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ABSTRACT: In the present study, we demonstrated whether a neuropathic pain-like state induced by sciatic nerve ligation in rodents could cause a long-lasting change in intracellular signaling in both supraspinal and spinal cord related to the suppression of morphine's effect. Mice with sciatic nerve ligation exhibited a significant suppression of the morphine-induced antinociception. Under this condition, phosphorylated-conventional protein kinase C-like immunoreactivity (p-cPKC-IR) and phosphorylated-micro-opioid receptor (p-MOR)-IR were clearly increased on the ipsilateral side in the dorsal horn of the spinal cord of nerve-ligated mice. It is of interest to note that astroglial hypertrophy as well as its proliferation was also noted in this area of sciatic nerve-ligated mice. Like nerve injury, the increase in cPKC activities and astroglial hypertrophy/proliferation in this region was observed by repeated morphine treatment. These findings suggest that the phosphorylation of both cPKC and MOR in the dorsal horn of the spinal cord by sciatic nerve ligation may play a substantial role in the suppression of morphine-induced antinociception under a neuropathic pain-like state. Sciatic nerve injury also caused a significant inhibition of MOR-mediated G-protein activation onto GABAergic neurons and a dramatic reduction in ERK activities onto dopaminergic neurons in the ventral tegmental area (VTA) regulating the rewarding effect of opioids. Furthermore, we found that the inhibition of ERK cascade in the VTA by treatment with specific inhibitors suppressed the morphine-induced rewarding effect in normal mice. These findings provide evidence that the direct reduction in MOR function and the persistent decrease in ERK activity of dopaminergic neurons in the VTA may contribute to the suppression of the morphine-induced rewarding effect under a neuropathic pain-like state. Conclusively, our recent findings provide novel evidences for the mechanism underlying the less sensitivity to opioids under a neuropathic pain-like state.
Life Sciences 05/2004; 74(21):2655-73. · 2.53 Impact Factor
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ABSTRACT: We recently reported that micro-opioid receptor agonist morphine failed to induce its rewarding effects in rodents with sciatic nerve injury. In the present study, we investigated whether a state of neuropathic pain induced by sciatic nerve ligation could change the activities of the extracellular signal-regulated kinase (ERK) and p38 in the mouse lower midbrain area including the ventral tegmental area (VTA), and these changes could directly affect the development of the morphine-induced rewarding effect in mice. The sciatic nerve ligation caused a long-lasting and profound thermal hyperalgesia. A dose-dependent place preference induced by s.c. administration of morphine was observed in sham-operated mice, but not in sciatic nerve-ligated mice. We found here for the first time that nerve injury produces a sustained and significant reduction in protein levels of phosphorylated-ERK and -p38 in cytosolic preparations of the mouse lower midbrain. The inhibition of ERK activity by i.c.v. pre-treatment with either PD98059 or U0126 impaired the morphine-induced place preference. In contrast, i.c.v. treatment with a specific inhibitor of p38, SB203580, did not interfere with the morphine-induced rewarding effect. Immunohistochemical study showed a drastic reduction in phosphorylated-ERK immunoreactivity within tyrosine hydroxylase-positive cells of the VTA. These results suggest that a sustained reduction in the ERK-dependent signalling pathway in dopamine cells of the VTA may be implicated in the suppression of the morphine-induced rewarding effect under neuropathic pain.
Journal of Neurochemistry 04/2004; 88(6):1389-97. · 4.06 Impact Factor
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ABSTRACT: A novel mu-opioid receptor (MOR) subtype, named MOR-1B, derived from alternatively spliced variants of MOR gene, has been isolated from the rat brain. Here we found for the first time that CXBK recombinant-inbred mice display a significant reduction in the expression of MOR-1B mRNA in the brain as compared to that in their progenitor C57BL/6 mice. In contrast, the expression level of MOR-1 mRNA in the brain of CXBK mice was similar to that found in C57BL/6 mice. Furthermore, relatively lower levels of MOR-1B immunoreactivity were detected in the periaqueductal grey matter (PAG) of CXBK mice than that observed in C57BL/6 mice. To investigate further the possible changes in MOR function to activate G-proteins under the condition of a reduced MOR-1B expression, the guanosine-5'-o-(3-[35S]thio)triphosphate ([35S]GTPgammaS) binding assay was performed. We found that the increased level of [35S]GTPgammaS bindings to whole brain membranes induced by a selective MOR agonist endomorphin-1 was significantly decreased in CXBK mice, indicating that CXBK strain can be classified as MOR-1B-knockdown mice. We next investigated whether intracerebroventricular (i.c.v.) pretreatment with an antisence oligodeoxynucleotide against exon 5 of MOR gene (MOR-1B) could affect the endomorphin-1-induced supraspinal antinociception. The i.c.v. pretreatment with antisence oligodeoxynucleotide against MOR-1B produced a significant reduction in the i.c.v.-administered endomorphin-1-induced antinociceptive effect. The present data provide first evidence that a lack of MOR-1B expression may, at least in part, contribute to the reduced sensitivity to MOR agonists in CXBK mice, and MOR-1B may play a potential role in the MOR-mediated supraspinal antinociception.
European Journal of Neuroscience 01/2004; 18(12):3193-8. · 3.63 Impact Factor
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ABSTRACT: A little or none is known about the direct evidence for the possible change in the expression of c-fos at the supraspinal level after nerve injury. Therefore, the present study was designed to investigate the level of c-fos in some brain regions following sciatic nerve ligation in the rat. Immunoblot analysis clearly showed that the levels of c-fos in the rat frontal cortex, thalamus and periaqueductal gray matter were significantly increased, whereas it was significantly decreased in the nucleus accumbens and ventral tegmental area. Under these conditions, the levels of c-fos in the rat amygdala, hippocampus and hypothalamus were not changed. These results provide direct evidence that the neuropathic pain-like state causes a substantial change in the expression of c-fos in the rat brain.
Neuroscience Letters 01/2004; 352(3):231-3. · 2.11 Impact Factor
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ABSTRACT: The present study was designed to investigate the possible change in spinal micro -opioid receptor function after repeated administration of a selective kappa-opioid receptor agonist (1S-trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl) cyclohexyl]-benzeneacetamide hydrochloride [(-)U-50,488H] in the ICR mouse. A single s.c. or i.t. injection of (-)U-50,488H produced a dose-dependent antinociception. Repeated s.c. or i.t. administration of (-)U-50,488H resulted in the development of tolerance to (-)U-50,488H-induced antinociception. Under these conditions, we demonstrated here that repeated s.c. injection of (-)U-50,488H significantly enhanced the antinociceptive effect induced by the i.t. administration of a selective micro -opioid receptor agonist [d-Ala2,N-Me-Phe4,Gly5-ol] enkephalin (DAMGO). Using the guanosine-5'-o-(3-[35S]thio) triphosphate ([35S]GTPgammaS) binding assay, we found that (-)U-50,488H was able to produce a dose-dependent increase in [35S]GTPgammaS binding to membranes of the mouse spinal cord. Repeated administration of (-)U-50,488H caused a significant reduction in the (-)U-50,488H-stimulated [35S]GTPgammaS binding in this region, whereas repeated treatment with (-)U-50,488H exhibited an increase in the DAMGO-stimulated [35S]GTPgammaS binding in membranes of the spinal cord. Using a receptor binding assay, repeated treatment with (-)U-50,488H significantly increased the density of [3H]DAMGO binding sites in membranes of the mouse spinal cord. In contrast, the expression of micro -opioid receptor was not affected after repeated treatment with (-)U-50,488H. These results suggest that repeated stimulation of kappa-opioid receptors leads to the up-regulation of micro -opioid receptor functions in the spinal cord, which may be associated with an increase in the number of functional micro -opioid receptors in the mouse spinal cord.
European Journal of Neuroscience 12/2003; 18(9):2498-504. · 3.63 Impact Factor
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ABSTRACT: The present study was designed to investigate the effect of repeated administration of a selective kappa-opioid receptor agonist (1S-trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-benzeneacetamide hydrochloride [(-)U-50,488H] on antinociception and G-protein activation induced by mu-opioid receptor agonists in mice. A single s.c. injection of (-)U-50,488H produced a dose-dependent antinociception, and this effect was reversed by a selective kappa-opioid receptor antagonist nor-binaltorphimine (nor-BNI). Furthermore, a single s.c. pre-treatment with (-)U-50,488H had no effect on the mu-opioid receptor agonist-induced antinociception. In contrast, repeated s.c. administration of (-)U-50,488H resulted in the development of tolerance to (-)U-50,488H-induced antinociception. Under these conditions, we demonstrated here that repeated s.c. injection of (-)U-50,488H significantly enhanced the antinociceptive effect of selective mu-opioid receptor agonists endomorphin-1, endomorphin-2 and [d-Ala2,N-MePhe4,Gly-ol5] enkephalin (DAMGO). Using the guanosine-5'-o-(3-[35S]thio) triphosphate ([35S]GTP gamma S) binding assay, we found that (-)U-50,488H was able to produce a nor-BNI-reversible increase in [35S]GTP gamma S binding to membranes of the mouse thalamus, which has a high level of kappa-opioid receptors. Repeated administration of (-)U-50,488H caused a significant reduction in the (-)U-50,488H-stimulated [35S]GTP gamma S binding in this region, whereas chronic treatment with (-)U-50,488H exhibited the increase in the endomorphin-1-, endomorphin-2- and DAMGO-stimulated [35S]GTP gamma S bindings in membranes of the thalamus and periaqueductal gray. These results suggest that repeated stimulation of kappa-opioid receptors leads to the heterologous up-regulation of mu-opioid receptor functions in the thalamus and periaqueductal gray regions, which may be associated with the supersensitivity of mu-opioid receptor-mediated antinociception.
Journal of Neurochemistry 07/2003; 85(5):1171-9. · 4.06 Impact Factor
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ABSTRACT: The aim of the present study was to investigate whether mice with a deletion of the gene that encodes the protein kinase C gamma (PKC gamma) isoform could affect the G-protein activation mediated through the opioid receptor-like (ORL-1) receptor and mu-opioid receptor in the mouse pons/medulla and spinal cord, monitoring the guanosine-5'-o-(3-[(35)S]thio) triphosphate ([(35)S]GTP gamma S) binding assay. The increases in [(35)S]GTP gamma S bindings to pons/medulla membranes of the wild-type mice induced by either an endogenous ligand for the ORL-1 receptor, nociceptin or a selective mu-opioid receptor agonist [D-Ala(2),N-MePhe(4),Gly-ol(5)]enkephalin were significantly enhanced in PKC gamma knockout mice. In contrast, the levels of [(35)S]GTP gamma S binding stimulated by nociceptin in spinal cord membranes obtained from PKC gamma knockout mice were similar to those from wild-type mice. These findings suggest that the loss of the PKC gamma gene may protect the functional ORL-1 and mu-opioid receptors from degradation by phosphorylation in the mouse pons/medulla. Furthermore, the present data provide first evidence for the differential mechanism of the ORL-1 receptor-mediated signaling between the supraspinal and spinal sites.
Neuroscience Letters 11/2002; 331(1):5-8. · 2.11 Impact Factor
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ABSTRACT: The present study was designed to investigate the rewarding effect, G-protein activation and dopamine (DA) release following partial sciatic nerve ligation in the rat. Here we show for the first time that morphine failed to produce a place preference in rats with nerve injury. Various studies provide arguments to support that the mesolimbic dopaminergic system, which projects from the ventral tegmental area (VTA) to the nucleus accumbens (N.Acc), is critical of the motivational effects of opioids. In the present study, there were no significant differences between sham-operated and sciatic nerve-ligated rats in the increases in guanosine-5'-o-(3-[35S]thio)triphosphate ([35S]GTPgammaS) binding to membranes of the N.Acc stimulated by either DA, the D1 receptor agonist SKF81297, the D2 receptor agonist N-propylnoraporphine or the D3 receptor agonist 7-hydroxy-2-dipropylaminotetralin (7-OH DPAT). In contrast, the increases in [35S]GTPgammaS binding to membranes of the VTA induced by either morphine or a selective micro -opioid receptor agonist [d-Ala2, NMePhe4, Gly(ol)5]enkephalin were significantly attenuated in nerve-ligated rats as compared with sham- operated rats. Furthermore, the enhancement of DA release in the N.Acc stimulated by morphine was significantly suppressed by sciatic nerve ligation. These findings suggest that attenuation of the morphine-induced place preference under neuropathic pain may result from a decrease in the morphine-induced DA release in the N.Acc with reduction in the mu-opioid receptor-mediated G-protein activation in the VTA.
Journal of Neurochemistry 10/2002; 82(5):1192-8. · 4.06 Impact Factor
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ABSTRACT: The newly discovered endogenous mu-opioid receptor (MOP-R) ligands endomorphin-1 (EM-1) and -2 (EM-2) exhibit the highest specificity and affinity for the MOP-R of any endogenous substance so far described in the mammalian nervous system. This review focuses on differential mechanism of the motivational effects induced by EM-1 and EM-2. In the [35S]GTPgammaS binding assay, either EM-1 or EM-2 causes a concentration-dependent G-protein activation in brain membrane of normal mice, whereas neither EM-1 nor EM-2 produces any activation of G-protein in membranes obtained from the MOP-R knockout mice. These results provide direct evidence at the molecular level that both EMs act on the MOP-R as the endogenous MOP-R agonists. Based on the conditioned place preference paradigm in mice, EM-1 given intracerebroventriculally produced a dose-related place preference. This effect was abolished by pretreatment with the MOP-R antagonist beta-funaltrexamine (FNA) but not the delta-opioid receptor (DOP-R) antagonist naltrindole and the kappa-opioid receptor (KOP-R) antagonist nor-bialtorphimine (BNI). Unlike EM-1, EM-2 exhibited a place aversion. The aversive effect was inhibited by not only beta-FNA but also nor-BNI. Place aversion produced by EM-2 was also attenuated by pretreatment with an antiserum against an endogenous KOP-R ligand dynorphin A(1-17). These findings indicate that EM-1 may produce its rewarding effect via MOP-Rs. Furthermore, the aversive effect induced by EM-2 may be associated with the stimulation of the EM-1-insensitive MOP-R subtype and necessarily activate an endogenous KOPergic system in the mouse brain.
The Japanese Journal of Pharmacology 08/2002; 89(3):224-8.
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ABSTRACT: Partial nerve injury induced by tying a tight ligature around the sciatic nerve induced a marked hyperalgesia, and this persistent painful state lasted for 14 days in mice. Under these conditions, the nerve injury induced a significant increase in protein level of protein kinase Cγ isoform in plasma membranes in the spinal cord. We report here for the first time that protein level of TrkB receptor located in plasma membranes was clearly up-regulated in the spinal cord obtained from the nerve-injured mice. These findings suggest that the up-regulation of protein kinase Cγ associated with activated TrkB receptors following partial sciatic nerve ligation may induce sensitization of synaptic transmission and may in turn cause the persistent pain in mice.
European Journal of Pharmacology.
