| Project/Area Number |
15590237
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
General pharmacology
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| Research Institution | Hoshi University |
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Principal Investigator |
MINORU Narita Hoshi University, Department of Toxicology, assistant professor, 薬品毒性学教室, 助教授 (40318613)
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| Project Period (FY) |
2003 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥2,800,000 (Direct Cost: ¥2,800,000)
Fiscal Year 2004: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2003: ¥1,400,000 (Direct Cost: ¥1,400,000)
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| Keywords | neuropharhic pain / psychological dependence / mesolimbic dopamine neuron / morphine / μ-opioid receptor / ventral tegmental area / signal transduction / emotion / μ受容体 / 中脳辺縁ドパミン神経系 / 機能低下 / 可塑性 |
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| Research Abstract |
Recent clinical studies have demonstrated that when morphine is used to control pain, psychological dependence is not a major concern. Here, I confirmed that sciatic nerve ligation suppress the morphine-induced rewarding effect in rodents accompanied with the inhibition of dopamine(DA) release in the nucleus accumbens. The present study was then undertaken to investigate whether a neuropathic pain induced by sciatic nerve ligation could change the activities of the extracellular signal-regulated kinase(ERK) and p38 in the ventral tegmental area(VTA), and these changes could directly affect the development of the morphine-induced rewarding effect in mice. I demonstrated that nerve injury produced a sustained and significant reduction in protein levels of phosphorylated-ERK and -p38 in cytosolic fractions of the mouse lower midbrain. The inhibition of ERK activity by i.c.v.pretreatment with a selective inhibitor of MEK suppressed the morphine-induced place preference, whereas i.c.v.treatment with a specific inhibitor of p38 did not affect the morphine-induced rewarding effect. Immunohistochemical study showed a drastic reduction in phosphorylated-ERK immunoreactivity within tyrosine hydroxylase-positive cells of the VTA in sciatic nerve-ligated mice. In addition, the increased guanosine-5'-o-(3-[^<35>S]thio) triphosphate ([^<35>S]GTPγS) binding to membranes of the VTA induced by either morphine or a selective MOR agonist was significantly attenuated in nerve-ligated rats as compared to that observed in sham-operated rats.
These findings provide direct evidence that the decrease in the morphine-induced DA release in the N.Acc with the reduction in MOR function in the VTA and the persistent decrease in ERK activity of DAnergic neurons in the VTA may contribute to the suppression of the morphine-induced rewarding effect under a neuropathic pain-like state.
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