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NEUROPHARMACOLOGY
Department of Physiology and Anatomy, Tohoku Pharmaceutical University, Sendai, Japan (H.W., D.N., K.I., C.W., H.M., S.S.); Division of Biochemical Analysis, Central Laboratory of Medical Sciences, Juntendo University School of Medicine, Tokyo, Japan (T.F., K.M.); Educational Center for Pharmaceutical Sciences, Tohoku Pharmaceutical University, Sendai, Japan (S.K.); Department of Pharmacology, Nihon Pharmaceutical University, Saitama, Japan (T. Sat.); and Department of Biochemistry, Daiichi College of Pharmaceutical Sciences, Fukuoka, Japan (C.S., T. Sak.)
Received August 5, 2004; Revision received November 18, 2004.
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Abstract |
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) and bovine hypothalamus (Hackler et al., 1993) and is named for its structural similarity to the melanocyte-stimulating hormone-release inhibiting factor-1 (MIF-1) family of brain peptides (Reed et al., 1994). Tyr-W-MIF-1 has a high affinity for µ-opioid receptors (Erchegyi et al., 1992, 1993; Hackler et al., 1993) and its own specific nonopioid receptors in the brain (Zadina et al., 1990), without any appreciable affinities for 
- and 
-opioid receptors (Zadina et al., 1994a,b). Tyr-W-MIF-1 has been reported to show a prolonged and naloxone-reversible antinociception after both intracerebroventricular (i.c.v.) and intrathecal (i.t.) administration (Gergen et al., 1996a,b). Tyr-W-MIF-1 also showed a potent inhibition of the electrically elicited contraction of the guinea pig ileum, a property of an agonistic for µ- or -opioid receptors (Erchegyi et al., 1992, 1993). The Tyr-W-MIF-1-induced inhibition of the contractions was eliminated by the selective µ-opioid receptor antagonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2, but not by the selective -opioid receptor antagonist nor-binaltorphimine (Erchegyi et al., 1992). This evidence clearly suggests that Tyr-W-MIF-1 is a potent agonist for µ-opioid receptors.
The µ-opioid receptor has been divided into µ1- and µ2-opioid receptors based on their sensitivity to the µ-opioid receptor antagonist naloxonazine, which irreversibly binds to µ1-opioid receptors (Hahn et al., 1982; Ling et al., 1986). In fact, the antinociception mediated by the spinal or supraspinal µ-opioid receptors can be divided into naloxonazine (35 mg/kg s.c.)-sensitive (µ1-opioid receptor-mediated) antinociception and naloxonazine-insensitive (µ2-opioid receptor-mediated) antinociception (Sakurada et al., 1999; Sato et al., 1999). The antinociception induced by Tyr-W-MIF-1 was significantly attenuated by pretreatment with 
-funaltrexamine but not by naloxonazine (Zadina et al., 1993; Gergen et al., 1996a,b), indicating that Tyr-W-MIF-1-induced antinociception may be mediated through the spinal or supraspinal µ2-opioid receptors. However, the extensive characterization of µ2-opioid receptor-mediated antinociception has been limited because a selective antagonist for the µ2-opioid receptor was not available.
The antinociception induced by the endogenous µ-opioid receptor agonists Tyr-Pro-Trp-Phe-NH2 (endomorphin-1) and Tyr-Pro-Phe-Phe-NH2 (endomorphin-2) is considered to be mediated by the spinal µ2- and µ1-opioid receptors, respectively. This contention is supported by the evidence that the antinociception induced by i.t. administration of endomorphin-2, but not endomorphin-1, is suppressed by the pretreatment with the µ1-opioid receptor antagonist naloxonazine (Sakurada et al., 1999, 2000a). We recently found that Tyr-D-Pro-Trp-Phe-NH2 (D-Pro2 -endomorphin-1) and Tyr-D-Pro-Phe-Phe-NH2 (D-Pro2 -endomorphin-2), in which the L-Pro2 of endomorphin-1 and endomorphin-2 has been replaced with D-Pro2, selectively attenuated the antinociception induced by endomorphin-1 and endomorphin-2, respectively (Sakurada et al., 2002). This evidence suggests the possibility that the synthetic peptides, which have replaced the L-Pro2 of their parent peptide with D-Pro2, are antagonists against their parent peptide. Based on the above-mentioned hypothesis, in the present study, we newly synthesized D-Pro2-Tyr-W-MIF-1 as a possible and primary antagonist for the Tyr-W-MIF-1 binding site, probably the µ2-opioid receptor.
The purpose of the present study is now to characterize the antagonistic properties of D-Pro2-Tyr-W-MIF-1 against the spinal antinociception induced by four distinct µ-opioid receptor agonists, Tyr-W-MIF-1, [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO), endomorphin-1, and endomorphin-2.
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Materials and Methods |
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Animals. Male ddY mice weighing 22 to 25 g (SLC, Hamamatsu, Japan) were housed in a light- and temperature-controlled room (lights on at 9:00 AM and off at 9:00 PM; 23°C). Food and water were available ad libitum. Animals were used only once.
Assessment of Antinociceptive Response. The antinociceptive response was assessed with the thermal paw-withdrawal test, using an automated tail-flick unit (BM Kiki, Tokyo, Japan). Mice were adapted to the testing environment for at least 1 h before any stimulation. Each animal was restrained with a soft cloth to reduce visual stimuli, and the light beam as a noxious radiant heat stimulation was applied from underneath the glass floor toward the hind paw. The light beam focused on the plantar surface of the hind paw, and the latency for the paw-withdrawal response against the noxious radiant heat stimulation was measured. The intensity of the noxious radiant heat stimulation was adjusted so that the predrug latency for the paw-withdrawal response was 2.5 to 3.5 s. The antinociceptive effect was expressed as percentage of the maximum possible effect (%MPE), which was calculated with the following equation: [(T1 – T0)/(10 – T0)] x 100, where T0 and T1 are the predrug and postdrug latencies for the paw-withdrawal response, respectively. To prevent tissue damage in paw, the noxious radiant heat stimulation was terminated automatically if the mouse did not lift the paw within 10 s. The measurement of the paw-withdrawal latency was performed by only one individual who was uninformed for drug treatment for each mouse.
Intrathecal Administration. The i.t. administration was performed according to the procedure described by Hylden and Wilcox (1980) using a 10-µl Hamilton microsyringe with a 29-gauge needle. The injection volume was 2 µl.
Drugs. Drugs used were Tyr-W-MIF-1 (Bachem California, San Carlos, CA); DAMGO (Sigma-Aldrich, St. Louis, MO); endomorphin-1 (Tocris Cookson, Bristol, UK); endomorphin-2 (Tocris Cookson); deltorphin II (Bachem California); (–)-U-50,488 hydrochloride (Tocris Cookson); D-Pro2-Tyr-W-MIF-1 (synthesized in our laboratory); -funaltrexamine hydrochloride (Tocris Cookson); naloxonazine dihydrochloride (Sigma/RBI, Natick, MA); naltrindole hydrochloride (Tocris Cookson); and nor-binaltorphimine dihydrochloride (Tocris Cookson). All drugs were dissolved in sterile artificial cerebrospinal fluid (ACSF) containing 7.4 g of NaCl, 0.19 g of KCl, 0.19 g of MgCl2, and 0.14 g of CaCl2 1000 ml–1.
Statistical Analysis. The data are expressed as the mean ± S.E.M. The statistical significance of the differences between groups was assessed with a one-way analysis of variance (ANOVA) followed by either Dunnett's test or Newman-Keuls test, or a two-way ANOVA followed by Bonferroni's test. The ED50, ID50, and Hill slope values with their 95% confidence intervals were calculated with a computer-associated curve-fitting program (GraphPad Prism; GraphPad Software, Inc., San Diego, CA). For the statistical significance of differences between groups, the entire curves were compared using the F-test, according to the instruction provided with GraphPad Prism.
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Effects of -Funaltrexamine, Nor-Binaltorphimine, and Naltrindole on the Antinociception Induced by Tyr-W-MIF-1. Groups of mice were pretreated i.t. with the µ-opioid receptor antagonist -funaltrexamine (4.0 nmol), the -opioid receptor antagonist nor-binaltorphimine (4.0 nmol), or ACSF 24 h before, or with the -opioid receptor antagonist naltrindole (0.033 nmol) or ACSF 5 min before the i.t. administration of Tyr-W-MIF-1 (16 nmol), and the antinociception induced by Tyr-W-MIF-1 was measured 10 min after the treatment. The antinociception induced by i.t. administration of Tyr-W-MIF-1 was almost eliminated by i.t. pretreatment with -funaltrexamine, whereas i.t. pretreatment with nor-binaltorphimine or naltrindole failed to affect the Tyr-W-MIF-1-induced antinociception (Table 1). The same pretreatment with either nor-binaltorphimine or naltrindole completely attenuated the antinociception induced by i.t. administration of either the -opioid receptor agonist U-50,488H or the -opioid receptor agonist deltorphin II, respectively (data not shown).
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Effect of Naloxonazine on the Antinociception Induced by µ-Opioid Receptor Agonists. Groups of mice were pretreated i.t. with various doses of the µ1-opioid receptor antagonist naloxonazine (1.4–44.2 nmol) or ACSF 24 h before the i.t. administration of equipotent doses of Tyr-W-MIF-1 (16 nmol), DAMGO (20 pmol), endomorphin-1 (5.0 nmol), or endomorphin-2 (5.0 nmol). The antinociception induced by i.t. administration of Tyr-W-MIF-1, DAMGO, endomorphin-1, and endomorphin-2 was measured 10, 5, 5, and 5 min after the treatment, respectively, as peak effects. The pretreatment with naloxonazine attenuated the antinociception induced by these four distinct µ-opioid receptor agonists in a dose-dependent manner (Fig. 2a). However, naloxonazine at a dose of 5.5 nmol only significantly antagonized the antinociceptive effect induced by endomorphin-2, without affecting the antinociception induced by endomorphin-1, DAMGO, and Tyr-W-MIF-1. Higher doses (11.1 or 22.1 nmol) of naloxonazine significantly attenuated endomorphin-1- and DAMGO-induced antinociception, but they still had no effect against the antinociception induced by Tyr-W-MIF-1. The Tyr-W-MIF-1-induced antinociception was significantly, but not completely, attenuated by the pretreatment with a much higher dose of naloxonazine (44.2 nmol), which completely eliminated the antinociception induced by endomorphin-1 and DAMGO. The ID50 values for naloxonazine against the antinociception induced by endomorphin-2, DAMGO, endomorphin-1, and Tyr-W-MIF-1 were 4.58 (95% CI, 3.82–5.49), 13.66 (95% CI, 10.35–18.04), 15.79 (95% CI, 14.99–16.63), and 35.34 (95% CI, 33.69–37.07) nmol, respectively (Fig. 2b; Table 2). The dose-response curves for inhibition by naloxonazine against DAMGO- and endomorphin-1-induced antinociception were statistically distinct from those against endomorphin-2- and Tyr-W-MIF-1-induced antinociception.
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Effect of D-Pro2-Tyr-W-MIF-1 on the Antinociception Induced by µ-Opioid Receptor Agonists. Groups of mice were coadministered various i.t. doses of D-Pro2-Tyr-W-MIF-1 (0.025–1.2 nmol) with equipotent doses of Tyr-W-MIF-1 (16 nmol), DAMGO (20 pmol), endomorphin-1, (5.0 nmol), or endomorphin-2 (5.0 nmol), and the antinociception induced by Tyr-W-MIF-1, DAMGO, endomorphin-1, and endomorphin-2 was measured 10, 5, 5, and 5 min after the treatment, respectively, as peak effects. D-Pro2-Tyr-W-MIF-1 at any of the doses used did not show any antinociceptive or hyperalgesic effect by itself at 5 or 10 min after the treatment. Coadministered D-Pro2-Tyr-W-MIF-1 dose dependently attenuated the antinociception induced by Tyr-W-MIF-1 (Fig. 3a). The ID50 value for D-Pro2-Tyr-W-MIF-1 against Tyr-W-MIF-1-induced antinociception was 0.21 (95% CI, 0.15–0.28) nmol (Fig. 3b; Table 2). In contrast, coadministered D-Pro2-Tyr-W-MIF-1 at a dose of 0.4 nmol, which almost completely attenuated Tyr-W-MIF-1-induced antinociception, did not affect the antinociception induced by DAMGO and endomorphin-1, whereas higher doses of D-Pro2-Tyr-W-MIF-1 (0.8–1.2 nmol) significantly attenuated the antinociception induced by either DAMGO or endomorphin-1. The ID50 values for D-Pro2-Tyr-W-MIF-1 against DAMGO- and endomorphin-1-induced antinociception were 0.98 (95% CI, 0.82–1.18) and 0.75 (95% CI, 0.63–0.89) nmol, respectively (Fig. 3b; Table 2). The dose-response curves for inhibition by D-Pro2-Tyr-W-MIF-1 against DAMGO- and endomorphin-1-induced antinociception were statistically distinct from that against Tyr-W-MIF-1-induced antinociception. On the other hand, the antinociception induced by endomorphin-2 was not affected by coadministration of D-Pro2-Tyr-W-MIF-1 at any of the doses used (Fig. 3, a and b; Table 2).
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Effect of D-Pro2-Tyr-W-MIF-1 on the Antinociception Induced by U-50,488H and Deltorphin II. Groups of mice were coadministered various i.t. doses of D-Pro2-Tyr-W-MIF-1 (0.025–1.2 nmol) with equipotent doses of the -opioid receptor agonist U-50,488H (30 nmol) or -opioid receptor agonist deltorphin II (4 nmol), and the antinociception induced by U-50,488H and deltorphin II was measured 10 and 5 min after the treatment, respectively. As shown in Table 3, coadministered D-Pro2-Tyr-W-MIF-1 at any of the doses used failed to affect the antinociception induced by either U-50,488H or deltorphin II.
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Discussion |
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).
We used a variety of i.t. doses of naloxonazine to determine the sensitivity to antagonists of the µ-opioid receptor subclasses involved in the antinociceptive responses to Tyr-W-MIF-1. There is biochemical and pharmacological evidence supporting the existence of µ-opioid receptor subclasses that are localized in the spinal and supraspinal structures involved in the modulation of nociception (Wolozin and Pasternak, 1981; Moskowitz and Goodman, 1985). At least two µ-opioid receptor subclasses have been proposed: µ1- and µ2-opioid receptors. -Funaltrexamine irreversibly antagonizes both µ1- and µ2-opioid receptors and inhibits both supraspinal and spinal antinociception, whereas naloxonazine selectively antagonizes the µ1-opioid receptors and inhibits supraspinal antinociception. Recent behavioral pharmacological studies suggest the presence of µ1-opioid receptors sensitive to naloxonazine in spinal sites as assayed with the formalin, hot-plate, tail-pressure, and tail-flick tests (Sakurada et al., 1999, 2000b; Sato et al., 1999). Autoradiographic studies show that µ1- and µ2-opioid receptor subclasses are localized in the spinal and supraspinal structures involved in the modulation of nociception (Moskowitz and Goodman, 1985). The difference in µ1 and µ2 binding could be due to induced differences in the receptor conformation.
It is noteworthy that both the s.c. 35 mg/kg dose and the i.t. 5.5 nmol/mouse dose of naloxonazine are reasonable doses to selectively block µ1-opioid receptors in mice (Ling and Goodman, 1986; Sakurada et al., 2000a). Recent studies have shown that the antinociceptive response to DAMGO is not blocked by pretreatment with naloxonazine at a dose of 35 mg/kg s.c. or 5.5 nmol/mouse i.t., whereas higher doses of naloxonazine (52.5, 65.6, or 78.8 mg/kg s.c. or 11.1 nmol/mouse i.t.) significantly attenuated DAMGO-induced antinociception (Sakurada et al., 2000a), indicating that naloxonazine at high doses loses much of its selectivity for µ1-opioid receptors (Sakurada et al., 2000a). The antinociception induced by i.t. administration of Tyr-W-MIF-1 was significantly attenuated by pretreatment with -funaltrexamine, whereas the antinociceptive activity was not antagonized by pretreatment with a reasonable i.t. dose of naloxonazine, i.e., 5.5 nmol/mouse. The present results with naloxonazine on Tyr-W-MIF-1-induced antinociception are in agreement with those of Gergen et al. (1996b). This result suggests that the antinociception with Tyr-W-MIF-1 is mediated through µ2-opioid receptors, since higher doses of i.t. naloxonazine attenuated the antinociception with Tyr-W-MIF-1 (Fig. 2, a and b). Furthermore, i.t. pretreatment with the -opioid receptor antagonist nor-binaltorphimine or the -opioid receptor antagonist naltrindole did not attenuate the antinociception induced by i.t. administration of Tyr-W-MIF-1 (Table 1). These results strongly support the previous reports that the antinociception induced by i.t. administration of Tyr-W-MIF-1 was mediated by stimulation of the µ2-opioid receptor at the spinal cord level (Gergen et al., 1996b). Unexpectedly, higher doses of naloxonazine (11.1 or 22.1 nmol/mouse i.t.), which suppressed the antinociception with DAMGO, did not significantly inhibit the Tyr-W-MIF-1-induced antinociception. Even the highest dose of naloxonazine (44.2 nmol/mouse i.t.) did not completely antagonize the antinociception with Tyr-W-MIF-1.
Two new endogenous opioid peptides, endomorphin-1 (Tyr-Pro-Trp-Phe-NH2) and endomorphin-2 (Tyr-Pro-Phe-Phe-NH2), have been found to be highly selective for µ-opioid receptors (Zadina et al., 1997). Both endomorphin-1 and endomorphin-2 significantly increase nociceptive thresholds after both i.t. and i.c.v. administration, and these effects are antagonized by the µ-opioid receptor-selective antagonists naloxone and -funaltrexamine. However, more recent results indicate that different subclasses of µ-opioid receptors may be involved in the antinociceptive effects induced by endomorphin-1 and endomorphin-2. The antinociception induced by endomorphin-1 is blocked by the µ1- and µ2-opioid receptor antagonist -funaltrexamine, but not by the selective µ1-opioid receptor antagonist naloxonazine, whereas the antinociception induced by endomorphin-2 is blocked by both -funaltrexamine and naloxonazine (Tseng et al., 2000; Sakurada et al., 2002).
The µ1-opioid receptor antagonist naloxonazine was more effective in blocking the antinociceptive effects in mice induced by endomorphin-2 than by endomorphin-1 (Sakurada et al., 1999). A reasonable dose of naloxonazine, 35 mg/kg s.c. or 5.5 nmol/mouse i.t., to obtain a relative µ1-opioid receptor selectivity (Ling et al., 1986) did not attenuate the antinociceptive effects induced by i.t. administration of endomorphin-1 (Sakurada et al., 2000a) or Tyr-W-MIF-1 (Gergen et al., 1996b), but it did attenuate the antinociception due to endomorphin-2, suggesting that endomorphin-1 acts as a µ2-opioid receptor agonist and endomorphin-2 acts as a µ1-opioid receptor agonist at the spinal site. Thus, based on antagonism by naloxonazine, endomorphin-1, but not endomorphin-2, has behavioral and pharmacological similarities to Tyr-W-MIF-1.
We have demonstrated that D-Pro2-endomorphin-1 and D-Pro2-endomorphin-2, analogs of the endomorphins (Hung et al., 2002; Sakurada et al., 2002), are opioid receptor antagonists that selectively block the antinociception induced by endomorphin-1 and endomorphin-2, respectively, in the spinal cord. Furthermore, D-Pro2-endomorphin-2 attenuated the antinociception induced by i.t. administration of endomorphin-2 or the selective µ1-opioid receptor agonist Tyr-D-Arg-Phe--Ala (Sakurada et al., 2000b) but not that induced by DAMGO or endomorphin-1 (Hung et al., 2002; Sakurada et al., 2002), indicating that D-Pro2-endomorphin-2 is an antagonist that selectively blocks the antinociception induced by µ1-opioid receptor agonists in the spinal cord. D-Pro2-endomorphin-2 acts as a selective µ1-opioid receptor antagonist, like naloxonazine. On the other hand, D-Pro2-endomorphin-1 attenuated the antinociception induced by i.t.-administered endomorphin-1 and DAMGO but not endomorphin-2, suggesting that D-Pro2-endomorphin-1 may act as a selective µ2-opioid receptor antagonist (Sakurada et al., 2002).
We found in the present study that D-Pro2-Tyr-W-MIF-1, an analog of Tyr-W-MIF-1 containing D-Pro in position 2, inhibited the antinociception induced by Tyr-W-MIF-1, endomorphin-1, and DAMGO, but not endomorphin-2, deltorphin II, or U-50,488H, in a dose-dependent manner. The present results clearly suggest that D-Pro2-Tyr-W-MIF-1 is a selective antagonist for µ2-opioid receptor. Interestingly, the antinociception of Tyr-W-MIF-1 was significantly attenuated at the doses of 0.1–0.4 nmol (Fig. 3, a and b), doses that did not affect endomorphin-1-, endomorphin-2-, or DAMGO-induced antinociception (Fig. 3, a and b). A higher dose (0.8 nmol) of D-Pro2-Tyr-W-MIF-1 significantly attenuated the antinociception with endomorphin-1 or DAMGO without affecting the antinociception with endomorphin-2, deltorphin II, or U-50,488H (Fig. 3, a and b; Table 3). The finding that the antinociception induced by Tyr-W-MIF-1 can be antagonized by D-Pro2-Tyr-W-MIF-1 at doses that are inactive against endomorphin-1 and DAMGO indicates that it could be used to distinguish the different antinociceptive mechanism within the µ2-opioid receptor agonists. We previously reported that D-Pro2-endomorphin-1 shows the antagonistic property for µ2-opioid receptor. Like a D-Pro2-Tyr-W-MIF-1, the i.t. coadministration of D-Pro2-endomorphin-1 significantly attenuated the antinociception induced by endomorphin-1, DAMGO, and Tyr-W-MIF-1 (Sakurada et al., 2002; H. Watanabe, unpublished observation). However, the antagonistic property of D-Pro2-endomorphin-1 against Tyr-W-MIF-1 is characteristically similar to those against endomorphin-1 and DAMGO, suggesting that unlike D-Pro2-Tyr-W-MIF-1, D-Pro2-endomorphin-1 cannot discriminate the antinociception induced by these µ2-opioid receptor agonists. The present study is the first to show that D-Pro2-Tyr-W-MIF-1 can also distinguish the actions of different peptidic µ2-opioid receptor agonists. D-Pro2-Tyr-W-MIF-1 selectively blocked the antinociception of Tyr-W-MIF-1 far more effectively than that of endomorphin-1 and DAMGO, whereas the antinociception induced by endomorphin-2 was not reduced by coadministered with D-Pro2-Tyr-W-MIF-1 (Fig. 3, a and b). The differential antagonistic sensitivity of D-Pro2-Tyr-W-MIF-1 on inhibition of the thermal nociceptive response by µ2-opioid receptor agonists led us to speculate that the µ2-opioid receptors could be subdivided into a subclass of the µ2-opioid receptor that is relatively insensitive to D-Pro2-Tyr-W-MIF-1 and a subclass of the µ2-opioid receptor that is extremely sensitive to D-Pro2-Tyr-W-MIF-1, whereas D-Pro2-endomorphin-1 failed to separate the different subclasses of µ2-opioid receptors.
D-Pro2-Tyr-W-MIF-1 selectively blocked the antinociceptive effect of i.t. administration of Tyr-W-MIF-1, whereas the antinociceptive effect of DAMGO or endomorphin-1, which are insensitive to naloxonazine, was not inhibited at same dose at which the antinociception caused by Tyr-W-MIF-1 was eliminated. These results also indicate that D-Pro2-Tyr-W-MIF-1 may be a useful tool to discriminate between the antinociceptive effects of µ2-opioid receptor agonists that act via the different subclasses of the µ2-opioid receptor.
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Footnotes |
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ABBREVIATIONS: MIF-1 melanocyte-stimulating hormone-release inhibiting factor-1; D-Pro2-endomorphin-1, Tyr-D-Pro-Trp-Phe-NH2; D-Pro2-endomorphin-2, Tyr-D-Pro-Phe-Phe-NH2; D-Pro2-Tyr-W-MIF-1, Tyr-D-Pro-Trp-Gly-NH2; endomorphin-1, Tyr-Pro-Trp-Phe-NH2; endomorphin-2, Tyr-Pro-Phe-Phe-NH2; Tyr-W-MIF-1, Tyr-Pro-Trp-Gly-NH2; DAMGO, [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin; (–)-U-50,488, (–)-(trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide; MPE, maximal possible effect; ACSF, artificial cerebrospinal fluid; ANOVA, analysis of variance; CI, confidence interval.
Address correspondence to: Dr. Shinobu Sakurada, Department of Physiology and Anatomy, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan. E-mail: s-sakura{at}tohoku-pharm.ac.jp
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