9Inflammatory Pain and Corticosterone Response in Infant Rats

8/18/2019 9Inflammatory Pain and Corticosterone Response in Infant Rats

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Hindawi Publishing CorporationMediators o In ammationVolume , Article ID , pageshttp://dx.doi.org/ . / /

Research ArticleInflammatory Pain and Corticosterone Response in Infant Rats:Effect of 5-HT1A Agonist Buspirone Prior to Gestational Stress

Irina P. Butkevich, 1 Viktor A. Mikhailenko, 1 Tat’yana R. Bagaeva, 2 Elena A. Vershinina, 3

Anna Maria Aloisi, 4 and Vladimir A. Otellin 1

Laboratory of Ontogeny of the Nervous System, I. P. Pavlov Institute of Physiology, Russian Academy of Sciences, Nab. Makarova ,St. Petersburg , RussiaLaboratory of Experimental Endocrinology, I. P. Pavlov Institute of Physiology, Russian Academy of Sciences, Nab. Makarova ,St. Petersburg , RussiaDepartment of Applied Mathematics, I. P. Pavlov Institute of Physiology, Russian Academy of Sciences, Nab. Makarova ,St. Petersburg , RussiaDepartment of Physiology, University of Siena, Neuroscience and Applied Physiology Section, Via Aldo Moro , Siena, Italy

Correspondence should be addressed to Irina P. Butkevich; [email protected] ran.ru

Received January ; Accepted March

Academic Editor: Metoda Lipnik-Stangelj

Copyright © Irina P. Butkevich et al. Tis is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Our researches have shown that gestational stress causes exacerbation o in ammatory pain in the offspring; the maternal -H Aagonist buspirone be ore the stress prevents the adverse effect. Te serotonergic system and hypothalamo-pituitary-adrenal (HPA)axis are closely interrelated. However, interrelations between in ammatory pain and the HPA axis during the hyporeactive periodo the latter have not been studied. Te present research demonstrates that ormalin-induced pain causes a gradual and prolongedincrease in plasma corticosterone level in -day-oldmale rats; twenty- our hours afer injectiono ormalin, the basal corticosteronelevel still exceeds the initial basal corticosterone value. Chronic treatments o rat dams with buspirone be ore restraint stressduring gestation normalize in the offspring pain-like behavior and induce during the acute phase in the ormalin test the strongercorticosterone increaseascompared tothestress hormonalelevationin animals withother prenatal treatments.Negative correlationbetween plasma corticosterone level and the number o exes+shakes is revealed in buspirone+stress rats. Te new data enhancethe idea about relativity o the HPA axis hyporeactive period and suggest that maternal buspirone prior to stress during gestationmayenhance an adaptive mechanism o the in ammatory nociceptive system in the in ant male offspring through activation o theHPA axis peripheral link.

1. Introduction

Interrelations between the serotonergic system andhypothalamo-pituitary-adrenal (HPA) axis determine the

ormation o mechanisms o stress adaptation [– ]. Pain is astress and there ore can activate the HPA axis [ – ]. In thiscase, in ammatory pain is still not clearly understood, andthe data available are inconsistent [ , – ]. In a widely usedmodel o in ammatory pain, the ormalin test, activationo the HPA axis with the nociceptive stimulus ormalinhas been shown on adult awake rodents and differencesin the dynamics o release o AC H and corticosterone

in response to pain impact ound [ , , – ]. Te HPAaxis during the postnatal development goes through theperiod o hyporesponsiveness, which extends rom thesecond to ourteenth postnatal days and is characterizedby a low level o the response o adrenals to many stressstimuli [ ]. Investigations o ormalin-induced pain effectson the HPA axis in in ant rats could elucidate unexploredpreviously interrelations between the tonic nociceptive andstress systems during the period o hyporesponsiveness o the latter. We revealed or the rst time that prenatal stressinduces strengthening in ammatory pain-related responsein the ormalin test and decrease o adaptive capacities in


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in ant rats; chronic injections o an agonist o serotonin( -H ) receptors A ( -H A) buspirone to dams priorto stress during gestation cancel the adverse consequenceso the stress in the offspring [ ]. In prenatally stressedindividuals, abnormalities in the HPA axis unction [ ] andneurotransmitter systems including the serotonergic one

[ ] were shown.Serotonin acts as a growth actor in early cell division,migration, and differentiation in the brain speci cally indevelopment o the serotonergic system [ – ]. Many o regulator in uences on developing neurons -H mediatesthrough presynaptic -H A autoreceptors in the raphenuclei [ , ]. Later -H and -H A receptors take partin many kinds o behavior. Te serotonergic system playsan important role in pain transmission, its processing andregulation [ – ]. Buspirone, serotoninergic anxiolytic andantidepressant, mediates its effect through the serotonergicsystem and the HPA axis. Tere are synergistic interrela-tions between these systems impaired in prenatally stressedindividuals [ , – ]. A peculiar mechanism o buspironeaction has not been completely understood; it is also true orits analgesic effect. Studies o effects o buspirone, an agonisto presynaptic and a partial agonist o -H A receptors, onthe nociceptive system are limited, and the results obtaineddo not coincide [ , ]. Prenatal effect o buspirone on thenociceptive system has not been studied until our researches.Activation o the antinociceptive descending serotonergicsystem and the decrease in hyperactivity o the HPA axis areconsidered as potential mechanisms o analgesic action o antidepressants. Activating effects o buspirone on the HPAsystem are ound in adult persons [ ]. It may be suggestedthat the period o hyporesponsiveness o the HPA, which ischaracterized bya lowlevelo reaction o adrenals in responseto many stress stimuli [ ], will allow to prevent activatingin uences o buspirone on the HPA axis.

Te aim o our work was to study effects o maternalbuspirone prior to stress during gestation on the dynamics o the in ammatory pain-like behavior and stress response o corticosterone during the ormalin test in the in ant male ratoffspring and also to evaluate correlation between pain-likeand hormonal parameters.

2. Materials and Methods

. . Animals. All experimental procedures were approved by the Local Ethics Committee or Animal Experiments o theI. P. Pavlov Institute o Physiology and ollowed the guide-lines published by the Committee or Research and EthicalIssues o the IASP on ethical standards or investigations o experimental pain in animals.

Adult emale rats and male rats (Wistar) at the ageo days were obtained rom the vivarium o the I. P.Pavlov Institute o Physiology RAN, St. Petersburg, Russia.

wo days afer adaptation, the rats were mated. Te dayso insemination and delivery were considered as gestationalday (GD) and postnatal day (PD) , respectively. Allanimals were maintained at constant temperature ( – ∘C)under the standard light-dark cycle ( . AM– . PM) with

unrestricted access to ood and water. Seventeen rat dams(controls) were not exposed to any impacts during gestation.Te equal number o remaining dams ( = 6 8) was ran-domly treated with the -H A agonist buspirone (buspironehydrochloride, Sigma, mg/kg, mL, i.p. at AM) or withinjection o saline (control animals rom the same litters, in

the same conditions o injections) rom GD to GD . A hal o the treated rats rom each group were randomly exposed torestraint stress or min (in min afer buspironeinjection)

rom GD to GD . All in uences on gestational emaleswere identical to those used in our previous study [ ]. Tedose o buspirone was sufficient or inducing an anxiolyticeffect in adult rats [ ] and did not exceed the dose used orpregnant rat dams to protect the etal serotonergic systemagainst damaging effects o in utero ethanol exposure [ ].It should be noted that such dose o buspirone was not ableto implicate dopamine and norepinephrine in the mediationo buspirone effects [ , ]. Litters were called to pups( emales and males, as ar as possible) in hours aferbirth. In the study, -day-old males born to thedams with theabove-mentioned treatments during gestation and to controldams were used; emales and remaining males were used inother researches. Tere were males offspring o control,saline, saline + stress, buspirone, andbuspirone+ stressdamsin the study with ormalin injection (about – males per agroup, no more than animals rom one dam); in addition,

male rats rom the same litters were used as control or theormalin, with saline injection into the hind limb.

. . Experimental Formalin-Induced In ammatory Pain inInfant Male Rats. Formalin test is widely used or evaluationo tonic in ammatory pain and analgesic effects o various

pharmacological drugs [ , – ]. Flexing and shakingbehaviors are the speci c expression o in ammatory pain-related behavior in the ormalin test in both in ant andadult rats [ , , , ]; we used the ormalin test aspreviously described [ ]. Te ormalin test allows evaluatingacute nociception (the rst phase, – min afer ormalininjection), tonic persistent nociception (the second phaseabout – min), and unctional activity o the descendingserotonergic inhibitory system (the interphase about –

min). Te second phase appears during postnatal devel-opment when the descending serotonergic inhibitory systemmatures [ , ]. Characteristics o the phases depend onmany actors including age and sex [ ].

Each male rat was taken rom thenest, injected intraplan-tarly to the lef hindpaw with ormalin solution ( . %, L),and placed singly in a warm ( ∘C) chamber ( × × cm)with transparent glass walls encircled by mirrors to improvethe observation o the animal’s behavior [ , ]. Te numbero exes + shakes was recorded using a computer programthat allows recording, quanti ying, and analyzing the pain-related behavior. In each group o the males, the number o

exes + shakes was averaged or , , , , and min aferormalin injection. Each animal was used only once.

. . Corticosterone Determination in Infant Male Rats. Bloodsamples were collected by decapitation in the rats with differ-ent prenatal treatments and in controls at : - : be ore


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and hoursafer the ormalin test ordetermination o basalplasma corticosterone levels. During the ormalin-inducedpain, blood sampling by decapitation occurred at , , , ,and min afer ormalin injection. Te blood samples werecentri uged and theplasmawas kept at − ∘C nomore than aweek. Te plasma corticosterone (SIGMA-ALDRICH, USA)

levels ( g/dL) were measured by micro uorometry [ ].

. . Statistical Analysis. Data are presented as mean ±S.D. Formalin-evoked exing + shaking, and corticosteroneresponseswere analyzedby two-way ANOVA, with treatment(control, saline, saline + stress, buspirone, and buspirone +stress) and time as actors. Behavioral and corticosteroneresponses during , , , , and minutes were separately evaluated. Comparisons between the basal levels and thedata over time as well as comparisons between groupswith different types o treatment were conducted using testso simple effects. Besides pairwise comparisons, t -test andMann-Whitney test were per ormed. Pearson and Spear-man Correlations were calculated to estimate relationshipsbetween behavioral andhormonal variables. For all tests, <0.05 was considered to be statistically signi cant.

3. Results

wo-way ANOVA applied to pain-like responses ( Figure )resultedin a signi cant effecto the actorprenatal treatments(F( , ) = . , = 0.001); (F( , ) = . , < 0.001).

ests o simple effects showed a signi cant increase in thenumber o exes + shakes at , , and min afer ormalininjection in saline + stress as compared to saline ( < 0.05 ,

< 0.05 , and = 0.014 , resp.) and in saline + stressas compared to the control ( = 0.002 , = 0.03, resp.)(Figure ). ests o simple effects showed a decrease in thenumber o exes + shakes at , , , and min afer

ormalin injection in buspirone+ stressas compared to saline+ stress ( = 0.002 , < 0.05 , < 0.05, and = 0.002 , resp.)(Figure ).

wo-way ANOVA applied to the level o plasma cor-ticosterone ( Figure ) resulted in a signi cant effect o the

actor prenatal treatments (F( , ) = . , P = . )and time (F( , ) = . , P < . ). Te signi canteffects o actor prenatal treatment on dependent variablecorticosterone were revealed at and min (F( , ) = . ,P < . ; F( , ) = . , P < . , resp.). ests o simpleeffects showed the corticosterone level at min afer ormalininjectionwashigher than basal level ( = 0.037 ) in buspirone+ stress males; during the ollowing time periods ( , , ,and min), corticosterone was higher than basal level inanimals with all prenatal treatments ( < 0.05 ) (Figure ).

ests o simple effects (pairwise comparisons) or/and Mann-Whitney test showed that only in buspirone + stress malesat and min afer ormalin injection, the corticosteronelevel was higher than similar hormonal level in animalswith all different prenatal treatments ( < 0.05 ). Duringthe ollowing time course o ormalin-induced pain, therewere no differences in the stress level o hormone betweenanimals with different prenatal treatments. ests o simple

effects (pairwise comparisons) or/and Mann-Whitney testshowed that in the course o in ammatory pain, the level o plasma corticosterone gradually increased (F , ) = . ,P < . ) and to the end o the ormalin test (at min)was signi cantly higher than basal level (P = . ). Pairwisecomparisons showed that basal level h afer the ormalin

test was greater than thatprior to the ormalin test ( P = . )in animals with all prenatal treatments ( < 0.05 ) (Figure ).Tere were no signi cant differences in indices under

study in buspirone, saline, and control animals.Correlation between plasma corticosterone level and the

number o exes + shakes was revealed in buspirone + stressmaleratsat (− = 0.925, = 0.008 ) , min(− = 0.937, =0.002), and min (− = 0.690, = 0.05) and in control ratsat min (− = 0.90, = 0.037) afer injection o ormalin.

Injection o saline to the lef hindpaw (controls orormalin injection) resulted in a ew weak exes + shakes

during some rst minutes afer injection only in prenatally stressed males.Corticosterone response to pain wasa speci creaction; in control animals, an increase in the plasmacorticosterone in responseto theprocedure o salineinjectioninto the paw was less prolonged (no more than min)and did not exceed the value o corticosterone response to

ormalin-induced pain (the data are not shown in the table).

4. Discussion

Te dynamics o corticosterone stress response to in am-matory pain and participation o -H A receptors in itwere investigated in the present study in -day-old malerats with various prenatal treatments. Evidence o increased

ormalin-induced pain in prenatally stressed animals is inagreement with thedata that weobtained earlier [ ]. Chronictreatments o rat dams with the -H A agonist buspironeprior to stress during gestational period increased resistanceo the tonic nociceptive system normalizing behavior in thein ammatory pain model and changed the time course o stress corticosterone response to ormalin-induced pain inthe offspring.

Be ore our studies, in a widely accepted model o in am-matory pain, the ormalin test, it was demonstrated in adultawake rats that the nociceptive stimulus ormalin inducedactivation o the HPA axis and increased concentration o AC Handcorticosterone[ , , ]. Interestingly, the authorsthat ound the peak o the corticosterone release at minand its restored level at min afer ormalin injectionconcluded that the resulting release o corticosterone isnot antinociceptive as neither adrenalectomy nor high-dosedexamethasone changed behavioral nociceptive responses[ ]. It is worthy to note that peaked time in release o corticosterone in response to the ormalin test as well asthe time o the hormonal restoration level afer ormalininjection vary according to the authors rom the – minto – min, respectively [, , ]. Tese differencesmay be attributed to peculiarities o the ormalin test. Tebehavioral response in the ormalin test, representedby acuteand tonic phases o different chemical nature, depends onconcentrations and volumes o ormalin solution, a place


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Time (min)

ControlSaline

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Saline + stressBuspirone + stress

F : Pain-like responses recordedover differentperiods o time( , , , , and min) afer injection o ormalin (mean ± SEM)in -day-old male rats with different prenatal treatments. ∗ P < .different rom saline; + P < . different rom saline + stress;

# P <. different rom controls.

+

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Saline + stressBuspirone + stressSalineBuspirone

3 9 21 30 60Time (min)

Control

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Basallevel

Basal level24 hours aferinjection o

ormalin

F : Basal levels o corticosterone and plasma corticosteronelevels ( g/dl) determined , , , , and min afer injection

o ormalin (mean ± SEM) in -day-old male rats with differentprenatal treatments. ∗ P < . different rom the basal level; + P <. different rom thecontrol, saline, saline+ stress, andbuspirone;

# P < . different rom the basal level be ore injection o ormalin.

o its injection, temperature in the room, a strain o rats,and conditions o experimental per ormances [ , , ,

]. Tese actors determine involvement in the response o various mediators in uencing the intensity and dynamics o release o corticosterone.

Our study is the rst to evaluate the dynamics o corticos-terone release in conditions o in ammatory pain in in ant

rats during the hyporesponsive period o the HPA axis [ ].Te new data obtained testi y that in ammatory ormalin-induced pain evokes the stress response o corticosterone inmale rats during the hyporesponsive period o the HPA axis.Tis reaction is a speci c reaction to pain; in control animals,an increase in the plasma corticosterone in response to the

procedure o saline injection into the paw was less prolongedandweaker than the hormonal response to ormalin-inducedpain. We have revealed that the characteristic eature o thedynamics o corticosterone response to in ammatory painin in ant rats is a gradual increase o hormonal release inthe ormalin test, so to the end o the response the level o corticosterone considerably exceeded its initial level. Mostimportantly, the results indicate that hours afer the

ormalin test, the corticosterone level still exceeds the basalcorticosterone value be ore the ormalin test in males o allthe groups under study. Tis act cannot be associated withan increase in corticosterone basal level in intact -day-oldmale rats as compared to that in -day-olds, as available dataand our own results indicate equal value in the basal levelo plasma corticosterone in – -day-old male rats that werenot exposed to any prenatal impacts [ ]. Based on theseresults, we conclude that the peripheral link o the HPA axisresponds to in ammatory pain in the ormalin test in in antrats with a prolonged reaction. Experimental data reportedhere enhance the idea o relativity o hyporesponsive periodo the HPA axis [ ]. Up to now, there has not been any detailed work done to nd a clear explanation or this periodin the development o the HPA axis.

Te results obtained provide new important in ormationthat maternal -H A agonist buspirone prior to stressduring gestation induces in the offspring during the acutephase in the ormalin test thestronger corticosterone increaseas compared to the stresshormonal elevation in animals withother prenatal treatments. In the ollowing time periods o

ormalin-induced pain, the animals with different prenataltreatments do not show signi cant differences in stresscorticosterone level. Negative correlation revealed betweenthe corticosterone concentration and the number o exes+ shakes during the rst nine minutes afer injection o

ormalin in buspirone + stress male rats is noteworthy. Teseresults suggest that activation o thecorticosterone release via

-H A receptors may acilitate some adaptive mechanismsassociated with a decrease o in ammatorypain in buspirone+ stress rats.

Tere are multiple pathways through which -H andits agonists may stimulate the HPA axis [ ]. It is shownthat ormalin activates ascending ways to the HPA [ ]. Techemical stimulus ormalin induces appearance o “in am-matory soup” rom various chemical substances including -H released rom platelets and also activation o neutrophilsand leucocytes that produce proin ammatory cytokines IL-

[ ]. Cytokines contribute to the increase in AC H andcorticosterone [ ] and to the exacerbation o nociceptiveprocessing [ ]. Interaction between the HPA axis and -H system would be dependent on concentration o -Hreleased rom platelets during in ammation which reachesthe central nervous sites, but this question is poorly known.Both systems are highly plastic during maturation [ ], and


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prenatal stress impairs interaction between the HPA axis and-H system and alters their unctional activity in adults

[ , ]. Te expression o -H A receptors is ound duringthe initial stageso prenatal development o thehippocampus[ ] andprenatal stress impairs their development [ ].Tereis evidence that buspirone penetrates through the placental

andbloodbrainbarriers [ ] and isable toexert the protectiveeffects presumably through its ability to overcome the de cito etal serotonin and to stimulate etal -H A receptors[ ]. Further studies are needed to evaluate in uences o maternal buspirone prior to stress during gestation to theHPA axis response during the in ammatory pain immedi-ately afer nishing the period o responsiveness in the HPAaxis development. Tus, new data indicate an important roleo -H Areceptorsin thedevelopmento close relationshipsbetween the HPA axis and tonic nociceptive system thatmediate adaptation o organism to extreme conditions.

5. Summary

Te ormalin-induced pain causes a gradual and prolongedincrease in plasma corticosterone level during the persistentpain-like behavior in -day-oldmale rats. Chronic treatmentso rat dams with buspirone be ore restraint stress duringgestation normalize in the offspring in ammatory painbehavior and induce during the acute phase in the ormalintest the stronger corticosterone increase as compared to thestress hormonal elevation in animals with other prenataltreatments. Buspirone + stress rats display the negative cor-relation between plasma corticosterone level and the numbero exes + shakes. Tus, the new data enhance the idea aboutrelativity o the HPA axis hyporeactive period and suggestthat maternal buspirone prior to stress during gestationmay enhance an adaptive mechanism o the in ammatory nociceptive system in the in ant male offspring throughactivation o the HPA axis peripheral link.

Conflict of Interest

Te authors declare that they have no con ict o interest.

Acknowledgment

Te reported studywassupportedby RFBR, Research Projectno. - - .

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9Inflammatory Pain and Corticosterone Response in Infant Rats

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