recovers a complete limb function (López-Muñoz et al., 1993). Based on those elements we decided to per-form a 10 h continuous recording in two different moments.

2.4. Uric acid intra-articular administration (UAIA)

In this study, the intra-articular injection of 0.05 ml of 30% uricacid suspended in mineral oil inside the knee joint of the right hindlimb was performed under anesthesia with ether vapor. The sus-pension was prepared by grinding 3.0 g of uric acid with 10 ml ofmineral oil in a glass mortar and pestle (Pirex). The intra-articularinjection was performed through the patellar ligament using a 1 mldisposable syringe (Becton-Dickinson LTDA, Brazil) with a 24gauge needle of 5 mm (López-Muñoz et al., 1993).

2.5. Sleep parameters

After criteria for defining the different states of vigilance wereestablished, electrocorticographic recordings were assessed visu-ally. Recordings were scored in 25 s epochs as: (i) W, (ii) SWS,and (iii) REM sleep. From each 10 h continuous electrocortico-graphic recording we obtained the total sleep time, SWS and

148 U. Guevara-López et al. / European Journal of Pain 13 (2009) 146–153

REM latencies, and the duration and number of events spent byanimals in each state of vigilance.

2.6. Behavioral assessment

During the experiment, the same researcher performed a dailyassessment of behavioural patterns of each rat, and it was docu-mented as follows: (i) mobility, (ii) activity level, (iii) eating, (iv)drinking, and (v) grooming. The presence or absence of each ofthese functions were recorded in three specific moments: (i) beforesurgical implantation of electrodes, (ii) seven days after surgicalimplantation of electrodes, and (iii) 2.5 h after UAIA.

2.7. Final experimental procedures

The duration of the study and the number of animals were keptto minimum. The day after the UAIA recording was obtained, theanimals were sacrificed by an administration of intraperitoneal so-dium barbiturate (120 mg/kg). After the animal had died, the skullsocket was removed and the placement of cortical electrodes wasverified by direct microscopy.

2.8. Statistical analysis

Sleep parameters were expressed as mean ± SD. Data from thebasal recording were compared with those obtained in the UAIArecording. Student’s paired t-test was used to analyze the meanduration in seconds of each sleep-wake stage. This test was alsoused to analyzed SWS and REM latencies, and the total sleep time.Distribution of these variables was assessed by Kolmogorov–Smir-nov test. A Wilcoxon test was used to analyze number of episodesobserved in each sleep-wake stage; a McNemar test was also usedto evaluate behavioral changes. The level of significance was set atp 6 0.05. Data were analyzed with statistical software (SPSS v.11.0for Windows; SPSS, Inc.; Chicago, IL).

3. Results

3.1. Surgical implantation procedure

The registered animals survived the surgical implantation ofelectrodes and the postoperative period. Full recovery was ob-served 7 days after implantation. None of the animals presentedinfection signs in the socket location.

3.2. Behavioral assessment

Behavioral patterns, as described in the method, were evaluatedin three different moments, and underwent a comparative analy-

Table 1Duration and number of episodes of sleep-wake patterns before and after uric acid intra-

Sleep-wake pattern Before UAIA After UAIAMean ± SD Mean ± SD

Duration in seconds of each state of vigilance

TST 3515.27 ± 540.61 2706.46 ± 822.56Wakefulness 10224.00 ± 2540.70 15796.14 ± 3467.52SWS 21414.71 ± 2386.09 17747.29 ± 3053.45REM sleep 4676.28 ± 545.94 2149.57 ± 1119.16SWS latency 1129.57 ± 1359.44 3637.57 ± 1910.52REM sleep latency 2506.28 ± 1476.92 9645.28 ± 7125.20

Number of episodes in each state of vigilance

Wakefulness 62.00 ± 20.00 78.00 ± 30.00SWS 94.00 ± 17.00 95.00 ± 27.00REM sleep 43.00 ± 7.00 25.00 ± 14.00

Abbreviations: UAIA, uric acid intra-articular administration; SWS, slow wave sleep; RE

sis. Significant differences in mobility, activity level, eating, drink-ing, and grooming were not observed when those moments werecompared. However, subsequent to uric acid intra-articular admin-istration (rats with acute gouty arthritis), the evaluated responseswere absent in all animals; and behavioral changes were character-ized by: (i) an immediate rubbing of the joint with forepaws, (ii) aconstant movement of the animals all along the acrylic housingcage which was followed by a period of inactivity, and (iii) a dec-rement in food and water intake.

3.3. Duration of sleep parameters

Data from each vigilance state, as shown in Table 1, are ex-pressed as mean and standard deviation. Electrocorticographicrecordings before (baseline) and after UAIA (arthritic rats) werecompared; the recording after UAIA (arthritic rats) presented: (i)a significant decrement in the total sleep time (p = 0.001), (ii) a sig-nificant increment in the duration of wakefulness (p = 0.014), and(iii) a significant decrement in the duration of REM sleep(p = 0.001). The duration of SWS did not show statistical differ-ences between groups.

3.4. Number of events of sleep parameters

As shown in Table 1, when both electrocorticographic record-ings were compared, the recording after UAIA (arthritic rats) pre-sented a significant decrement in the number of REM sleepevents (p = 0.027). However, statistical differences were not ob-served neither in the number of wake events nor in the numberof SWS events.

3.5. Sleep latencies

Both SWS and REM latencies were significantly increased in ar-thritic rats (after uric acid administration: Table 1, Fig. 1). In therecording before UAIA (baseline), the SWS latency presented amean duration of 1129.6 s (SD: 1359.4), and subsequent to uricacid administration a mean duration of 3637.6 (SD: 1910.5)(p = 0.017). Before UAIA, the recorded REM latency, presented amean duration of 2506.3 s (SD: 1477); subsequent to uric acidadministration, this latency, showed a mean duration of 9645.3 s(SD: 7125.2) (p = 0.022).

3.6. States of vigilance throughout the 10 h continuouselectrocorticographic recordings

An hourly analysis of sleep parameters duration (Fig. 2) andnumber of events (Fig. 3), throughout the 10 h continuous electro-corticographic recordings, using a Bonferroni’s test was made.

articular administration (n = 7)

Mean difference Statistical analysis

p value (paired Student’s t test)

808.81 0.001�5572.14 0.0143667.42 0.0582526.71 0.001�2508.00 0.017�7139.00 0.022

Mean difference p value (Wilcoxon signed ranks test)

�16.00 0.128�1.00 0.61218.00 0.027

M, rapid eye movement; TST, total sleep time; SD, standard deviation.

Fig. 1. The figure shows the latencies to SWS and REM sleep. Bars represents meansand error bars represent the SE. Figure 1A represents the duration of SWS latency,and figure 1B represents the duration of REM sleep latency. A comparative analysis,before and after UAIA, was made and the paired Student’s t-test p value < 0.05 isrepresented by an asterisk (�). As observed, nociception promoted an increment inthe duration of both latencies.

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Subsequent to uric acid administration (arthritic rats) the electro-corticographic recording presented a significant decrement in theduration of REM sleep during the second (p = 0.03), fourth(p = 0.04), and fifth hours (p = 0.02). On the contrary, statistical dif-ferences were absent in wake and SWS sleep duration, and in thenumber of events of these stages.

4. Discussion

The administration of intra-articular uric acid in the knee jointis a well documented procedure (Van Arman et al., 1970; Okudaet al., 1984a,b; Granados-Soto et al., 1992; López-Muñoz et al.,1993; Martı́nez-Quiroz et al., 2005; Jiménez-Velázquez et al.,2006). Intra-articular injection of uric acid in the right hind knee

produced local acute inflammation. Histopathological analysisshowed edema and inflammatory infiltration in synovial mem-branes with no effect on the joint cartilage. Groups of polymorpho-nuclear leukocytes forming masses or free filaments were presentin the articular cavity. Fibrin, hemorrhage, or necrosis were absentand no synovial call proliferation was detected (López-Muñozet al., 1993). The intra-articular knee injection of one uric acid sus-pension in mineral oil (UAIA) is a well described model (López-Muñoz et al., 1993), and has been utilized in basic animal researchto simulate an acute painful condition and to produce: (i) an acuteinflammation, (ii) nociception, and (iii) a reversible dysfunction ofthe injected limb. For that reason, this experimental model mightprovide some information about sleep patterns in non-autoim-mune arthritic condition such as acute gouty arthritis.

Experimental evaluation of sleep disturbances caused by an ar-thritic condition had used an adjuvant-induced arthritis model(Landis et al., 1988, 1989a,b; Andersen and Tufik, 2000; Schutzet al., 2003; Schutz et al., 2004); this is achieved by an injectionof Freund’s adjuvant, and simulates an autoimmune disease suchas rheumatoid arthritis (Lim, 2003). The impact of other painfulconditions, such as acute gouty arthritis, on sleep patterns hadnot been assessed yet. For that reason, our intention is to evaluatethe presence of disturbances on sleep patterns after the adminis-tration of intra-articular uric acid in rats (rats with acute goutyarthritis).

Our data shows a decrement in the total sleep time and in themean duration and number of REM sleep episodes, and an increasein the number of awakenings; these findings are in agreement withprevious reports of sleep assessment in arthritic rats (Landis et al.,1988, 1989a,b; Andersen and Tufik, 2000). The decrement of REMsleep and the increase of awakenings produce a fragmentation ofsleep patterns and lengthening of sleep latencies (Hicks et al.,1979). Moreover, sleep fragmentation may generate a hyperalgesicresponse (Onen et al., 2000, 2001; Nascimento et al., 2007); sug-gesting that this phenomenon may be caused by the interactionbetween sleep and pain pathways.

REM sleep initiates only after a series of preparative mecha-nisms occur in SWS (Le Bon et al., 2002) and it has been proposedthat is mediated by an antagonistic interaction between the mech-anisms that initiate sleep and those that promote wakefulness(Ocampo-Garces et al., 2000; McCarley, 2007; McKenna et al.,2007). Furthermore, it is possible that their interaction may be en-hanced by the presence of persistent pain (Hicks et al., 1979; Hir-ase et al., 2001; Tartar et al., 2006) leading to fragmentation ofsleep patterns and sleep deprivation (Hicks et al., 1979).

Studies which evaluate sleep patterns in a model of adjuvant-induced arthritis had reported a decrement in SWS (Landis et al.,1988, 1989a,b; Andersen and Tufik, 2000; Schutz et al., 2003;Schutz et al., 2004); however, our data did not showed statisticaldifferences in this sleep stage. Experimental models of neuropathicpain had also reported an absence of SWS disturbances (Kontinenet al., 2003; Tokunaga et al., 2007). The absence of SWS distur-bances may be explained by a circadian disorganization producedby adjuvant-induced arthritis (Cardinali and Esquifino, 2003). Onthe other hand, it is possible that a decrement in REM sleep mightpromote a compensatory increase in SWS (Akerstedt et al., 1998;Shiromani et al., 2000).

It has been proposed that experimental pain in animals may al-ter the sleep-wake patterns by an unknown action of the nocicep-tive stimuli in (i) the cerebral structures related to wakefulness, (ii)the brain centers of sleep induction, and/or (iii) its simultaneousaction on both structures (Menetrey and Besson, 1982; Pesschan-ski and Besson, 1984; Landis et al., 1988). Since pain and sleepmodulation is mainly carried out in the brainstem (Millan, 1999,2002; Foo and Masson, 2003); it is possible that some mechanismsfor this interaction may be located in that anatomic site.

Fig. 2. The figure shows the duration in seconds observed in each vigilance state, before and after UAIA, and during the 10 h electrocorticographic record. Data is expressed asmean ± SE. Symbols represents means and error bars represent the SE. Black circles (�) represents values before UAIA; while white squares (h) represents the values afterUAIA. Figure 2A shows the duration of wake, figure 2B shows the duration of SWS, and Figure 2C shows the duration of REM sleep. A comparative analysis, before and afterUAIA, was made and the paired Student’s t-test p value < 0.05 is represented by an asterisk (�). As observed, nociception induces sleep fragmentation as manifested by aprogressive increment of awakening episodes that interrupt SWS throughout the recording time. REM sleep is initially inhibited followed by a progressive increment in itsfrequency.

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It has been documented that sleep deprivation inhibits hippo-campal neurogenesis (Grassi-Zucconi et al., 2006) and disturbsthe synaptic excitatory transmission of hippocampal neurons(McDermott et al., 2006). Even more, the evidence about the brainstructures involved in pain (Millan, 1999, 2002) and sleep brain-stem modulation (Foo and Masson, 2003) shows that similar cere-bral structures may participate in both functions. For that reason, itis possible that changes in sleep architecture may be caused by thedirect action of pain mechanisms over those that originate and/ormaintain sleep.

On the other hand, it has been reported that acute experimentalarthritis causes plasma extravasation and edema after the releaseof neuropeptides (Lam and Ferrell, 1993) and other inflammatorymediators (Herbert and Schmidt, 1992; Birrell and McQueen,1993; Lam et al., 1993). Diverse inflammatory mediators, such asprostaglandins (Rang et al., 1991; Malmberg and Yaksh, 1992;Schutz et al., 2007), cytokines (Boddeke, 2001) and cyclooxigen-ase-2 (Schutz et al., 2007); play an important role in nociceptionand inflammation. Therefore, it is possible that those substancesmay be also related to sleep modulation (Schutz et al., 2007).

Fig. 3. The figure shows the number of events observed in each vigilance state, before and after UAIA, and during the 10 h electrocorticographic record. Data is expressed asmean ± SE. Black circles (�) represents values before UAIA; while white squares (h) represents the values after UAIA. Figure 3A shows the number of events of wake, figure 3Bshows the number of events of SWS, and figure 3C shows the number of events of REM sleep. A comparative analysis, before and after UAIA, was made and Wilcoxon test pvalue < 0.05 is represented by an asterisk (�). As observed, nociception induces significant disturbances on sleep. The number of awakening events is increased, whereas thatof sleep decreases involving both SWS and REM sleep. Sleep fragmentation affects SWS because its frequency increases due to the increase in awakenings. REM sleep isinhibited because its frequency decreases.

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Diverse studies had documented that sleep disturbances maybe mediated by the anti-nociceptive action of endogenous neuro-peptides (Watkins et al., 1986; Stein et al., 1989; Appelgrenet al., 1991; Mauborgne et al., 2002) and cytokines (Dicksteinand Moldofsky, 1999; Hsu et al., 2003). In fact, it has been sug-gested that diverse circuits located in the central nervous systemcould activate the immune response and modulate the nociceptiveresponse (Richardson and Vasko, 2002; Herbert and Holzer,2002a,b) and/or sleep (Dickstein and Moldofsky, 1999; Hsu et al.,2003). For that reason, the sleep disturbances found in arthriticconditions suggest the possibility that the immune system couldbe involved in pain/sleep modulation.

We evaluated the sleep patterns in an experimental model ofacute gouty arthritis. This induced nociceptive response producedan alteration characterized by: (i) a decrement in total sleep time,(ii) a decrement in the mean duration and number of REM sleepepisodes, and (iii) an increase in the number of awakenings. How-ever, SWS did not present significant differences; well character-ized models of induced arthritis had documented significantalterations in this particular sleep stage. Reports of induced neuro-pathic pain may be coincident with our findings; neverthelessstudies on which this observation might be supported are needed.

Until now, currently available data are unable to characterize ifa specific type of pain (nociceptive, neuropathic, or visceral)

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generates a specific disruption in sleep architecture; consequently,it is convenient to continue electrocorticographic animal researchusing diverse types of induced pain models (nociceptive, visceralor neuropathic).

Declaration of interests

No financial support from commercial sources has been re-ceived for this study.

Acknowledgements

We acknowledge the important contributions of those personswho collaborated in this study.

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