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Suppressive effects by cysteine protease inhibitors on naloxone-precipitated withdrawal jumping in morphine-dependent mice
Neuropeptides 44 (2010) 279–283
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Neuropeptides journal homepage: www.elsevier.com/locate/npep
Suppressive effects by cysteine protease inhibitors on naloxone-precipitated withdrawal jumping in morphine-dependent mice Koichi Tan-No a,*, Tasuku Sato a, Masakazu Shimoda a, Osamu Nakagawasai a, Fukie Niijima a, Shunsuke Kawamura b, Seiichi Furuta c, Takumi Sato d, Susumu Satoh d, Jerzy Silberring e, Lars Terenius f, Takeshi Tadano a a
Department of Pharmacology, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan Educational Center for Pharmaceutical Sciences, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan Division of Community Health Care, Hokkaido Pharmaceutical University School of Pharmacy, 7-1 Katsuraoka, Otaru 047-0264, Japan d Department of Pharmacology and Pharmacotherapy, Nihon Pharmaceutical University, Kitaadachi-gun, Saitama 362-0806, Japan e Department of Biochemistry and Neurobiology, AGH University of Science and Technology, Krakow, Poland f Department of Clinical Neuroscience, Section of Alcohol and Drug Dependence Research, Karolinska Institute, Stockholm S-171 76, Sweden b c
a r t i c l e
i n f o
Article history: Received 6 August 2009 Accepted 4 February 2010 Available online 1 March 2010 Keywords: Protease inhibitors Dynorphins Withdrawal jumping Intracerebroventricular injection Morphine-dependent mouse
a b s t r a c t The effects of various protease inhibitors on naloxone-precipitated withdrawal jumping were examined in morphine-dependent mice. The doses of morphine were subcutaneously given twice daily for 2 days (day 1, 30 mg/kg; day 2, 60 mg/kg). On day 3, naloxone (8 mg/kg) was intraperitoneally administered 3 h after final injection of morphine (60 mg/kg), and the number of jumping was immediately recorded for 20 min. Naloxone-precipitated withdrawal jumping was significantly suppressed by the intracerebroventricular administration of N-ethylmaleimide (0.5 nmol) and Boc-Tyr-Gly-NHO-Bz (0.4 nmol), inhibitors of cysteine proteases involved in dynorphin degradation, 5 min before each morphine treatment during the induction phase, with none given on the test day, as well as by dynorphin A (62.5 pmol) and dynorphin B (250 pmol). However, amastatin, an aminopeptidase inhibitor, phosphoramidon, an endopeptidase 24.11 inhibitor, and captopril, an angiotensin-converting enzyme inhibitor, caused no changes. The present results suggest that cysteine protease inhibitors suppress naloxone-precipitated withdrawal jumping in morphine-dependent mice, presumably through the inhibition of dynorphin degradation. Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction Dynorphin A, dynorphin B and a-neoendorphin are opioid peptides derived from the pre-prodynorphin precursor. They possess high affinity for j-opioid receptors (for a review, see Höllt, 1986). Similarly to other neuropeptides, they are converted to shorter, bioactive fragments and/or degraded with loss of activity by several proteases. Among the proteases degrading dynorphin-related peptides, dynorphin-converting enzymes that convert dynorphins to shorter opioid peptides have been purified from bovine and human spinal cord (Silberring and Nyberg, 1989; Silberring et al., 1992, 1993). These proteases belong to the cysteine proteases family and cleave dynorphin A and dynorphin B between the Arg6-Arg7 and, to a lesser degree, the Leu5-Arg6 bonds, thus generating [Leu5]enkephalin-Arg6 as a major product and small amounts of Abbreviations: Boc-, tert-butyloxycarbonyl; -Bz, benzoyl. * Corresponding author. Tel./fax: +81 22 727 0123. E-mail address: [email protected] (K. Tan-No). 0143-4179/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.npep.2010.02.001
[Leu5]enkephalin, both of which are primarily active at d-opioid receptors. We have previously shown that p-hydroxymercuribenzoate (PHMB), a general cysteine protease inhibitor, and Boc-TyrGly-NHO-Bz (BYG-Bz), a representative of a novel class of cysteine protease inhibitors, significantly prolong dynorphin-induced antinociception, when co-administered by intrathecal (i.t.) injection with dynorphin A or dynorphin B, in the mouse formalin and capsaicin tests (Tan-No et al., 1996, 2005). This observation indicates that cysteine proteases may be important for terminating dynorphin A- and dynorphin B-induced antinociception. Morphine is an important drug in the clinical treatment of severe pain. However, chronic use of morphine results in the development of antinociceptive tolerance and physical dependence. The development of antinociceptive tolerance and physical dependence on morphine is suppressed by dynorphins (Takemori et al., 1992, 1993; Hooke et al., 1995). Moreover, chronic administration of morphine increases the conversion of dynorphin A to [Leu5]enkephalin-Arg6 in the cerebrospinal fluid of rats (Persson et al., 1989) and also increases dynorphin-converting enzyme
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activity in primary cultures of rat cerebral cortex, which is further elevated by naloxone-precipitated withdrawal (Vlaskovska et al., 1997). We have recently reported that i.t. administration of N-ethylmaleimide and BYG-Bz, both cysteine protease inhibitors, suppresses the development of antinociceptive tolerance to morphine, presumably through the inhibition of dynorphin degradation (Tan-No et al., 2008). Collectively, these observations suggest that the inhibition of cysteine proteases not only suppresses the development of antinociceptive tolerance but also the physical dependence on morphine. In the present study, we examined the effects of intracerebroventricular (i.c.v.) administration of N-ethylmaleimide and BYGBz on the development of physical dependence on morphine by assessing naloxone-precipitated withdrawal jumping, and compared these effects with inhibitors of different proteases.
Day 1 Each agent Morphine (30 mg/kg, s.c.) (i.c.v.)
Each agent (i.c.v.)
Morphine (30 mg/kg, s.c.)
5 min
5 min Day 2 Each agent Morphine (60 mg/kg, s.c.) (i.c.v.)
Each agent (i.c.v.)
Morphine (60 mg/kg, s.c.)
5 min
5 min Day 3 Morphine (60 mg/kg, s.c.)
Naloxone (0.5-8 mg/kg, i.p.)
3 hr Observation (20 or 30 min)
2. Materials and methods
Fig. 1. The experimental protocol for induction and assessment of physical dependence on morphine. Details are described in the Section 2.
2.1. Animals the number of jumps was measured for 20 min with exception of the experiments with a longer observation time.
Experiments were performed using male ddY-strain mice weighing 22–25 g (Japan SLC, Japan) under a 12 h light–dark cycle (light 8:00 a.m.–8:00 p.m.) with constant temperature (23 ± 1 °C) and relative humidity (55 ± 5%). Groups of 10–18 mice were used only once for each experiment. All experiments were performed following the approval of the Ethics Committee for Animal Experiments at Tohoku Pharmaceutical University, and in accordance with the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health.
I.c.v. administration of various drugs was performed 5 min prior to each morphine injection during the induction phase, to determine the effects of these compounds on the development of a physical dependence on morphine (Fig. 1). No treatment was given on the test day.
2.2. Drugs
2.6. Statistics
The following drugs and chemicals were used: dynorphin A, dynorphin B (Bachem, Switzerland), N-ethylmaleimide, captopril, naloxone, trans-(1S, 2S)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl) cyclohexyl] benzenacetamide hydrochloride (( ) U-50,488) (Sigma–Aldrich, USA), amastatin, phosphoramidon (Peptide Institute, Japan), morphine hydrochloride (Sankyo, Japan). BYG-Bz was kindly donated by Dr. Hans-Ulrich Demuth (Probiodrug AG, Biocenter, Halle, Germany). For i.c.v. injections, test compounds were dissolved in Ringer’s solution. Morphine and naloxone were dissolved in saline.
The results are presented as the means and S.E.M. Significant differences between groups were determined by Fisher’s PLSD post hoc test for multiple comparisons after analysis of variance (ANOVA) using the Statview-J5.0 computer program (SAS Institute, USA). In all statistical comparisons, P < 0.05 was used as the criterion for statistical significance.
2.3. Intracerebroventricular injections I.c.v. injections (5 ll) were made directly into the lateral ventricle of unanesthetized mice as described by a previous report (TanNo et al., 2001). 2.4. Induction and assessment of physical dependence on morphine The experimental protocol for induction and assessment of physical dependence on morphine is shown in Fig. 1. For induction of morphine dependence, the doses of morphine were subcutaneously (s.c.) given as pretreatment twice daily (at 9:00 a.m. and 7:00 p.m.) for 2 days (day 1, 30 mg/kg; day 2, 60 mg/kg). The schedule for induction of morphine dependence was decided by referring to our previously published method for induction of antinociceptive tolerance (Tan-No et al., 2008, 2009). On day 3, naloxone-precipitated withdrawal jumping was measured to assess physical dependence on morphine. Namely, naloxone was intraperitoneally administered 3 h after final injection of morphine at a dose of 60 mg/kg. Immediately after naloxone injection, mice were placed in a cylinder (10 cm diameter 50 cm height) and
2.5. Treatment with tested drugs
3. Results 3.1. Naloxone-precipitated withdrawal jumping in morphine-dependent mice Jumping, paw tremor, backward locomotion, sniffing and defecation are known as withdrawal signs and used to assess physical dependence on morphine (Ueda et al., 2000). Because the jumping was remarkable in these signs, only the number of jumps was counted under the environment (using a cylinder of 10 cm diameter) to observe the jumping easily. Time-courses of naloxone-precipitated withdrawal jumping were examined, with results showing that jumping peaked at 0–5 min, and had almost disappeared at 20 min after injection (Fig. 2A). As shown in Fig. 2B, a dose-dependent increase in the total number of jumps was observed following administration of naloxone in doses ranging from 0.5 to 8 mg/kg. Therefore, 8 mg/kg naloxone and a 20 min observation time were used in subsequent experiments to determine the inhibitory potency of various drugs on morphine dependence. 3.2. Effects of dynorphin A, dynorphin B, ( ) U-50,488, N-ethylmaleimide and BYG-Bz on naloxone-precipitated withdrawal jumping in morphine-dependent mice Naloxone-precipitated withdrawal jumping was significantly suppressed by the i.c.v. injection of dynorphin A (62.5 pmol) and
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A
B
30
20
Saline
** **
Number of jumps / 20 min
Number of jumps
40
Naloxone (0.5 mg/kg)
**
*
Naloxone (2.0 mg/kg) Naloxone (8.0 mg/kg)
* *
10
0
90
**
**
2.0
8.0
60
* 30
0 0-5
5-10
10-15
15-20
20-25
25-30
Saline
Time after injection ( min )
0.5
Naloxone (mg/kg)
Number of jumps / 20 min
Fig. 2. Naloxone-precipitated withdrawal jumping in morphine-dependent mice. The doses of morphine (mg/kg, s.c. per injection) were given twice daily for 2 days (day 1, 30; day 2, 60). On day 3, naloxone (0.5–8 mg/kg, i.p.) or saline was administered 3 h after the final injection of morphine at a dose of 60 mg/kg, and the number of jumps was immediately measured. (A) Time-course of jumping. The ordinate shows the total number of jumps that occurred during each 5 min period of measurement. (B) Total number of jumps measured during a 20 min period, beginning immediately after injection of naloxone or saline. The data are given as the means ± S.E.M. for groups of 10 mice. *P < 0.05, **P < 0.01 when compared with saline controls.
60
40
*
*
20
0 31.25
Ringer
62.5
31.25
Dynorphin A ( pmol )
250
1.25
Dynorphin B ( pmol )
5
20
(-)-U-50,488 ( nmol )
Fig. 3. Effects of dynorphin A, dynorphin B and ( ) U-50,488 on naloxone-precipitated withdrawal jumping in morphine-dependent mice. Dynorphin A, dynorphin B, ( ) U50,488 or Ringer’s solution was administered i.c.v. 5 min before each morphine pretreatment during the induction phase, with no administration on the test day. The number of jumps was measured during a 20 min period beginning immediately after injection of naloxone (8 mg/kg, i.p.). The data are given as the means ± S.E.M. for groups of 10–18 mice. *P < 0.05 when compared with Ringer’s solution as controls. For other details see Fig. 2.
B
50
25
*
0
Ringer
0.125
0.25
0.5
N -Ethylmaleimide (nmol)
Number of jumps / 20 min
Number of jumps / 20 min
A
50
25
*
0
Ringer
0.2
0.283
0.4
BYG-Bz (nmol)
Fig. 4. Suppressive effects by N-ethylmaleimide (A) and BYG-Bz (B) on naloxone-precipitated withdrawal jumping in morphine-dependent mice. N-ethylmaleimide, BYG-Bz or Ringer’s solution was administered i.c.v. 5 min before each morphine pretreatment during the induction phase, with no administration on the test day. The number of jumps was measured during a 20 min period beginning immediately after injection of naloxone (8 mg/kg, i.p.). The data are given as the means ± S.E.M. for groups of 18 mice. *P < 0.05 when compared with Ringer’s solution as controls. For other details see Fig. 2.
dynorphin B (250 pmol), but not ( ) U-50,488 (1.25–20 nmol) 5 min before each morphine pretreatment during the induction phase (Fig. 3). Similarly to dynorphin A and dynorphin B, both cys-
teine protease inhibitors N-ethylmaleimide (0.125–0.5 nmol) and BYG-Bz (0.2–0.4 nmol), dose-dependently suppressed naloxoneprecipitated withdrawal jumping (Fig. 4).
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Table 1 Effects of amastatin, phosphoramidon and captopril on naloxone-precipitated withdrawal jumping in morphine-dependent mice. Agents
Number of jumps /20 min
Ringer Amastatin (4 nmol) Phosphoramidon (4 nmol) Captopril (4 nmol)
36.6 ± 6.8 51.6 ± 17.5 23.4 ± 6.0 44.7 ± 9.8
Each agent was administered i.c.v. 5 min before each morphine pretreatment during the induction phase, with no administration on the test day. The number of jumps was measured during a 20 min period beginning immediately after injection of naloxone (8 mg/kg, i.p.). The data are given as the means ± S.E.M. for groups of 10 mice. For other details see Fig. 2.
3.3. Effects of amastatin, phosphoramidon and captopril on naloxoneprecipitated withdrawal jumping in morphine-dependent mice As shown in Table 1, amastatin (4 nmol), an aminopeptidase inhibitor, phosphoramidon (4 nmol), an endopeptidase 24.11 inhibitor, and captopril (4 nmol), an angiotensin-converting enzyme inhibitor, did not affect naloxone-precipitated withdrawal jumping. 4. Discussion Dynorphin-converting enzymes purified from the bovine (Silberring and Nyberg, 1989) and human (Silberring et al., 1992, 1993) spinal cords are cysteine proteases, and cleave dynorphin A and dynorphin B between the Arg6-Arg7 and Leu5-Arg6 bonds, generating [Leu5]enkephalin-Arg6 as the major product and [Leu5]enkephalin. We have previously shown that i.c.v. administration of dynorphin A at a subthreshold dose of 0.5 nmol, in combination with PHMB, produces a significant antinociceptive effect in the mouse formalin test during the second phase (10– 30 min after formalin injection), which is completely antagonized by nor-binaltorphimine, a selective j-opioid receptor antagonist (Tan-No et al., 2001). In other experiments, the degradation of dynorphin A by mouse brain extracts in vitro was markedly inhibited by PHMB and N-ethylmaleimide; whereas captopril, phosphoramidon or bestatin, an aminopeptidase inhibitor, had no effect (Tan-No et al., 2001). These findings indicate that dynorphin-converting enzymes may be important proteases responsible for the degradation of dynorphins, thereby causing a modulation of their functions in the brain. On the other hand, treatment with morphine (10 lM) for 5 days results in a 360% increase in the generation of [Leu5]enkephalin-Arg6 from dynorphin B by rat brain cortical cells in primary culture. This is inhibited by PHMB and N-ethylmaleimide, thus indicating that chronic treatment with morphine markedly increases dynorphin-converting enzyme activity (Vlaskovska et al., 1997). Moreover, acute treatment of cells previously exposed chronically to morphine with 50 mM naloxone elevates dynorphin-converting enzyme activity by 540% (Vlaskovska et al., 1997). We have recently reported that in addition to dynorphin A, dynorphin B and ( ) U-50,488, i.t. administration of N-ethylmaleimide and BYG-Bz 5 min before each morphine pretreatment during the induction phase suppresses the development of tolerance to morphine antinociception in the formalin test, and that the suppressive effect of cysteine protease inhibitors is mediated presumably through the inhibition of the endogenous dynorphin degradation (Tan-No et al., 2008). These reports lead us to the anticipation that cysteine protease inhibitors not only suppress the development of antinociceptive tolerance but also the physical dependence on morphine. In the present study, i.c.v. administration of N-ethylmaleimide (0.5 nmol) and BYG-Bz (0.4 nmol), 5 min before each morphine pretreatment in the induction phase, significantly sup-
pressed naloxone-precipitated withdrawal jumping in morphinedependent mice, with nearly the same efficacy as dynorphin A (62.5 pmol) and dynorphin B (250 pmol). In contrast, ( ) U50,488 had no effect on naloxone-precipitated withdrawal jumping, which is distinct from that of inducing antinociceptive tolerance (Tan-No et al., 2008). It is known that j-opioid receptors can be classified into at least three subtypes, i.e. j1-, j2- and j3-opioid receptor subtypes (Zukin et al., 1988; Clark et al., 1989; Meng et al., 1993; Pan et al., 1995). Dynorphins bind to all j-opioid receptor subtypes, whereas U-50,488H has a high affinity for j1-opioid receptors (Clark et al., 1989). Furthermore, the possibility has been indicated that although a novel j-opioid receptor agonist 17-cyclopropylmethyl-3,14b-dihydroxy-4,5a-epoxy-6b[N-methyl-trans-3-(3-furyl) acrylamido]morphinan hydrochloride (TRK-820) exhibits high potency and high selectivity for j-opioid receptors, the affinity of this compound for j-opioid receptor subtypes may be different from that of U-50,488H (Nagase et al., 1998). Tsuji et al. (2000) have previously reported that co-administration of TRK-820, but not U-50,488H, during chronic morphine treatment suppresses naloxone-precipitated withdrawal signs including jumping, suggesting that TRK-820 may suppress the development of physical dependence on morphine via the activation of j2- and/or j3-opioid receptor subtypes. Therefore, it is possible that N-ethylmaleimide and BYG-Bz suppress the development of physical dependence on morphine through an inhibition of dynorphin degradation, by decreasing the elevated dynorphin-converting enzyme activity, which subsequently activates j2- and/or j3-opioid receptor subtypes. On the other hand, no further suppression of naloxone-precipitated withdrawal jumping in morphine-dependent mice was observed at higher dose of dynorphin A (125 pmol), dynorphin B (500 pmol), N-ethylmaleimide (1 nmol) and BYG-Bz (1 nmol) (data not shown). It is well known that the other agents such as NMDA receptor antagonists (for a review, see Noda and Nabeshima, 2004) and nociceptin/orphanin FQ receptor antagonist (Ueda et al., 2000) also suppress naloxone-precipitated withdrawal jumping. Therefore, it seems that dynorphins and cysteine protease inhibitors were not able to completely suppress naloxone-precipitated withdrawal jumping. This is due to the fact that not only dynorphin system regulation but also other systems including NMDA receptor and nociceptin/orphanin FQ system are involved in physical dependence on morphine. I.c.v. administration of amastatin, phosphoramidon and captopril 5 min before each morphine pretreatment during the induction phase, did not suppress naloxone-precipitated withdrawal jumping in the morphine-dependent mice. In contrast to our results, it has been reported that i.c.v. administration of thiorphan, an endopeptidase 24.11 inhibitor, kelatorphan and R-3-(N-hydroxycarboxamido-2-benzylpropanoyl)-L-phenylalanine (RB38A), the complete inhibitors of enkephalin metabolism, 30 min before naloxone injection, with no administration in the induction phase, reduces withdrawal symptoms including jumping in morphine-dependent rats (Maldonado et al., 1989). This indicates that aminopeptidases, endopeptidase 24.11 and angiotensin-converting enzyme in the mouse brain are not involved in the induction of physical dependence on morphine, but are involved in the expression of physical dependence. In conclusion, the present study suggests that cysteine protease inhibitors suppress naloxone-precipitated withdrawal jumping, presumably through an inhibition of dynorphin degradation. Acknowledgements The authors wish to thank Dr. Hans-Ulrich Demuth (Probiodrug AG, Biocenter, Halle, Germany) for providing BYG-Bz. This study was supported in part by a Grant-in-Aid for Scientific Research
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Neuropeptides journal homepage: www.elsevier.com/locate/npep
Suppressive effects by cysteine protease inhibitors on naloxone-precipitated withdrawal jumping in morphine-dependent mice Koichi Tan-No a,*, Tasuku Sato a, Masakazu Shimoda a, Osamu Nakagawasai a, Fukie Niijima a, Shunsuke Kawamura b, Seiichi Furuta c, Takumi Sato d, Susumu Satoh d, Jerzy Silberring e, Lars Terenius f, Takeshi Tadano a a
Department of Pharmacology, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan Educational Center for Pharmaceutical Sciences, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan Division of Community Health Care, Hokkaido Pharmaceutical University School of Pharmacy, 7-1 Katsuraoka, Otaru 047-0264, Japan d Department of Pharmacology and Pharmacotherapy, Nihon Pharmaceutical University, Kitaadachi-gun, Saitama 362-0806, Japan e Department of Biochemistry and Neurobiology, AGH University of Science and Technology, Krakow, Poland f Department of Clinical Neuroscience, Section of Alcohol and Drug Dependence Research, Karolinska Institute, Stockholm S-171 76, Sweden b c
a r t i c l e
i n f o
Article history: Received 6 August 2009 Accepted 4 February 2010 Available online 1 March 2010 Keywords: Protease inhibitors Dynorphins Withdrawal jumping Intracerebroventricular injection Morphine-dependent mouse
a b s t r a c t The effects of various protease inhibitors on naloxone-precipitated withdrawal jumping were examined in morphine-dependent mice. The doses of morphine were subcutaneously given twice daily for 2 days (day 1, 30 mg/kg; day 2, 60 mg/kg). On day 3, naloxone (8 mg/kg) was intraperitoneally administered 3 h after final injection of morphine (60 mg/kg), and the number of jumping was immediately recorded for 20 min. Naloxone-precipitated withdrawal jumping was significantly suppressed by the intracerebroventricular administration of N-ethylmaleimide (0.5 nmol) and Boc-Tyr-Gly-NHO-Bz (0.4 nmol), inhibitors of cysteine proteases involved in dynorphin degradation, 5 min before each morphine treatment during the induction phase, with none given on the test day, as well as by dynorphin A (62.5 pmol) and dynorphin B (250 pmol). However, amastatin, an aminopeptidase inhibitor, phosphoramidon, an endopeptidase 24.11 inhibitor, and captopril, an angiotensin-converting enzyme inhibitor, caused no changes. The present results suggest that cysteine protease inhibitors suppress naloxone-precipitated withdrawal jumping in morphine-dependent mice, presumably through the inhibition of dynorphin degradation. Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction Dynorphin A, dynorphin B and a-neoendorphin are opioid peptides derived from the pre-prodynorphin precursor. They possess high affinity for j-opioid receptors (for a review, see Höllt, 1986). Similarly to other neuropeptides, they are converted to shorter, bioactive fragments and/or degraded with loss of activity by several proteases. Among the proteases degrading dynorphin-related peptides, dynorphin-converting enzymes that convert dynorphins to shorter opioid peptides have been purified from bovine and human spinal cord (Silberring and Nyberg, 1989; Silberring et al., 1992, 1993). These proteases belong to the cysteine proteases family and cleave dynorphin A and dynorphin B between the Arg6-Arg7 and, to a lesser degree, the Leu5-Arg6 bonds, thus generating [Leu5]enkephalin-Arg6 as a major product and small amounts of Abbreviations: Boc-, tert-butyloxycarbonyl; -Bz, benzoyl. * Corresponding author. Tel./fax: +81 22 727 0123. E-mail address: [email protected] (K. Tan-No). 0143-4179/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.npep.2010.02.001
[Leu5]enkephalin, both of which are primarily active at d-opioid receptors. We have previously shown that p-hydroxymercuribenzoate (PHMB), a general cysteine protease inhibitor, and Boc-TyrGly-NHO-Bz (BYG-Bz), a representative of a novel class of cysteine protease inhibitors, significantly prolong dynorphin-induced antinociception, when co-administered by intrathecal (i.t.) injection with dynorphin A or dynorphin B, in the mouse formalin and capsaicin tests (Tan-No et al., 1996, 2005). This observation indicates that cysteine proteases may be important for terminating dynorphin A- and dynorphin B-induced antinociception. Morphine is an important drug in the clinical treatment of severe pain. However, chronic use of morphine results in the development of antinociceptive tolerance and physical dependence. The development of antinociceptive tolerance and physical dependence on morphine is suppressed by dynorphins (Takemori et al., 1992, 1993; Hooke et al., 1995). Moreover, chronic administration of morphine increases the conversion of dynorphin A to [Leu5]enkephalin-Arg6 in the cerebrospinal fluid of rats (Persson et al., 1989) and also increases dynorphin-converting enzyme
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activity in primary cultures of rat cerebral cortex, which is further elevated by naloxone-precipitated withdrawal (Vlaskovska et al., 1997). We have recently reported that i.t. administration of N-ethylmaleimide and BYG-Bz, both cysteine protease inhibitors, suppresses the development of antinociceptive tolerance to morphine, presumably through the inhibition of dynorphin degradation (Tan-No et al., 2008). Collectively, these observations suggest that the inhibition of cysteine proteases not only suppresses the development of antinociceptive tolerance but also the physical dependence on morphine. In the present study, we examined the effects of intracerebroventricular (i.c.v.) administration of N-ethylmaleimide and BYGBz on the development of physical dependence on morphine by assessing naloxone-precipitated withdrawal jumping, and compared these effects with inhibitors of different proteases.
Day 1 Each agent Morphine (30 mg/kg, s.c.) (i.c.v.)
Each agent (i.c.v.)
Morphine (30 mg/kg, s.c.)
5 min
5 min Day 2 Each agent Morphine (60 mg/kg, s.c.) (i.c.v.)
Each agent (i.c.v.)
Morphine (60 mg/kg, s.c.)
5 min
5 min Day 3 Morphine (60 mg/kg, s.c.)
Naloxone (0.5-8 mg/kg, i.p.)
3 hr Observation (20 or 30 min)
2. Materials and methods
Fig. 1. The experimental protocol for induction and assessment of physical dependence on morphine. Details are described in the Section 2.
2.1. Animals the number of jumps was measured for 20 min with exception of the experiments with a longer observation time.
Experiments were performed using male ddY-strain mice weighing 22–25 g (Japan SLC, Japan) under a 12 h light–dark cycle (light 8:00 a.m.–8:00 p.m.) with constant temperature (23 ± 1 °C) and relative humidity (55 ± 5%). Groups of 10–18 mice were used only once for each experiment. All experiments were performed following the approval of the Ethics Committee for Animal Experiments at Tohoku Pharmaceutical University, and in accordance with the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health.
I.c.v. administration of various drugs was performed 5 min prior to each morphine injection during the induction phase, to determine the effects of these compounds on the development of a physical dependence on morphine (Fig. 1). No treatment was given on the test day.
2.2. Drugs
2.6. Statistics
The following drugs and chemicals were used: dynorphin A, dynorphin B (Bachem, Switzerland), N-ethylmaleimide, captopril, naloxone, trans-(1S, 2S)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl) cyclohexyl] benzenacetamide hydrochloride (( ) U-50,488) (Sigma–Aldrich, USA), amastatin, phosphoramidon (Peptide Institute, Japan), morphine hydrochloride (Sankyo, Japan). BYG-Bz was kindly donated by Dr. Hans-Ulrich Demuth (Probiodrug AG, Biocenter, Halle, Germany). For i.c.v. injections, test compounds were dissolved in Ringer’s solution. Morphine and naloxone were dissolved in saline.
The results are presented as the means and S.E.M. Significant differences between groups were determined by Fisher’s PLSD post hoc test for multiple comparisons after analysis of variance (ANOVA) using the Statview-J5.0 computer program (SAS Institute, USA). In all statistical comparisons, P < 0.05 was used as the criterion for statistical significance.
2.3. Intracerebroventricular injections I.c.v. injections (5 ll) were made directly into the lateral ventricle of unanesthetized mice as described by a previous report (TanNo et al., 2001). 2.4. Induction and assessment of physical dependence on morphine The experimental protocol for induction and assessment of physical dependence on morphine is shown in Fig. 1. For induction of morphine dependence, the doses of morphine were subcutaneously (s.c.) given as pretreatment twice daily (at 9:00 a.m. and 7:00 p.m.) for 2 days (day 1, 30 mg/kg; day 2, 60 mg/kg). The schedule for induction of morphine dependence was decided by referring to our previously published method for induction of antinociceptive tolerance (Tan-No et al., 2008, 2009). On day 3, naloxone-precipitated withdrawal jumping was measured to assess physical dependence on morphine. Namely, naloxone was intraperitoneally administered 3 h after final injection of morphine at a dose of 60 mg/kg. Immediately after naloxone injection, mice were placed in a cylinder (10 cm diameter 50 cm height) and
2.5. Treatment with tested drugs
3. Results 3.1. Naloxone-precipitated withdrawal jumping in morphine-dependent mice Jumping, paw tremor, backward locomotion, sniffing and defecation are known as withdrawal signs and used to assess physical dependence on morphine (Ueda et al., 2000). Because the jumping was remarkable in these signs, only the number of jumps was counted under the environment (using a cylinder of 10 cm diameter) to observe the jumping easily. Time-courses of naloxone-precipitated withdrawal jumping were examined, with results showing that jumping peaked at 0–5 min, and had almost disappeared at 20 min after injection (Fig. 2A). As shown in Fig. 2B, a dose-dependent increase in the total number of jumps was observed following administration of naloxone in doses ranging from 0.5 to 8 mg/kg. Therefore, 8 mg/kg naloxone and a 20 min observation time were used in subsequent experiments to determine the inhibitory potency of various drugs on morphine dependence. 3.2. Effects of dynorphin A, dynorphin B, ( ) U-50,488, N-ethylmaleimide and BYG-Bz on naloxone-precipitated withdrawal jumping in morphine-dependent mice Naloxone-precipitated withdrawal jumping was significantly suppressed by the i.c.v. injection of dynorphin A (62.5 pmol) and
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A
B
30
20
Saline
** **
Number of jumps / 20 min
Number of jumps
40
Naloxone (0.5 mg/kg)
**
*
Naloxone (2.0 mg/kg) Naloxone (8.0 mg/kg)
* *
10
0
90
**
**
2.0
8.0
60
* 30
0 0-5
5-10
10-15
15-20
20-25
25-30
Saline
Time after injection ( min )
0.5
Naloxone (mg/kg)
Number of jumps / 20 min
Fig. 2. Naloxone-precipitated withdrawal jumping in morphine-dependent mice. The doses of morphine (mg/kg, s.c. per injection) were given twice daily for 2 days (day 1, 30; day 2, 60). On day 3, naloxone (0.5–8 mg/kg, i.p.) or saline was administered 3 h after the final injection of morphine at a dose of 60 mg/kg, and the number of jumps was immediately measured. (A) Time-course of jumping. The ordinate shows the total number of jumps that occurred during each 5 min period of measurement. (B) Total number of jumps measured during a 20 min period, beginning immediately after injection of naloxone or saline. The data are given as the means ± S.E.M. for groups of 10 mice. *P < 0.05, **P < 0.01 when compared with saline controls.
60
40
*
*
20
0 31.25
Ringer
62.5
31.25
Dynorphin A ( pmol )
250
1.25
Dynorphin B ( pmol )
5
20
(-)-U-50,488 ( nmol )
Fig. 3. Effects of dynorphin A, dynorphin B and ( ) U-50,488 on naloxone-precipitated withdrawal jumping in morphine-dependent mice. Dynorphin A, dynorphin B, ( ) U50,488 or Ringer’s solution was administered i.c.v. 5 min before each morphine pretreatment during the induction phase, with no administration on the test day. The number of jumps was measured during a 20 min period beginning immediately after injection of naloxone (8 mg/kg, i.p.). The data are given as the means ± S.E.M. for groups of 10–18 mice. *P < 0.05 when compared with Ringer’s solution as controls. For other details see Fig. 2.
B
50
25
*
0
Ringer
0.125
0.25
0.5
N -Ethylmaleimide (nmol)
Number of jumps / 20 min
Number of jumps / 20 min
A
50
25
*
0
Ringer
0.2
0.283
0.4
BYG-Bz (nmol)
Fig. 4. Suppressive effects by N-ethylmaleimide (A) and BYG-Bz (B) on naloxone-precipitated withdrawal jumping in morphine-dependent mice. N-ethylmaleimide, BYG-Bz or Ringer’s solution was administered i.c.v. 5 min before each morphine pretreatment during the induction phase, with no administration on the test day. The number of jumps was measured during a 20 min period beginning immediately after injection of naloxone (8 mg/kg, i.p.). The data are given as the means ± S.E.M. for groups of 18 mice. *P < 0.05 when compared with Ringer’s solution as controls. For other details see Fig. 2.
dynorphin B (250 pmol), but not ( ) U-50,488 (1.25–20 nmol) 5 min before each morphine pretreatment during the induction phase (Fig. 3). Similarly to dynorphin A and dynorphin B, both cys-
teine protease inhibitors N-ethylmaleimide (0.125–0.5 nmol) and BYG-Bz (0.2–0.4 nmol), dose-dependently suppressed naloxoneprecipitated withdrawal jumping (Fig. 4).
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Table 1 Effects of amastatin, phosphoramidon and captopril on naloxone-precipitated withdrawal jumping in morphine-dependent mice. Agents
Number of jumps /20 min
Ringer Amastatin (4 nmol) Phosphoramidon (4 nmol) Captopril (4 nmol)
36.6 ± 6.8 51.6 ± 17.5 23.4 ± 6.0 44.7 ± 9.8
Each agent was administered i.c.v. 5 min before each morphine pretreatment during the induction phase, with no administration on the test day. The number of jumps was measured during a 20 min period beginning immediately after injection of naloxone (8 mg/kg, i.p.). The data are given as the means ± S.E.M. for groups of 10 mice. For other details see Fig. 2.
3.3. Effects of amastatin, phosphoramidon and captopril on naloxoneprecipitated withdrawal jumping in morphine-dependent mice As shown in Table 1, amastatin (4 nmol), an aminopeptidase inhibitor, phosphoramidon (4 nmol), an endopeptidase 24.11 inhibitor, and captopril (4 nmol), an angiotensin-converting enzyme inhibitor, did not affect naloxone-precipitated withdrawal jumping. 4. Discussion Dynorphin-converting enzymes purified from the bovine (Silberring and Nyberg, 1989) and human (Silberring et al., 1992, 1993) spinal cords are cysteine proteases, and cleave dynorphin A and dynorphin B between the Arg6-Arg7 and Leu5-Arg6 bonds, generating [Leu5]enkephalin-Arg6 as the major product and [Leu5]enkephalin. We have previously shown that i.c.v. administration of dynorphin A at a subthreshold dose of 0.5 nmol, in combination with PHMB, produces a significant antinociceptive effect in the mouse formalin test during the second phase (10– 30 min after formalin injection), which is completely antagonized by nor-binaltorphimine, a selective j-opioid receptor antagonist (Tan-No et al., 2001). In other experiments, the degradation of dynorphin A by mouse brain extracts in vitro was markedly inhibited by PHMB and N-ethylmaleimide; whereas captopril, phosphoramidon or bestatin, an aminopeptidase inhibitor, had no effect (Tan-No et al., 2001). These findings indicate that dynorphin-converting enzymes may be important proteases responsible for the degradation of dynorphins, thereby causing a modulation of their functions in the brain. On the other hand, treatment with morphine (10 lM) for 5 days results in a 360% increase in the generation of [Leu5]enkephalin-Arg6 from dynorphin B by rat brain cortical cells in primary culture. This is inhibited by PHMB and N-ethylmaleimide, thus indicating that chronic treatment with morphine markedly increases dynorphin-converting enzyme activity (Vlaskovska et al., 1997). Moreover, acute treatment of cells previously exposed chronically to morphine with 50 mM naloxone elevates dynorphin-converting enzyme activity by 540% (Vlaskovska et al., 1997). We have recently reported that in addition to dynorphin A, dynorphin B and ( ) U-50,488, i.t. administration of N-ethylmaleimide and BYG-Bz 5 min before each morphine pretreatment during the induction phase suppresses the development of tolerance to morphine antinociception in the formalin test, and that the suppressive effect of cysteine protease inhibitors is mediated presumably through the inhibition of the endogenous dynorphin degradation (Tan-No et al., 2008). These reports lead us to the anticipation that cysteine protease inhibitors not only suppress the development of antinociceptive tolerance but also the physical dependence on morphine. In the present study, i.c.v. administration of N-ethylmaleimide (0.5 nmol) and BYG-Bz (0.4 nmol), 5 min before each morphine pretreatment in the induction phase, significantly sup-
pressed naloxone-precipitated withdrawal jumping in morphinedependent mice, with nearly the same efficacy as dynorphin A (62.5 pmol) and dynorphin B (250 pmol). In contrast, ( ) U50,488 had no effect on naloxone-precipitated withdrawal jumping, which is distinct from that of inducing antinociceptive tolerance (Tan-No et al., 2008). It is known that j-opioid receptors can be classified into at least three subtypes, i.e. j1-, j2- and j3-opioid receptor subtypes (Zukin et al., 1988; Clark et al., 1989; Meng et al., 1993; Pan et al., 1995). Dynorphins bind to all j-opioid receptor subtypes, whereas U-50,488H has a high affinity for j1-opioid receptors (Clark et al., 1989). Furthermore, the possibility has been indicated that although a novel j-opioid receptor agonist 17-cyclopropylmethyl-3,14b-dihydroxy-4,5a-epoxy-6b[N-methyl-trans-3-(3-furyl) acrylamido]morphinan hydrochloride (TRK-820) exhibits high potency and high selectivity for j-opioid receptors, the affinity of this compound for j-opioid receptor subtypes may be different from that of U-50,488H (Nagase et al., 1998). Tsuji et al. (2000) have previously reported that co-administration of TRK-820, but not U-50,488H, during chronic morphine treatment suppresses naloxone-precipitated withdrawal signs including jumping, suggesting that TRK-820 may suppress the development of physical dependence on morphine via the activation of j2- and/or j3-opioid receptor subtypes. Therefore, it is possible that N-ethylmaleimide and BYG-Bz suppress the development of physical dependence on morphine through an inhibition of dynorphin degradation, by decreasing the elevated dynorphin-converting enzyme activity, which subsequently activates j2- and/or j3-opioid receptor subtypes. On the other hand, no further suppression of naloxone-precipitated withdrawal jumping in morphine-dependent mice was observed at higher dose of dynorphin A (125 pmol), dynorphin B (500 pmol), N-ethylmaleimide (1 nmol) and BYG-Bz (1 nmol) (data not shown). It is well known that the other agents such as NMDA receptor antagonists (for a review, see Noda and Nabeshima, 2004) and nociceptin/orphanin FQ receptor antagonist (Ueda et al., 2000) also suppress naloxone-precipitated withdrawal jumping. Therefore, it seems that dynorphins and cysteine protease inhibitors were not able to completely suppress naloxone-precipitated withdrawal jumping. This is due to the fact that not only dynorphin system regulation but also other systems including NMDA receptor and nociceptin/orphanin FQ system are involved in physical dependence on morphine. I.c.v. administration of amastatin, phosphoramidon and captopril 5 min before each morphine pretreatment during the induction phase, did not suppress naloxone-precipitated withdrawal jumping in the morphine-dependent mice. In contrast to our results, it has been reported that i.c.v. administration of thiorphan, an endopeptidase 24.11 inhibitor, kelatorphan and R-3-(N-hydroxycarboxamido-2-benzylpropanoyl)-L-phenylalanine (RB38A), the complete inhibitors of enkephalin metabolism, 30 min before naloxone injection, with no administration in the induction phase, reduces withdrawal symptoms including jumping in morphine-dependent rats (Maldonado et al., 1989). This indicates that aminopeptidases, endopeptidase 24.11 and angiotensin-converting enzyme in the mouse brain are not involved in the induction of physical dependence on morphine, but are involved in the expression of physical dependence. In conclusion, the present study suggests that cysteine protease inhibitors suppress naloxone-precipitated withdrawal jumping, presumably through an inhibition of dynorphin degradation. Acknowledgements The authors wish to thank Dr. Hans-Ulrich Demuth (Probiodrug AG, Biocenter, Halle, Germany) for providing BYG-Bz. This study was supported in part by a Grant-in-Aid for Scientific Research
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