Original Research Paper

Effects of repeated tooth pulp stimulation on concentrations of plasma catecholamines, corticosterone, and glucose in rats Makoto Hasegawa1, Junichi Hada2, Masanori Fujiwara1, Kousuke Honda1 1

Department of Dentistry and Oral Surgery, Hyogo College of Medicine, Nishinomiya-shi, Japan, 2Hirakata General Hospital for Developmental Disorders, Hirakata-shi, Japan In this study, we examined whether tooth pulp stimulation (TPS) affects the stress responses in anesthetized rats. As for stress response indices, we monitored changes in the concentrations of plasma catecholamines (CAs) (adrenaline, noradrenaline, and dopamine), corticosterone (CS), and glucose (Glu). We observed that repeated TPS attenuated plasma adrenaline, dopamine, CS, and Glu levels compared with those of sham-TPS. After administering naloxone, an opioid antagonist, repeated TPS reversed the decreases in plasma CAs, CS, and Glu. These findings showed that the effects of repeated TPS may be mediated by endogenous opioid administration. Our findings suggest that repeated TPS can induce stressanalgesia and that an endogenous descending pain modulation system exists.

Keywords: Catecholamines, Corticosterone, Descending pain modulation, Glucose, Tooth pulp stimulation

Introduction Acute symptomatic tooth pain serves the useful purpose of warning the individual that something is wrong.1 Also, pain is a negative force that often causes severe emotional and physical stress.2 In the same way, dental pain has a close relationship with emotional responses. A positive relationship between anxiety and pain is a common experience in the dental clinic.3–5 We previously showed that tooth pulp stimulation (TPS) increases hippocampal blood flow (HBF) in rats.6,7 This finding suggested that hippocampal activity plays a role in the modulation of nociceptive transmission by TPS. Therefore, we suggested that the hippocampal response to TPS may be involved in fear memory and anxiety related to tooth pain. For these issues, there is a report that acute augmentation in synaptic 5-serotonin and/or norepinephrine levels in the hippocampus may be associated with certain type of clinical anxiety disorder.8 Thus, there is no doubt that tooth pain may cause physical stress and stress responses. Selye suggested that a living body’s unique reactions are modulated through two kinds of neuroendocrine systems.9 It has been established that stressful stimuli are accompanied by the sympathetic adrenal system and the pituitary adenocortical system activity, resulting in increased plasma concentration of the catecholamines (CAs) and the corticosterone (CS).10 On the Correspondence to: Makoto Hasegawa, Department of Dentistry and Oral Surgery, Hyogo College of Medicine, 1-1, Mukogawa-cho, Nishinomiyashi, Hyogo, 663-8501, Japan. Email: [email protected]

ß W. S. Maney & Son Ltd 2014 DOI 10.1179/1743132813Y.0000000313

other hand, some studies suggested that the brain can induce intrinsic stimulation-produced analgesia.11,12 Their findings demonstrated that intrinsic analgesia systems are mediated by endogenous opioids. De Boer et al. provided data supporting the hypothesis that neuroendocrine adaptation to stress is similar to the process of behavioral or neurophysiological habituation to a sensory stimulus.13 Therefore, our first hypothesis is that tooth pain may increase the release of plasma CAs, CS, and glucose (Glu). A second hypothesis is as follows. If TPS suppressed release of pain-induced stress hormones, it would be due to stimulation-produced analgesia involving an endogenous opioid. In the present study, we measured the concentrations of plasma CAs, CS, and Glu, and verified whether TPS affects the release of plasma CAs, CS, and Glu. We investigated the relation between TPS and endogenous opioid action.

Methods All procedures were conducted with the approval of ‘The Animal Care and Use Committee of Hyogo College of Medicine’ and according to ‘The Guiding Principles for Care and Use of Animals Approved by the Council of the Physiological Society of Japan’. Male Wistar rats weighing between 400 and 420 g were used. The rats were anesthetized with urethane (1.2 g/kg), and their rectal temperature was maintained at 37–38uC with a heating pad. A pair of silver wire electrodes was inserted into the pulp of the lower

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Figure 1 Schematic diagram showing the experimental setup for the tooth pulp stimulation (TPS). S: silver wire stimulating electrodes; D: dentin; E: enamel.

incisor with a dental bar and fixed with acrylic resin (Fig. 1). The rats were then placed into stereotaxic frames. A canula filled with heparinized saline was inserted into the right femoral vein for blood sampling. In all, 1 hour was required to collect data from anesthesia. As TPS, the pulp of the lower incisor was stimulated electrically with a negative square wave using a constant isolated current source (isolator: SS202J with an electronic stimulator: SEN-3301; Nihon Kohden, Tokyo, Japan). The threshold stimulus intensity was determined in each rat with 0.5 ms duration, at 100 Hz, for 10 seconds by slowly increasing the current from zero until a clear HBF increase was observed. The mean threshold was 0.6 mA. We used five times the threshold as the stimulus intensity. TPS were repeated 30 times (i.e. for approximately 10 minutes), electrically by stimulation in the above parameter (repeated TPS). Sham-TPS procedures were repeated 30 times by stimulation in the conditions at intensity 0.0 mA (sham-TPS).

The blood samples were taken from before, at 1 and 2 hours after TPS. Each 2 ml blood sample was used to measure CAs, CS, and Glu levels. The loss of blood volume was compensated by transfusion of an equivalent volume of normal saline. Blood samples were centrifuged at 3000 rpm for 5 minutes at 4uC. The plasma was taken, and the levels of plasma CAs, CS, and Glu were measured. Determinations of plasma CAs concentrations were performed using high-performance liquid chromatography (HPLC) in combination with electrochemical detection.14 Plasma CS was measured by reversed-phase HPLC.15 Glu concentrations in blood were determined using an iSTAT analyzer.16 Next, naloxone (2 mg/kg), a specific opioid antagonist, was intraperitoneally administered 30 minutes before TPS. The experimental procedures were repeated under the same conditions. Rats were randomly assigned to four groups [repeated TPS (n 5 8); sham-TPS (n 5 5); repeated TPS after naloxone administration (n 5 8); sham-TPS after naloxone administration (n 5 6)]. In order to examine the effect of TPS on the concentrations of plasma CAs, CS, and Glu, we compared between the repeated TPS and sham-TPS groups. Furthermore, we evaluated the effects of naloxone administration on the concentration changes in CAs, CS, and Glu by TPS. Data of CAs, CS, and Glu were expressed as a percentage of the baseline value before TPS. All data are expressed as the mean¡standard error of mean (SEM). To determine the differences between repeated TPS and sham-TPS groups regarding time courses of changes in CAs, CS, and Glu responses induced by TPS, statistical analysis was performed by mixed type analysis of variance (ANOVA) with repeated measures. Differences were considered significant at P , 0.05.

Results The basal concentration levels of plasma CAs, CS, and Glu before TPS are presented in Table 1. Basal concentrations of adrenaline, dopamine, CS, and Glu in the sham-TPS group were similar to those in repeated TPS group. Figure 2 illustrates changes in CAs, CS, and Glu following TPS. We compared the effects of repeated TPS on the changes of CAs, CS

Table 1 Basal concentrations of plasma catecholamines (CAs), corticosterone (CS), and glucose (Glu)

Adrenaline (pg/ml) Noradrenaline (pg/ml) Dopamine (pg/ml) CS (ng/ml) Glu (mg/dl)

Sham-TPS

Repeated TPS

1744.00¡93.34 (n 5 4) 351.25¡50.21 (n 5 4) 56.00¡6.41 (n 5 4) 764.80¡110.24 (n 5 4) 543.20¡61.34 (n 5 4)

1667.16¡158.49 (n 5 6) 499.00¡47.00 (n 5 7) 133.57¡14.57 (n 5 7) 731.71¡92.50 (n 5 4) 573.00¡98.45 (n 5 8)

TPS: tooth pulp stimulation. Mean¡standard error of mean (SEM).

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Figure 2 Effects of repeated tooth pulp stimulation (TPS) on plasma catecholamines (CAs), corticosterone (CS), and glucose (Glu) concentrations. In the TPS group, the concentrations of adrenaline, dopamine, and Glu at 1 and 2 hours after repeated TPS were significantly lower than those of the sham-TPS group, although there was no significant difference in noradrenaline and CS concentrations between the two groups. Values are the mean¡standard error of mean (SEM). *P , 0.05, **P , 0.01 versus sham-TPS group.

and Glu concentrations with sham-TPS (Fig. 2). For all plasma CAs, ANOVA revealed significant main effects of group (repeated TPS and sham-TPS) [adrenaline: F(1, 16) 5 11.52, P , 0.01; noradrenaline: F(1, 18) 5 0.10, P 5 0.95; dopamine: F(1, 18) 5 10.02, P , 0.01; CS: F(1, 22) 5 4.19, P 5 0.052; Glu: F(1, 12) 5 43.89, P , 0.01] and sampling time [adrenaline: F(1, 16) 5 1.92, P 5 0.39; noradrenaline: F(1, 18) 5 59.37, P 5 0.08; dopamine: F(1, 18) 5 328.32, P , 0.05; CS: F(1, 22) 5 2.35, P 5 0.37; Glu: F(1, 12) 5 0.74, P 5 0.54]. The interactions between group and time were not significant [adrenaline: F(1, 16) 5 0.54, P 5 0.73; noradrenaline: F(1, 18) 5 0.13, P 5 0.73; dopamine: F(1, 18) 5 0.02, P 5 0.89; CS: F(1, 22) 5 0.59, P 5 0.45; Glu: F(1, 12) 5 2.39, P 5 0.14]. The repeated TPS significantly attenuated adrenaline release at 2 hours after TPS, compared with that of the sham-TPS group (Fig. 2). For

noradrenaline release, there was no significant difference between the repeated TPS group and the sham-TPS group. Repeated TPS significantly attenuated dopamine release at 1 hour after TPS and Glu concentration at 1 and 2 hours after TPS, compared with those levels in the sham-TPS group (P , 0.01, P , 0.01, and P , 0.01, respectively). Basal concentrations of CAs, CS, and Glu after naloxone administration before TPS are shown in Table 2. Basal concentrations of noradrenaline, CS, and Glu in the sham-TPS group were similar to those in the repeated TPS group. Analysis of variance revealed no significant main effect of group [adrenaline: F(1, 14) 5 0.16, P 5 0.69; noradrenaline: F(1, 16) 5 0.22, P 5 0.65; dopamine: F(1, 16) 5 2.40, P 5 0.14; CS: F(1, 24) 5 2.57, P 5 12; Glu: F(1, 24) 5 0.03, P 5 0.84] and sampling time [adrenaline: F(1, 14) 5 1.02, P 5 0.49; noradrenaline: F(1, 16) 5 0.02, P 5 0.90;

Table 2 Basal concentrations of plasma catecholamines (CAs), corticosterone (CS), and glucose (Glu) after naloxone administration Sham-TPS Adrenaline (pg/ml) Noradrenaline (pg/ml) Dopamine (pg/ml) CS (ng/ml) Glu (mg/dl)

1097.70¡32.78 471.66¡98.55 157.57¡40.06 801.13¡37.84 567.01¡42.43

(n (n (n (n (n

Repeated TPS 5 5 5 5 5

4) 4) 4) 5) 6)

1540.50¡218.38 (n 5 5) 470.60¡49.13 (n 5 6) 278.67¡26.15 (n 5 6) 745.56¡34.51 (n 5 9) 554.00¡44.70 (n 5 8)

TPS: tooth pulp stimulation. Mean¡standard error of mean (SEM).

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Figure 3 Effects of repeated tooth pulp stimulation (TPS) on plasma catecholamines (CAs), corticosterone (CS), and glucose (Glu) concentrations in the naloxone (2 mg/kg) administration condition. These decreases with TPS were inhibited by pretreatment with naloxone. Values are the mean¡SEM.

dopamine: F(1, 16) 5 0.03, P 5 0.88; CS: F(1, 24) 5 37.95, P 5 0.10; Glu: F(1, 24) 5 0.77, P 5 0.54]. The interactions between group and time were not significant [adrenaline: F(1, 14) 5 0.39, P 5 0.54; noradrenaline: F(1, 16) 5 3.10, P 5 0.09; dopamine: F(1, 16) 5 4.46, P 5 0.051; CS: F(1, 24) 5 0.07, P 5 0.79; Glu: F(1, 24) 5 0.06, P 5 0.81]. Thus, the decreases in the above concentrations due to TPS were inhibited by pretreatment with naloxone (2 mg/kg) (Fig. 3).

Discussion The results of the present study indicate that concentrations of plasma CAs, CS, and Glu could be not increased by TPS. This goes against our hypothesis that TPS may increase plasma CAs and CS concentrations. Our previous study showed that TPS causes sympathetic stress responses such as a rise in arterial blood pressure.6,7 Jørum et al. reported that in a patient with sympathetically maintained pain, sensitized mechano-insensitive nociceptors were activated by endogenously released CAs.17 Han et al. showed that concentrations of plasma CAs, CS, and adenocorticotropic hormone were increased by TPS.18 In contrast, our study showed that TPS attenuated concentrations of CAs and Glu. The differences in TPS-induced response patterns of CAs, CS, and Glu may be explained by different electrical stimulation parameters of TPS (Han et al., 0.1 mA, 15 seconds vs ours, 3.3 mA, 600 seconds). The electrical stimulation used in the present study was very long, and very strong intensity, stimulation to the tooth pulp. It can be considered that the stronger and longer stimulation to

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the tooth pulp reduced the production of CAs in the adrenal gland through the hypothalamic–pituitary– adrenal axis.8 We gave the long and strong TPS for the purpose of obtaining a clear reaction from the experiment. It is possible that a phenomenon similar to stress-analgesia was caused by the long and strong stimulation to the tooth pulp. De Boer et al. showed that increases in plasma noradrenaline, CS, and Glu induced by water-immersion stress were attenuated by repeated stress.13 This may be explained by differences in the stress properties (electrical stimulation vs water-immersion stress). Lewis et al. showed that naloxone or dexamethasone significantly altered the analgesia effect of a brief, continuous footshock.12 These findings suggest that both opioid and non-opioid mechanisms induce stress-analgesia.19 The results of the present study suggest that inhibition of CAs and Glu release reflect stimulation-produced analgesia. A number of studies have been carried out on stress-analgesia.11,12,20 A specific opioid antagonist, naloxone, was administered to confirm the endogenous descending pain modulatory system with repeated TPS. Our findings showed that naloxone (2 mg/kg) reversed the adrenaline, dopamine, CS, and Glu concentrations, induced by repeated TPS. These results suggest that repeated TPS can induce analgesia, and the existence of an endogenous descending pain modulating system was proved.21 The exact mechanism of TPS effect on the sympathoadrenal system and hypothalamic–pituitary–adrenal axis is still unclear. However, many previous reports showed that opioid antagonist could counteract the

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opiodergic inhibitory action of sympathetic nervous system and the adrenal medulla.22–24 Research on organization of endogenous opiate pain control system was actively carried out in the 1980s. Basbaum and Fields reported a review summing up the endogenous pain control systems.25 There are a large body of evidence that descending pain modulation activates the endogenous opioid containing neurons to secrete betaendorphin or enkephalin.22,26,27 However, these results suggested that repeated TPS has suppressive effects on the stress responses through the mediation of an endogenous opioid. Murotani et al. reported that the endogenous descending pain modulating system had an antinociceptive effect via neural changes in the periaqueductal gray (PAG).28 The PAG is generally regarded as the core of this analgesic system29 and is an important region for integrating information from stressful situations into most opiate responses, including antinociception.30 Therefore, the present results suggested that repeated TPS may exert an antinociceptive effect via activation of an opioidergic descending pain modulating system. On the other hand, the stress activates the hippocampus. It receives negative input, partly as negative feedback from the circulating glucocorticoids of the hypothalamic–pituitary–adrenal axis to its hypothalamic center, hippocampal inhibitory input upon the stress system.31 The stress systems form a complex, integrated, positive, and negative feedback-system loop.32 This point is an important issue that must be studied in the future. Recently, it is proposed that vagal sensory fibers, directly activated by adrenaline and noradrenaline, represent the afferent limb of a negative feedback loop that adjusts the activity of the sympathoadrenal system according to actual plasma and tissue CA levels.33 In this study, increases in the release of plasma noradrenaline and dopamine in the sham-TPS group were observed. In the stress responses, the main stressor was considered to be TPS. However, the other stressors, such as head fixation, surgical operation, and blood sampling procedure should also be considered. The reason for the persistent increase in plasma noradrenaline and dopamine in the sham-TPS group was possibly post-operative pain or stress. The stress response to surgery is characterized by increased activation of the sympathetic nervous system. Noradrenaline is released from nerve terminals into the circulation by the stress.34 However, in the shamTPS group, only adrenaline release was reduced. The different release patterns among CAs may reflect the order of their formation pathways.35 Willer et al. demonstrated that the analgesic effect was attenuated with reduced anxiety by benzodiazepines administration.30 Therefore, anxiety was responsible for endogenous opioid effects. We speculate that

Repeated tooth pulp stimulation and stress response

TPS may be related to the memory of anxiety over tooth pain. This view is consistent with the finding of Wei et al., who provided evidence at the molecular and cellular levels that the hippocampus plays a role in pain-related memory.36

Conclusion To our knowledge, this is the first paper showing inhibitory effects of repeated TPS on plasma CAs and Glu concentrations. We have shown that repeated TPS has an inhibitory effect on stress responses represented by a rise in plasma concentrations of CAs, CS, and Glu. The inhibition was attenuated by naloxone administration. The findings of the present study suggest that the effects of repeated TPS may be mediated by endogenous opioids. Moreover, our findings suggest that repeated TPS can induce stress-analgesia and that an endogenous descending pain modulation system exists.

Disclaimer statements Contributors M. Hasegawa: responsible for all involved in this research. J. Hada: in charge of technical guidance and interpretation of data. M. Fujiwara: creating charge of figures and tables. K. Honda: assistance in the preparation of this manuscript. Funding Hyogo College of Medicine Research Grant and Grant-in-Aid for Scientific Research (KAKENH1). Conflicts of interest None of authors have any conflicts of interest associated with this study. Ethics approval All procedures were conducted with approval of ‘The Animal Care and Use Committee of Hyogo College of Medicine (registered under the number B11-205)’ and according to ‘Guiding Principles for Care and Use of Animals approved by Council of The Physiological Society of Japan’.

Acknowledgements This work was partly supported by a Hyogo College of Medicine Research Grant for M. Hasegawa and a Grant-in-Aid for Scientific Research (C) JSPS KAKENHI (21592438, 25462978).

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Effects of repeated tooth pulp stimulation on concentrations of plasma catecholamines, corticosterone, and glucose in rats.

In this study, we examined whether tooth pulp stimulation (TPS) affects the stress responses in anesthetized rats. As for stress response indices, we ...
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