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Role of extracellular signal‐regulated kinase in the ventral tegmental area in the suppression of the morphine‐induced rewarding effect in mice with sciatic nerve ligation
Author(s) -
Ozaki Satoru,
Narita Minoru,
Narita Michiko,
Ozaki Masahiko,
Khotib Junaidi,
Suzuki Tsutomu
Publication year - 2004
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2003.02272.x
Subject(s) - ventral tegmental area , sciatic nerve , conditioned place preference , sciatic nerve injury , morphine , neuropathic pain , mapk/erk pathway , pharmacology , endocrinology , tyrosine hydroxylase , medicine , chemistry , neuroscience , anesthesia , phosphorylation , dopamine , dopaminergic , biology , biochemistry
We recently reported that μ‐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.