European Journal of Pharmacology 742 (2014) 89–93
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European Journal of Pharmacology journal homepage: www.elsevier.com/locate/ejphar
Behavioural pharmacology
Splenectomy modifies hyperactive states of the dopaminergic system induced by morphine in C57BL/6J-bgJ/bgJ (beige-J) mice Masahiko Funada a,1, Tomohisa Mori a,1, Jun Maeda a, Yuko Tsuda a, Sachiko Komiya a, Norifumi Shimizu a, Junzo Kamei b, Tsutomu Suzuki a,n a
Department of Toxicology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan Department of Pathophysiology and Therapeutics, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan
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art ic l e i nf o
a b s t r a c t
Article history: Received 8 May 2014 Received in revised form 20 August 2014 Accepted 20 August 2014 Available online 30 August 2014
Genetic factors affect the locomotor activity induced by morphine, which mainly depends on the activation of dopaminergic systems, and morphine has distinct pharmacological activities in C57BL/6JbgJbgJ (beige-J) mice, which have genetic deficiencies in immunological function. We previously showed that beige-J mice exhibited greater locomotor activity and dopamine turnover, whereas splenectomy reduced this hyperlocomotion and dopamine turnover, which suggests that beige-J mice could be an experimental animal model for investigating hyperactivation of the dopaminergic system, and that the spleen may contribute to the susceptibility to activation of the dopaminergic system. Furthermore, morphine can induce hyperlocomotion mediated by activation of the dopaminergic system. Therefore, we examined the effects of splenectomy on the hyperlocomotion and regulation of the dopaminergic system induced by morphine in beige-J mice. Morphine induced hyperlocomotion, which was accompanied by activation of the dopaminergic system, in beige-J mice. Furthermore, splenectomy enhanced the hyperlocomotion and activation of the mesolimbic dopaminergic system induced by morphine in beige-J mice. Our findings indicate that substances originating from the spleen may regulate both spontaneous activation of the mesolimbic dopaminergic system and the m-opioidergic system-mediated activation of the mesolimbic dopaminergic system by morphine through different modes of action. These results imply that beige-J mice could be a practical animal model for investigating the interactions between immune-modulation and the m-opioidergic system and/or dopaminergic system. & 2014 Elsevier B.V. All rights reserved.
Keywords: Beige-J mice Morphine Hyperlocomotion Dopamine Splenectomy
1. Introduction The C57BL/6J-bgJbgJ (beige-J) strain of mouse originated as a spontaneous mutation from C57BL/6J lines and is of particular interest as a homolog of Chediak–Higashi syndrome in humans (Babior, 1985). The beige-J mouse has defects in lysosomecontaining cells and other immunological functions, particularly natural killer (NK) cell and cytotoxic T-leukocyte functions (Roder and Duwe, 1979; Biron et al., 1987). Several behavioral studies have shown that beige-J mice, in addition to their immunologic defects, are also less sensitive to the antinociceptive effects of μ-opioid receptor agonists, such as morphine and [D-Ala2, NMePhe4,Gly-ol5]enkephalin (DAMGO) (Mathiasen et al., 1987). Studies on [3H]-DAMGO binding have demonstrated that the density of
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Corresponding author. Tel./fax: þ 81 3 5498 5831. E-mail address: [email protected] (T. Suzuki). 1 These authors contributed equally to this work.
http://dx.doi.org/10.1016/j.ejphar.2014.08.018 0014-2999/& 2014 Elsevier B.V. All rights reserved.
opioid receptors in the brains of beige-J mice is comparable to that in the brains of their normal littermates and outbred albino mice (Raffa et al., 1988a; Pick et al., 1991). Based on these results, it is found that the antinociceptive defect in beige-J mice is not due to an insufficient number of μ-opioid receptors. This has led to the hypothesis that μ-opioid receptor-mediated signal transduction in the brain of beige-J mice might be altered (Raffa et al., 1988a,b). The analysis of a drug's effects on locomotor activity in rodents is an important tool for investigating the psychotic states induced by psychoactive drugs. The administration of morphine can produce dose-related hyperlocomotion in certain strains of mice, and the mesolimbic dopaminergic system plays an important role in regulating exploratory and locomotor behaviors (Funada et al., 1993, 1994; Mori et al., 2012; Shibasaki et al., 2014). On the other hand, morphine alone does not induce hyperlocomotion in BALB/c mice (Ito et al., 2007). We recently demonstrated that beige-J mice showed greater locomotor activity and dopamine turnover than C-57BL/6J mice and ddY mice, whereas splenectomy reduced this spontaneous hyperlocomotion and high levels of dopamine
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M. Funada et al. / European Journal of Pharmacology 742 (2014) 89–93
turnover, which suggests that beige-J mice could be an experimental animal model for investigating hyperactivation of the dopaminergic system, and some circulating substances that originate in the spleen may modulate activation of the dopaminergic system (Mori et al., 2014). Splenectomy restores the morphineinduced antinociception in beige-J (Raffa et al., 1988b) and diabetic mice (Kamei et al., 1992) to almost normal levels. Furthermore, splenectomy has been shown to normalize the hyperactivity of diabetic mice (Kamei and Saitoh, 1997). Thus, it is possible that morphine does not induce any hyperlocomotion in beige-J mice, and splenectomy may affect the behavioral changes induced by morphine, particularly locomotor activity, in mice. Information on this subject may shed light on the complex interactions between immune-modulation and the m-opioid receptor system or dopaminergic system. The aim of the present study was to examine the effects of morphine on locomotor activity in beige-J mice, and the effects of splenectomy on locomotor activity induced by morphine in beige-J mice. We found that morphine-induced hyperlocomotion in beigeJ mice was greater than that in ddY mice. Furthermore, morphineinduced hyperlocomotion in beige-J mice was enhanced by splenectomy. Therefore, the neurochemical properties of the activation of the mesolimbic system induced by morphine in beige-J mice were also documented.
2. Materials and methods 2.1. Animals Male beige-J mice (National Institute on Genetics, Mishima, Japan), weighing 25–35 g at the beginning of the experiments, were used. Male ddY mice were obtained from Tokyo Animal Laboratories Inc. (Tokyo, Japan). The mice were housed at a room temperature of 22 71 1C with a 12 h light-dark cycle (lights on 8:00 A.M. to 8:00 P.M.). Food and water were available ad libitum. Our studies were conducted in accordance with the Guide for Care and Use of Laboratory Animals of Hoshi University School of Pharmacy and Pharmaceutical Science, which is accredited by the Ministry of Education, Culture, Sports and Technology of Japan.
2.4. Neurochemical analysis The concentrations of dopamine (DA) and its metabolites 3,4dihydroxyphenyl acetic acid (DOPAC) and homovanillic acid (HVA) were determined as described previously (Funada et al., 1993, 1994). Sham-operated and splenectomized mice were killed 60 min after s.c. injection of morphine (10 mg/kg, s.c.). The time of killing corresponded to the peak of morphine-induced hyperlocomotion. The brain was quickly removed and dissected into the limbic forebrain (containing the nucleus accumbens and olfactory tubercles) on an ice-cold glass plate according to the modified method of Ahtee et al. (1989). Briefly, the brain was turned to expose the dorsal surface and a vertical cut was made through the anterior commissure. The resulting frontal portion was turned to expose the ventral surface. A vertical cut was made through the rhinal fissure, and a small part that included the accessory olfactory bulb and olfactory nucleus was removed. The resulting block of tissue was turned to expose the section and the area bordered by the caudate putamen and the nucleus accumbens was cut vertically. The block of tissue that included the nucleus accumbens and olfactory tubercle was considered to be the main portion of the limbic forebrain. The tissue samples were homogenized in 2 ml of 0.2 M perchloric acid containing 100 μM EDTA (2Na) and 100 ng isoproterenol, as an internal standard. For complete removal of the proteins, the homogenates were placed in cold water for 60 min. The homogenates were then centrifuged at 20,000 g for 20 min at 0 1C, and the supernatants were maintained at pH 3.0 using 1 M sodium acetate. Solution samples of 50 μl were injected by a refrigerated GILSON automatic sample injector (MODEL 231), and analyzed by high performance liquid chromatography (HPLC) with electrochemical detection (ECD). The HPLC system consisted of a delivery pump (880-PU, Jasco, Japan), an analytical column (Eicompak, MA-5ODS 4.6 150 mm, Eicom Co., Japan) and a guard column (Eicom Co.). The electrochemical detector (EC-100, Eicom Co.) included a graphite electrode (WE-3G Eicom Co.) and was used at a voltage setting of 0.7 V vs. an Ag/AgCl reference electrode. The mobile phase consisted of a 0.1 M sodium acetate/ 0.1 M citric acid buffer, pH 3.5, containing 13–15% methanol, sodium 1-octanesulfonate and EDTA (2Na). The flow rate was set to 1.0 ml/min with a column temperature of 25 1C. 2.5. Drugs
2.2. Effects of morphine on locomotor activity The locomotor activity of mice was measured by an ambulometer (ANB-M20, O’Hara Co. Ltd., Tokyo) as described previously (Funada et al., 1993). Briefly, a mouse was placed in a tilting-type round activity cage 20 cm in diameter and 19 cm high. Any slight tilt of the activity cage, which was caused by horizontal movement of the animal, was detected by microswitches. Mice were placed in the tilting cages for a habituation period of 30 min after the s.c. (1.0, 2.5, 5.0, 10 and 20 mg/kg) or i.c.v. (2.5 and 5.0 μg/mouse) administration of morphine, and total activity counts were automatically recorded for 180 min. I.c.v. drug administration was made under ether anesthesia in a volume of 5 μl according to the method of Haley and Mccormick (1957).
Morphine hydrochloride (Sankyo, Tokyo, Japan) was dissolved in sterile saline. Dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) were purchased from Research Biochemicals, Inc. (Wayland, MA, U.S.A.), and dissolved in 0.02 N acetic acid for HPLC. 2.6. Data analysis Behavioral data (total activity counts) were statistically evaluated with a one-way repeated measures analysis of variance (ANOVA) followed by a Newman–Keuls test for multiple comparisons. The time-course changes in behavioral data were analyzed using twoway repeated measures ANOVA. Neurochemical data were statistically evaluated with a one-way ANOVA followed by Dunnett's test. A value of Po0.05 was considered statistically significant.
2.3. Splenectomized mice Splenectomies were carried out under sterile and etheranesthetized conditions. Sham-operated animals were subjected to the same handling, anesthesia, surgical exposure of the spleen, and wound closure as splenectomized animals, as described previously (Kamei et al., 1992). Seven days after surgery (sham or splenectomy), morphine-induced hyperlocomotion was measured.
3. Results 3.1. Effects of morphine and/or splenectomy on locomotor activity We previously demonstrated that beige-J mice exhibited greater spontaneous locomotor activity than ddY mice and C57/BL/6J mice,
M. Funada et al. / European Journal of Pharmacology 742 (2014) 89–93
and apomorphine-induced hyperlocomotion in sham-operated beige-J mice was significantly greater than that in ddY mice. Furthermore, apomorphine (1 mg/kg) produced behavioral disruption (struggling-like behavior) accompanied by hypolocomotion in C-57BL/6J mice. Therefore, we previously examined the effects of splenectomy on the spontaneous locomotor activity in beige-J and ddY mice (Mori et al., 2014). In the present study we examined the effects of morphine on the spontaneous locomotor activity in beigeJ and ddY mice. Administration of morphine (s.c.) increased the total activity counts over 3 h in a dose-dependent manner in beige-J mice (F4,60 ¼ 27.3, Po0.01), and the effects were significant at doses of 2.5, 5 and 10 mg/kg (Fig. 1A). Consistent with our previous report (Funada et al., 1993), morphine also induced a dose-dependent increase in locomotor activity in ddY mice. We previously showed that beige-J mice exhibited greater spontaneous locomotor activity than ddY mice and C57/BL/6J mice (Mori et al., 2014). Therefore, we could not directly compare the morphine-induced hyperlocomotion in beige-J mice to that in another mouse strain. However, hyperlocomotion induced by s.c. administration of morphine in beige-J mice was greater than that in ddY mice. Furthermore, i.c.v. administration of morphine (2.5 and 5.0 μg) produced dose-dependent hyperlocomotion in beige-J mice; these effects were significant at doses of 2.5 and 5.0 μg, compared to the i.c.v. saline control group (Fig. 1B). Thus, hyperlocomotion induced by i.c.v. administration of morphine in beige-J mice was also markedly greater than that in ddY mice. Previous studies have demonstrated that splenectomy suppressed morphine-induced hyperlocomotion (Kamei et al., 1992) and did not increase dopamine turnover (Kamei and Saitoh, 1997) in diabetic mice. Furthermore, splenectomy reversed the decrease in the antinociceptive effects of morphine to the level in control littermates (Raffa et al., 1988b). Therefore, we next examined the effects of splenectomy on morphine-induced hyperlocomotion in beige-J mice. Fig. 2 shows the time-course changes in morphineinduced hyperlocomotion in sham-operated and splenectomized beige-J mice. Splenectomized beige-J mice showed a significant and marked increase in morphine-induced hyperlocomotion compared to sham-operated beige-J mice. At the peak in splenectomized beige-J mice, morphine produced locomotor activity of 361.9724.4 counts/10 min, which was significantly greater than that in sham-operated beige-J mice (139.4 720.0 counts/10 min,
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Fl,23 ¼42.3, P o0.01). Similarly, the hyperlocomotion induced by i.c. v. administration of morphine (2.5 μg) in sham-operated beige-J mice was significantly augmented by splenectomy (sham-operated group: 1637.6 7471.7 counts/3 h, n ¼12, splenectomized group: 3945.8 7902.8 counts/3 h, n ¼8, sham-operated group vs. splenectomized group, Fl,18 ¼6.1 Po 0.05, data not shown), suggesting that pharmacodynamic as well as pharmacokinetic effects may not be involved in the enhancement of morphine-induced hyperlocomotion in splenectomized beige-J mice.
3.2. Effects of splenectomy on the morphine-induced increase in DA turnover in the limbic forebrain Basal levels of DA, DOPAC and HVA in the limbic forebrain were 11,008.8 7533.3 0.54 ng/g of tissue, 2842.2 7384.2 ng/g and 2259.6 7466.4 ng/g, respectively. Consistent with previous results that splenectomy significantly increased DA levels, but decreased DOPAC and HVA levels in the limbic forebrain (Mori et al., 2014), basal levels of DA, DOPAC and HVA in the limbic forebrain were altered to 15,200.6 7 615.1 ng/g of tissue, 1991.27 214.2 ng/g and
Fig. 2. Effects of splenectomy on hyperlocomotion induced by morphine in beige-J mice. Morphine (10 mg/kg, s.c.)-induced hyperlocomotion was measured 7 days after sham operation or splenectomy. Each point represents the mean total activity counts7 S.E.M. for 3 h after morphine treatment of 10–15 animals. nPo 0.05 vs. sham-operated control group.
Fig. 1. Effects of s.c. administration of morphine on spontaneous locomotor activity in beige-J mice (filled circles) and ddY mice (open circles)(A). nPo 0.05 vs. respective saline control. #Po 0.05 vs. respective group of ddY mice. Effects of i.c.v. administration of morphine (B) on spontaneous locomotor activity in beige-J (filled column) and ddY (open column) mice. nP o0.05 vs. respective saline control. Each column represents the mean total activity counts7 S.E.M. of 10–15 animals for 3 h after morphine treatment.
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Fig. 3. Effects of splenectomy on morphine-induced changes in DOPAC (A), HVA (B) and dopamine (DA)(C) concentrations and DA turnover (D) in the limbic forebrain of beige-J mice. DA and its metabolites were measured 7 days after sham-operation or splenectomy. Beige-J mice were killed 60 min after the administration of morphine (10 mg/kg, s.c. filled column) or saline (open column). The DA ratio was calculated as (DOPAC þ HVA)/DA. Each column represents the mean 7 S.E.M. of 5 animals. nPo 0.05 vs. respective saline-treated group. #Po 0.05 vs. morphine-treated control group.
1847.67 218.7 ng/g, respectively. The administration of morphine significantly increased the dopamine turnover ratio in the limbic forebrain of beige-J mice (Fig. 3). We also found that morphine further elevated the levels of DOPAC and HVA, without altering dopamine levels in the limbic forebrain of splenectomized beige-J mice compared with sham-operated beige-J mice (Fig. 3). These results indicate that circulating substances that originate from the spleen may negatively regulate the activation of the mesolimbic dopaminergic system induced by morphine in beige-J mice, which in turn affects the hyperlocomotion induced by morphine.
4. Discussion Our previous study demonstrated that spontaneous locomotor activity and the dopamine receptor agonist apomorphine-induced hyperlocomotion in the beige-J mouse were greater than those in C57BL/6J and ddY mice (Mori et al., 2014). Furthermore, spontaneous hyperlocomotion accompanied by activation of the mesolimbic dopaminergic system, but not the dopamine receptor agonist apomorphine-induced hyperlocomotion, was suppressed by splenectomy in beige-J mice (Mori et al., 2014). These results suggest that the mesolimbic dopaminergic system is maintained in a hyperactive state at both postsynaptic and presynaptic levels in beige-J mice, and the increase in the release dopamine from nerve terminals in beige-J mice is regulated by circulating substances that originate from the spleen. Activation of the mesolimbic dopamine system plays an important role in the expression of morphine-induced hyperlocomotion in mice. Thus, administration of morphine increased dopamine metabolite (DOPAC and HVA) levels, as an indicator of the release of dopamine from nerve terminals, in the limbic forebrain of ddY mice (Funada et al., 1993, 1994). We hypothesized that morphine-induced hyperlocomotion could be suppressed by splenectomy. However, we found that morphine-induced hyperlocomotion was potently enhanced by splenectomy in beige-J mice. These results indicate that substances that originate from the spleen may negatively modify the susceptibility of the mesolimbic dopaminergic system to be in a hyperactive state induced by morphine in beige-J mice. The poor responsiveness of beige-J mice to morphine-induced antinociception could also be normalized by splenectomy (Mathiasen et al., 1987). The m-opioid receptor binding profiles in the cellular membrane fraction from beige-J mouse brain were not any different from those in Swiss CD-1 mouse brain (Raffa et al., 1988a). Therefore, it is likely that circulating substances
originating from the spleen may negatively modify m-opioid receptor signaling without affecting the function of the m-opioid receptor itself. As mentioned above, splenectomy suppressed the spontaneous dopamine turnover in beige-J mice, but enhanced the morphineinduced increase in dopamine turnover. These results indicate that substances originating from the spleen may regulate the mesolimbic dopaminergic system through different modes of action. It is well known that the mesolimbic dopaminergic system is spontaneously active, while recent studies have shown that activation of the mesolimbic dopaminergic system by morphine is mediated by the stimulation of μ-opioid receptors on GABAnergic neurons (Balcita-Pedicino et al., 2011) and glutaminergic neurons (Jalabert et al., 2011) located in the ventral tegmental area (VTA) and the tail of the VTA (the so-called rostromedial tegmental nucleus). However, very little information is available regarding how splenectomy affects central GABA, glutamate and dopamine neurons, and therefore further studies are needed to determine how circulating substances that originate in the spleen regulate activation of the mesolimbic dopaminergic system either with or without morphine in beige-J mice. Furthermore, it is not clear that the augmentation of dopamine turnover in the limbic forebrain is due to immune dysfunction in the beige-J mouse. It is well known that the central dopaminergic system modulates the activity of the immune system. For example, NK cell activities have been shown to be potently reduced in schizophrenic patients (DeLisi et al., 1983). It has been reported that changes in dopamine transmission in the nucleus accumbens, but not the striatum, impaired splenic NK cell activity (Deleplanque et al., 1994). These findings imply that the nucleus accumbens may be the most important region for the modulation of immune function and consequent pharmacological, neurochemical and/or behavioral changes in beige-J mice. It has been reported that beige-J mice are less responsive to the antinociceptive effects of the i.c.v. or s.c. administration of μopioid receptor agonists (Mathiasen et al., 1987; Muraki et al., 1991). In contrast, the present study demonstrated that morphine produced obvious hyperlocomotion, which may reflect activation of the dopaminergic system, in beige-J mice. Regarding these issues, a large and growing body of evidence has demonstrated that the periaqueductal gray is a key region for the expression of supraspinal morphine-induced antinociceptive effects. Therefore, it is likely that the poor responsiveness of beige-J mice to morphine-induced antinociception may be mediated by the dysfunction of central pain pathways (Mathiasen et al., 1987).
M. Funada et al. / European Journal of Pharmacology 742 (2014) 89–93
The present neurochemical studies demonstrated that the dopamine turnover ratio in the limbic forebrain was increased in beige-J mice to levels similar to those in other strains of mice, such as ddY (Funada et al., 1993, 1994) and ICR (Kamei and Saitoh, 1997), indicating that morphine activated the mesolimbic dopaminergic system even in beige-J mice. These different anatomical sites within the central nervous system may explain the discrepant results between the antinociception and hyperlocomotion caused by the stimulation of μ-opioid receptors. Importantly, both μ- and κ-opioid agonist-induced antinociception, but not δ-agonistinduced antinociception, were reduced by the Dl-receptor agonist SKF38393 in mice (Rooney and Sewell, 1989). We previously showed that high levels of dopaminergic tone were maintained in the brains of beige-J mice (Mori et al., 2014). Thus, the lower sensitivity to morphine-induced antinociception in beige-J mice may be due to hyperactivation of the central dopaminergic system. In summary, the present study as well as our recent study demonstrated that beige-J mice could be useful as an animal model in which the mesolimbic dopaminergic system is hyperactive. Furthermore, splenectomy suppressed the spontaneous hyperactivity of the mesolimbic dopaminergic system in beige-J mice, but enhanced morphine-induced activation of the mesolimbic dopaminergic system. These results suggest that some factor (s) of splenic origin in beige-J mice may regulate activation of the mesolimbic dopaminergic system through different pathways. Thus, the beige-J mouse may represent a practical animal model for investigating the interactions between immune-modulation and the m-opioid receptor system or dopaminergic system. References Ahtee, L., Attila, L.M., Carlson, K.R., Haikala, H., 1989. Changes in brain monoamine metabolism during withdrawal from chronic oral self-administration of morphine and in response to a morphine challenge in the withdrawn state. J. Pharmacol. Exp. Ther. 249, 303–310. Babior, M.B., 1985. Disorders of neutrophil function. In: Wyngaarden, J.M., Smith. Jr., H.L. (Eds.), Cecil Textbook of Medicine, vol. 1. WB Saunders Co., Philadelphia, pp. 951–952. Balcita-Pedicino, J.J., Omelchenko, N., Bell, R., Sesack, S.R., 2011. The inhibitory influence of the lateral habenula on midbrain dopamine cells: ultrastructural evidence for indirect mediation via the rostromedial mesopontine tegmental nucleus. J. Comp. Neurol. 519, 1143–1164. Biron, C.A., Pedersen, K.F., Welsh, R.M., 1987. Aberrant T cells in beige mutant mice. J. Immunol. 138, 2050–2056.
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Deleplanque, B., Vitiello, S., Le Moal, M., Neveu, P.J., 1994. Modulation of immune reactivity by unilateral striatal and mesolimbic dopaminergic lesions. Neurosci. Lett. 166, 216–220. DeLisi, L.E., Ortaldo, J.R., Maluish, A.E., Wyatt, R.J., 1983. Deficient natural killer cell (NK) activity and macrophage functioning in schizophrenic patients. J. Neural Transm. 58, 99–106. Funada, M., Suzuki, T., Narita, M., Misawa, M., Nagase, H., 1993. Modification of morphine-induced locomotor activity by pertussis toxin: biochemical and behavioral studies in mice. Brain Res. 619, 163–172. Funada, M., Suzuki, T., Misawa, M., 1994. The role of dopamine D1-receptors in morphine-induced hyperlocomotion in mice. Neurosci. Lett. 169, 1–4. Haley, T.J., Mccormick, W.G., 1957. Pharmacological effects produced by intracerebral injection of drugs in the conscious mouse. Br. J. Pharmacol. Chemother. 12, 12–15. Ito, S., Mori, T., Namiki, M., Suzuki, T., Sawaguchi, T., 2007. Complicated interaction between psychostimulants and morphine in expression of phenotype of behavior in the dopaminergic system of BALB/c mice. J. Pharmacol. Sci. 105, 326–333. Jalabert, M., Bourdy, R., Courtin, J., Veinante, P., Manzoni, O.J., Barrot, M., Georges, F., 2011. Neuronal circuits underlying acute morphine action on dopamine neurons. Proc. Natl. Acad. Sci. U.S.A 108, 16446–16450. Kamei, J., Kawashima, N., Kasuya, Y., 1992. Role of spleen or spleen products in the deficiency in morphine-induced analgesia in diabetic mice. Brain Res. 576, 139–142. Kamei, J., Saitoh, A., 1997. Evidence for the modulation of spontaneous locomotor activity by higher serum glucose levels and/or spleen-derived factor(s) in diabetic mice. Life Sci. 60, 1699–1708. Mathiasen, J.R., Raffa, R.B., Vaught, J.L., 1987. C57BL/6J-bgJ (beige) mice: differential sensitivity in the tail flick test to centrally administered mu- and delta-opioid receptor agonists. Life Sci. 40, 1989–1994. Mori, T., Shibasaki, M., Abe, M., Udagawa, Y., Suzuki, T., 2012. Effects of dronabinol on morphine-induced dopamine-related behavioral effects in animals. Synapse 66, 931–937. Mori, T., Funada, M., Tsuda, Y., Maeda, J., Suzuki, T., 2014. Dopaminergic hyperactivity accompanied by hyperlocomotion in C57BL/6J-bgJ/bgJ(beige-J) mice. J. Pharmacol. Sci. 125, 233–236. Muraki, T., Oike, N., Shibata, Y., Nomoto, T., 1991. Analgesic effect of mu- and kappaopioid agonists in beige and CXBK mice. J. Pharm. Pharmacol. 43, 210–212. Pick, C.G., Cheng, J., Paul, D., Pasternak, G.W., 1991. Genetic influences in opioid analgesic sensitivity in mice. Brain Res. 566, 295–298. Raffa, R.B., Kimball, E.S., Mathiasen, J.R., 1988a. The analgesic defect of C57BL/6J-bgJ/ bgJ (beige-J: Chediak–Higashi syndrome) mice transmitted by adoptive transfer of spleen cells to normal littermates. Life Sci. 42, 1231–1236. Raffa, R.B., Baldy Jr., W.J., Shank, R.P., Mathiasen, J.R., Vaught, J.L., 1988b. [3H][D-Ala2, NMePhe4,Gly-ol5]-enkephalin (mu-opioid) binding in beige-J mice. Peptides 9, 637–642. Roder, J., Duwe, A., 1979. The beige mutation in the mouse selectively impairs natural killer cell function. Nature 278, 451–453. Rooney, K.F., Sewell., R.D., 1989. Evaluation of selective actions of dopamine D-1 and D-2 receptor agonists and antagonists on opioid antinociception. Eur. J. Pharmacol. 168, 329–336. Shibasaki, M., Tsuyuki, T., Ando, K., Otokozawa, A., Udagawa, Y., Watanabe, K., Shibasaki, Y., Mori, T., Suzuki, T., 2014. Implication of KCC2 in the sensitization to morphine by chronic ethanol treatment in mice. Synapse 68, 39–43.
Contents lists available at ScienceDirect
European Journal of Pharmacology journal homepage: www.elsevier.com/locate/ejphar
Behavioural pharmacology
Splenectomy modifies hyperactive states of the dopaminergic system induced by morphine in C57BL/6J-bgJ/bgJ (beige-J) mice Masahiko Funada a,1, Tomohisa Mori a,1, Jun Maeda a, Yuko Tsuda a, Sachiko Komiya a, Norifumi Shimizu a, Junzo Kamei b, Tsutomu Suzuki a,n a
Department of Toxicology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan Department of Pathophysiology and Therapeutics, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan
b
art ic l e i nf o
a b s t r a c t
Article history: Received 8 May 2014 Received in revised form 20 August 2014 Accepted 20 August 2014 Available online 30 August 2014
Genetic factors affect the locomotor activity induced by morphine, which mainly depends on the activation of dopaminergic systems, and morphine has distinct pharmacological activities in C57BL/6JbgJbgJ (beige-J) mice, which have genetic deficiencies in immunological function. We previously showed that beige-J mice exhibited greater locomotor activity and dopamine turnover, whereas splenectomy reduced this hyperlocomotion and dopamine turnover, which suggests that beige-J mice could be an experimental animal model for investigating hyperactivation of the dopaminergic system, and that the spleen may contribute to the susceptibility to activation of the dopaminergic system. Furthermore, morphine can induce hyperlocomotion mediated by activation of the dopaminergic system. Therefore, we examined the effects of splenectomy on the hyperlocomotion and regulation of the dopaminergic system induced by morphine in beige-J mice. Morphine induced hyperlocomotion, which was accompanied by activation of the dopaminergic system, in beige-J mice. Furthermore, splenectomy enhanced the hyperlocomotion and activation of the mesolimbic dopaminergic system induced by morphine in beige-J mice. Our findings indicate that substances originating from the spleen may regulate both spontaneous activation of the mesolimbic dopaminergic system and the m-opioidergic system-mediated activation of the mesolimbic dopaminergic system by morphine through different modes of action. These results imply that beige-J mice could be a practical animal model for investigating the interactions between immune-modulation and the m-opioidergic system and/or dopaminergic system. & 2014 Elsevier B.V. All rights reserved.
Keywords: Beige-J mice Morphine Hyperlocomotion Dopamine Splenectomy
1. Introduction The C57BL/6J-bgJbgJ (beige-J) strain of mouse originated as a spontaneous mutation from C57BL/6J lines and is of particular interest as a homolog of Chediak–Higashi syndrome in humans (Babior, 1985). The beige-J mouse has defects in lysosomecontaining cells and other immunological functions, particularly natural killer (NK) cell and cytotoxic T-leukocyte functions (Roder and Duwe, 1979; Biron et al., 1987). Several behavioral studies have shown that beige-J mice, in addition to their immunologic defects, are also less sensitive to the antinociceptive effects of μ-opioid receptor agonists, such as morphine and [D-Ala2, NMePhe4,Gly-ol5]enkephalin (DAMGO) (Mathiasen et al., 1987). Studies on [3H]-DAMGO binding have demonstrated that the density of
n
Corresponding author. Tel./fax: þ 81 3 5498 5831. E-mail address: [email protected] (T. Suzuki). 1 These authors contributed equally to this work.
http://dx.doi.org/10.1016/j.ejphar.2014.08.018 0014-2999/& 2014 Elsevier B.V. All rights reserved.
opioid receptors in the brains of beige-J mice is comparable to that in the brains of their normal littermates and outbred albino mice (Raffa et al., 1988a; Pick et al., 1991). Based on these results, it is found that the antinociceptive defect in beige-J mice is not due to an insufficient number of μ-opioid receptors. This has led to the hypothesis that μ-opioid receptor-mediated signal transduction in the brain of beige-J mice might be altered (Raffa et al., 1988a,b). The analysis of a drug's effects on locomotor activity in rodents is an important tool for investigating the psychotic states induced by psychoactive drugs. The administration of morphine can produce dose-related hyperlocomotion in certain strains of mice, and the mesolimbic dopaminergic system plays an important role in regulating exploratory and locomotor behaviors (Funada et al., 1993, 1994; Mori et al., 2012; Shibasaki et al., 2014). On the other hand, morphine alone does not induce hyperlocomotion in BALB/c mice (Ito et al., 2007). We recently demonstrated that beige-J mice showed greater locomotor activity and dopamine turnover than C-57BL/6J mice and ddY mice, whereas splenectomy reduced this spontaneous hyperlocomotion and high levels of dopamine
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turnover, which suggests that beige-J mice could be an experimental animal model for investigating hyperactivation of the dopaminergic system, and some circulating substances that originate in the spleen may modulate activation of the dopaminergic system (Mori et al., 2014). Splenectomy restores the morphineinduced antinociception in beige-J (Raffa et al., 1988b) and diabetic mice (Kamei et al., 1992) to almost normal levels. Furthermore, splenectomy has been shown to normalize the hyperactivity of diabetic mice (Kamei and Saitoh, 1997). Thus, it is possible that morphine does not induce any hyperlocomotion in beige-J mice, and splenectomy may affect the behavioral changes induced by morphine, particularly locomotor activity, in mice. Information on this subject may shed light on the complex interactions between immune-modulation and the m-opioid receptor system or dopaminergic system. The aim of the present study was to examine the effects of morphine on locomotor activity in beige-J mice, and the effects of splenectomy on locomotor activity induced by morphine in beige-J mice. We found that morphine-induced hyperlocomotion in beigeJ mice was greater than that in ddY mice. Furthermore, morphineinduced hyperlocomotion in beige-J mice was enhanced by splenectomy. Therefore, the neurochemical properties of the activation of the mesolimbic system induced by morphine in beige-J mice were also documented.
2. Materials and methods 2.1. Animals Male beige-J mice (National Institute on Genetics, Mishima, Japan), weighing 25–35 g at the beginning of the experiments, were used. Male ddY mice were obtained from Tokyo Animal Laboratories Inc. (Tokyo, Japan). The mice were housed at a room temperature of 22 71 1C with a 12 h light-dark cycle (lights on 8:00 A.M. to 8:00 P.M.). Food and water were available ad libitum. Our studies were conducted in accordance with the Guide for Care and Use of Laboratory Animals of Hoshi University School of Pharmacy and Pharmaceutical Science, which is accredited by the Ministry of Education, Culture, Sports and Technology of Japan.
2.4. Neurochemical analysis The concentrations of dopamine (DA) and its metabolites 3,4dihydroxyphenyl acetic acid (DOPAC) and homovanillic acid (HVA) were determined as described previously (Funada et al., 1993, 1994). Sham-operated and splenectomized mice were killed 60 min after s.c. injection of morphine (10 mg/kg, s.c.). The time of killing corresponded to the peak of morphine-induced hyperlocomotion. The brain was quickly removed and dissected into the limbic forebrain (containing the nucleus accumbens and olfactory tubercles) on an ice-cold glass plate according to the modified method of Ahtee et al. (1989). Briefly, the brain was turned to expose the dorsal surface and a vertical cut was made through the anterior commissure. The resulting frontal portion was turned to expose the ventral surface. A vertical cut was made through the rhinal fissure, and a small part that included the accessory olfactory bulb and olfactory nucleus was removed. The resulting block of tissue was turned to expose the section and the area bordered by the caudate putamen and the nucleus accumbens was cut vertically. The block of tissue that included the nucleus accumbens and olfactory tubercle was considered to be the main portion of the limbic forebrain. The tissue samples were homogenized in 2 ml of 0.2 M perchloric acid containing 100 μM EDTA (2Na) and 100 ng isoproterenol, as an internal standard. For complete removal of the proteins, the homogenates were placed in cold water for 60 min. The homogenates were then centrifuged at 20,000 g for 20 min at 0 1C, and the supernatants were maintained at pH 3.0 using 1 M sodium acetate. Solution samples of 50 μl were injected by a refrigerated GILSON automatic sample injector (MODEL 231), and analyzed by high performance liquid chromatography (HPLC) with electrochemical detection (ECD). The HPLC system consisted of a delivery pump (880-PU, Jasco, Japan), an analytical column (Eicompak, MA-5ODS 4.6 150 mm, Eicom Co., Japan) and a guard column (Eicom Co.). The electrochemical detector (EC-100, Eicom Co.) included a graphite electrode (WE-3G Eicom Co.) and was used at a voltage setting of 0.7 V vs. an Ag/AgCl reference electrode. The mobile phase consisted of a 0.1 M sodium acetate/ 0.1 M citric acid buffer, pH 3.5, containing 13–15% methanol, sodium 1-octanesulfonate and EDTA (2Na). The flow rate was set to 1.0 ml/min with a column temperature of 25 1C. 2.5. Drugs
2.2. Effects of morphine on locomotor activity The locomotor activity of mice was measured by an ambulometer (ANB-M20, O’Hara Co. Ltd., Tokyo) as described previously (Funada et al., 1993). Briefly, a mouse was placed in a tilting-type round activity cage 20 cm in diameter and 19 cm high. Any slight tilt of the activity cage, which was caused by horizontal movement of the animal, was detected by microswitches. Mice were placed in the tilting cages for a habituation period of 30 min after the s.c. (1.0, 2.5, 5.0, 10 and 20 mg/kg) or i.c.v. (2.5 and 5.0 μg/mouse) administration of morphine, and total activity counts were automatically recorded for 180 min. I.c.v. drug administration was made under ether anesthesia in a volume of 5 μl according to the method of Haley and Mccormick (1957).
Morphine hydrochloride (Sankyo, Tokyo, Japan) was dissolved in sterile saline. Dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) were purchased from Research Biochemicals, Inc. (Wayland, MA, U.S.A.), and dissolved in 0.02 N acetic acid for HPLC. 2.6. Data analysis Behavioral data (total activity counts) were statistically evaluated with a one-way repeated measures analysis of variance (ANOVA) followed by a Newman–Keuls test for multiple comparisons. The time-course changes in behavioral data were analyzed using twoway repeated measures ANOVA. Neurochemical data were statistically evaluated with a one-way ANOVA followed by Dunnett's test. A value of Po0.05 was considered statistically significant.
2.3. Splenectomized mice Splenectomies were carried out under sterile and etheranesthetized conditions. Sham-operated animals were subjected to the same handling, anesthesia, surgical exposure of the spleen, and wound closure as splenectomized animals, as described previously (Kamei et al., 1992). Seven days after surgery (sham or splenectomy), morphine-induced hyperlocomotion was measured.
3. Results 3.1. Effects of morphine and/or splenectomy on locomotor activity We previously demonstrated that beige-J mice exhibited greater spontaneous locomotor activity than ddY mice and C57/BL/6J mice,
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and apomorphine-induced hyperlocomotion in sham-operated beige-J mice was significantly greater than that in ddY mice. Furthermore, apomorphine (1 mg/kg) produced behavioral disruption (struggling-like behavior) accompanied by hypolocomotion in C-57BL/6J mice. Therefore, we previously examined the effects of splenectomy on the spontaneous locomotor activity in beige-J and ddY mice (Mori et al., 2014). In the present study we examined the effects of morphine on the spontaneous locomotor activity in beigeJ and ddY mice. Administration of morphine (s.c.) increased the total activity counts over 3 h in a dose-dependent manner in beige-J mice (F4,60 ¼ 27.3, Po0.01), and the effects were significant at doses of 2.5, 5 and 10 mg/kg (Fig. 1A). Consistent with our previous report (Funada et al., 1993), morphine also induced a dose-dependent increase in locomotor activity in ddY mice. We previously showed that beige-J mice exhibited greater spontaneous locomotor activity than ddY mice and C57/BL/6J mice (Mori et al., 2014). Therefore, we could not directly compare the morphine-induced hyperlocomotion in beige-J mice to that in another mouse strain. However, hyperlocomotion induced by s.c. administration of morphine in beige-J mice was greater than that in ddY mice. Furthermore, i.c.v. administration of morphine (2.5 and 5.0 μg) produced dose-dependent hyperlocomotion in beige-J mice; these effects were significant at doses of 2.5 and 5.0 μg, compared to the i.c.v. saline control group (Fig. 1B). Thus, hyperlocomotion induced by i.c.v. administration of morphine in beige-J mice was also markedly greater than that in ddY mice. Previous studies have demonstrated that splenectomy suppressed morphine-induced hyperlocomotion (Kamei et al., 1992) and did not increase dopamine turnover (Kamei and Saitoh, 1997) in diabetic mice. Furthermore, splenectomy reversed the decrease in the antinociceptive effects of morphine to the level in control littermates (Raffa et al., 1988b). Therefore, we next examined the effects of splenectomy on morphine-induced hyperlocomotion in beige-J mice. Fig. 2 shows the time-course changes in morphineinduced hyperlocomotion in sham-operated and splenectomized beige-J mice. Splenectomized beige-J mice showed a significant and marked increase in morphine-induced hyperlocomotion compared to sham-operated beige-J mice. At the peak in splenectomized beige-J mice, morphine produced locomotor activity of 361.9724.4 counts/10 min, which was significantly greater than that in sham-operated beige-J mice (139.4 720.0 counts/10 min,
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Fl,23 ¼42.3, P o0.01). Similarly, the hyperlocomotion induced by i.c. v. administration of morphine (2.5 μg) in sham-operated beige-J mice was significantly augmented by splenectomy (sham-operated group: 1637.6 7471.7 counts/3 h, n ¼12, splenectomized group: 3945.8 7902.8 counts/3 h, n ¼8, sham-operated group vs. splenectomized group, Fl,18 ¼6.1 Po 0.05, data not shown), suggesting that pharmacodynamic as well as pharmacokinetic effects may not be involved in the enhancement of morphine-induced hyperlocomotion in splenectomized beige-J mice.
3.2. Effects of splenectomy on the morphine-induced increase in DA turnover in the limbic forebrain Basal levels of DA, DOPAC and HVA in the limbic forebrain were 11,008.8 7533.3 0.54 ng/g of tissue, 2842.2 7384.2 ng/g and 2259.6 7466.4 ng/g, respectively. Consistent with previous results that splenectomy significantly increased DA levels, but decreased DOPAC and HVA levels in the limbic forebrain (Mori et al., 2014), basal levels of DA, DOPAC and HVA in the limbic forebrain were altered to 15,200.6 7 615.1 ng/g of tissue, 1991.27 214.2 ng/g and
Fig. 2. Effects of splenectomy on hyperlocomotion induced by morphine in beige-J mice. Morphine (10 mg/kg, s.c.)-induced hyperlocomotion was measured 7 days after sham operation or splenectomy. Each point represents the mean total activity counts7 S.E.M. for 3 h after morphine treatment of 10–15 animals. nPo 0.05 vs. sham-operated control group.
Fig. 1. Effects of s.c. administration of morphine on spontaneous locomotor activity in beige-J mice (filled circles) and ddY mice (open circles)(A). nPo 0.05 vs. respective saline control. #Po 0.05 vs. respective group of ddY mice. Effects of i.c.v. administration of morphine (B) on spontaneous locomotor activity in beige-J (filled column) and ddY (open column) mice. nP o0.05 vs. respective saline control. Each column represents the mean total activity counts7 S.E.M. of 10–15 animals for 3 h after morphine treatment.
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Fig. 3. Effects of splenectomy on morphine-induced changes in DOPAC (A), HVA (B) and dopamine (DA)(C) concentrations and DA turnover (D) in the limbic forebrain of beige-J mice. DA and its metabolites were measured 7 days after sham-operation or splenectomy. Beige-J mice were killed 60 min after the administration of morphine (10 mg/kg, s.c. filled column) or saline (open column). The DA ratio was calculated as (DOPAC þ HVA)/DA. Each column represents the mean 7 S.E.M. of 5 animals. nPo 0.05 vs. respective saline-treated group. #Po 0.05 vs. morphine-treated control group.
1847.67 218.7 ng/g, respectively. The administration of morphine significantly increased the dopamine turnover ratio in the limbic forebrain of beige-J mice (Fig. 3). We also found that morphine further elevated the levels of DOPAC and HVA, without altering dopamine levels in the limbic forebrain of splenectomized beige-J mice compared with sham-operated beige-J mice (Fig. 3). These results indicate that circulating substances that originate from the spleen may negatively regulate the activation of the mesolimbic dopaminergic system induced by morphine in beige-J mice, which in turn affects the hyperlocomotion induced by morphine.
4. Discussion Our previous study demonstrated that spontaneous locomotor activity and the dopamine receptor agonist apomorphine-induced hyperlocomotion in the beige-J mouse were greater than those in C57BL/6J and ddY mice (Mori et al., 2014). Furthermore, spontaneous hyperlocomotion accompanied by activation of the mesolimbic dopaminergic system, but not the dopamine receptor agonist apomorphine-induced hyperlocomotion, was suppressed by splenectomy in beige-J mice (Mori et al., 2014). These results suggest that the mesolimbic dopaminergic system is maintained in a hyperactive state at both postsynaptic and presynaptic levels in beige-J mice, and the increase in the release dopamine from nerve terminals in beige-J mice is regulated by circulating substances that originate from the spleen. Activation of the mesolimbic dopamine system plays an important role in the expression of morphine-induced hyperlocomotion in mice. Thus, administration of morphine increased dopamine metabolite (DOPAC and HVA) levels, as an indicator of the release of dopamine from nerve terminals, in the limbic forebrain of ddY mice (Funada et al., 1993, 1994). We hypothesized that morphine-induced hyperlocomotion could be suppressed by splenectomy. However, we found that morphine-induced hyperlocomotion was potently enhanced by splenectomy in beige-J mice. These results indicate that substances that originate from the spleen may negatively modify the susceptibility of the mesolimbic dopaminergic system to be in a hyperactive state induced by morphine in beige-J mice. The poor responsiveness of beige-J mice to morphine-induced antinociception could also be normalized by splenectomy (Mathiasen et al., 1987). The m-opioid receptor binding profiles in the cellular membrane fraction from beige-J mouse brain were not any different from those in Swiss CD-1 mouse brain (Raffa et al., 1988a). Therefore, it is likely that circulating substances
originating from the spleen may negatively modify m-opioid receptor signaling without affecting the function of the m-opioid receptor itself. As mentioned above, splenectomy suppressed the spontaneous dopamine turnover in beige-J mice, but enhanced the morphineinduced increase in dopamine turnover. These results indicate that substances originating from the spleen may regulate the mesolimbic dopaminergic system through different modes of action. It is well known that the mesolimbic dopaminergic system is spontaneously active, while recent studies have shown that activation of the mesolimbic dopaminergic system by morphine is mediated by the stimulation of μ-opioid receptors on GABAnergic neurons (Balcita-Pedicino et al., 2011) and glutaminergic neurons (Jalabert et al., 2011) located in the ventral tegmental area (VTA) and the tail of the VTA (the so-called rostromedial tegmental nucleus). However, very little information is available regarding how splenectomy affects central GABA, glutamate and dopamine neurons, and therefore further studies are needed to determine how circulating substances that originate in the spleen regulate activation of the mesolimbic dopaminergic system either with or without morphine in beige-J mice. Furthermore, it is not clear that the augmentation of dopamine turnover in the limbic forebrain is due to immune dysfunction in the beige-J mouse. It is well known that the central dopaminergic system modulates the activity of the immune system. For example, NK cell activities have been shown to be potently reduced in schizophrenic patients (DeLisi et al., 1983). It has been reported that changes in dopamine transmission in the nucleus accumbens, but not the striatum, impaired splenic NK cell activity (Deleplanque et al., 1994). These findings imply that the nucleus accumbens may be the most important region for the modulation of immune function and consequent pharmacological, neurochemical and/or behavioral changes in beige-J mice. It has been reported that beige-J mice are less responsive to the antinociceptive effects of the i.c.v. or s.c. administration of μopioid receptor agonists (Mathiasen et al., 1987; Muraki et al., 1991). In contrast, the present study demonstrated that morphine produced obvious hyperlocomotion, which may reflect activation of the dopaminergic system, in beige-J mice. Regarding these issues, a large and growing body of evidence has demonstrated that the periaqueductal gray is a key region for the expression of supraspinal morphine-induced antinociceptive effects. Therefore, it is likely that the poor responsiveness of beige-J mice to morphine-induced antinociception may be mediated by the dysfunction of central pain pathways (Mathiasen et al., 1987).
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The present neurochemical studies demonstrated that the dopamine turnover ratio in the limbic forebrain was increased in beige-J mice to levels similar to those in other strains of mice, such as ddY (Funada et al., 1993, 1994) and ICR (Kamei and Saitoh, 1997), indicating that morphine activated the mesolimbic dopaminergic system even in beige-J mice. These different anatomical sites within the central nervous system may explain the discrepant results between the antinociception and hyperlocomotion caused by the stimulation of μ-opioid receptors. Importantly, both μ- and κ-opioid agonist-induced antinociception, but not δ-agonistinduced antinociception, were reduced by the Dl-receptor agonist SKF38393 in mice (Rooney and Sewell, 1989). We previously showed that high levels of dopaminergic tone were maintained in the brains of beige-J mice (Mori et al., 2014). Thus, the lower sensitivity to morphine-induced antinociception in beige-J mice may be due to hyperactivation of the central dopaminergic system. In summary, the present study as well as our recent study demonstrated that beige-J mice could be useful as an animal model in which the mesolimbic dopaminergic system is hyperactive. Furthermore, splenectomy suppressed the spontaneous hyperactivity of the mesolimbic dopaminergic system in beige-J mice, but enhanced morphine-induced activation of the mesolimbic dopaminergic system. These results suggest that some factor (s) of splenic origin in beige-J mice may regulate activation of the mesolimbic dopaminergic system through different pathways. Thus, the beige-J mouse may represent a practical animal model for investigating the interactions between immune-modulation and the m-opioid receptor system or dopaminergic system. References Ahtee, L., Attila, L.M., Carlson, K.R., Haikala, H., 1989. Changes in brain monoamine metabolism during withdrawal from chronic oral self-administration of morphine and in response to a morphine challenge in the withdrawn state. J. Pharmacol. Exp. Ther. 249, 303–310. Babior, M.B., 1985. Disorders of neutrophil function. In: Wyngaarden, J.M., Smith. Jr., H.L. (Eds.), Cecil Textbook of Medicine, vol. 1. WB Saunders Co., Philadelphia, pp. 951–952. Balcita-Pedicino, J.J., Omelchenko, N., Bell, R., Sesack, S.R., 2011. The inhibitory influence of the lateral habenula on midbrain dopamine cells: ultrastructural evidence for indirect mediation via the rostromedial mesopontine tegmental nucleus. J. Comp. Neurol. 519, 1143–1164. Biron, C.A., Pedersen, K.F., Welsh, R.M., 1987. Aberrant T cells in beige mutant mice. J. Immunol. 138, 2050–2056.
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Deleplanque, B., Vitiello, S., Le Moal, M., Neveu, P.J., 1994. Modulation of immune reactivity by unilateral striatal and mesolimbic dopaminergic lesions. Neurosci. Lett. 166, 216–220. DeLisi, L.E., Ortaldo, J.R., Maluish, A.E., Wyatt, R.J., 1983. Deficient natural killer cell (NK) activity and macrophage functioning in schizophrenic patients. J. Neural Transm. 58, 99–106. Funada, M., Suzuki, T., Narita, M., Misawa, M., Nagase, H., 1993. Modification of morphine-induced locomotor activity by pertussis toxin: biochemical and behavioral studies in mice. Brain Res. 619, 163–172. Funada, M., Suzuki, T., Misawa, M., 1994. The role of dopamine D1-receptors in morphine-induced hyperlocomotion in mice. Neurosci. Lett. 169, 1–4. Haley, T.J., Mccormick, W.G., 1957. Pharmacological effects produced by intracerebral injection of drugs in the conscious mouse. Br. J. Pharmacol. Chemother. 12, 12–15. Ito, S., Mori, T., Namiki, M., Suzuki, T., Sawaguchi, T., 2007. Complicated interaction between psychostimulants and morphine in expression of phenotype of behavior in the dopaminergic system of BALB/c mice. J. Pharmacol. Sci. 105, 326–333. Jalabert, M., Bourdy, R., Courtin, J., Veinante, P., Manzoni, O.J., Barrot, M., Georges, F., 2011. Neuronal circuits underlying acute morphine action on dopamine neurons. Proc. Natl. Acad. Sci. U.S.A 108, 16446–16450. Kamei, J., Kawashima, N., Kasuya, Y., 1992. Role of spleen or spleen products in the deficiency in morphine-induced analgesia in diabetic mice. Brain Res. 576, 139–142. Kamei, J., Saitoh, A., 1997. Evidence for the modulation of spontaneous locomotor activity by higher serum glucose levels and/or spleen-derived factor(s) in diabetic mice. Life Sci. 60, 1699–1708. Mathiasen, J.R., Raffa, R.B., Vaught, J.L., 1987. C57BL/6J-bgJ (beige) mice: differential sensitivity in the tail flick test to centrally administered mu- and delta-opioid receptor agonists. Life Sci. 40, 1989–1994. Mori, T., Shibasaki, M., Abe, M., Udagawa, Y., Suzuki, T., 2012. Effects of dronabinol on morphine-induced dopamine-related behavioral effects in animals. Synapse 66, 931–937. Mori, T., Funada, M., Tsuda, Y., Maeda, J., Suzuki, T., 2014. Dopaminergic hyperactivity accompanied by hyperlocomotion in C57BL/6J-bgJ/bgJ(beige-J) mice. J. Pharmacol. Sci. 125, 233–236. Muraki, T., Oike, N., Shibata, Y., Nomoto, T., 1991. Analgesic effect of mu- and kappaopioid agonists in beige and CXBK mice. J. Pharm. Pharmacol. 43, 210–212. Pick, C.G., Cheng, J., Paul, D., Pasternak, G.W., 1991. Genetic influences in opioid analgesic sensitivity in mice. Brain Res. 566, 295–298. Raffa, R.B., Kimball, E.S., Mathiasen, J.R., 1988a. The analgesic defect of C57BL/6J-bgJ/ bgJ (beige-J: Chediak–Higashi syndrome) mice transmitted by adoptive transfer of spleen cells to normal littermates. Life Sci. 42, 1231–1236. Raffa, R.B., Baldy Jr., W.J., Shank, R.P., Mathiasen, J.R., Vaught, J.L., 1988b. [3H][D-Ala2, NMePhe4,Gly-ol5]-enkephalin (mu-opioid) binding in beige-J mice. Peptides 9, 637–642. Roder, J., Duwe, A., 1979. The beige mutation in the mouse selectively impairs natural killer cell function. Nature 278, 451–453. Rooney, K.F., Sewell., R.D., 1989. Evaluation of selective actions of dopamine D-1 and D-2 receptor agonists and antagonists on opioid antinociception. Eur. J. Pharmacol. 168, 329–336. Shibasaki, M., Tsuyuki, T., Ando, K., Otokozawa, A., Udagawa, Y., Watanabe, K., Shibasaki, Y., Mori, T., Suzuki, T., 2014. Implication of KCC2 in the sensitization to morphine by chronic ethanol treatment in mice. Synapse 68, 39–43.
