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.
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.
Department of Toxicology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Shinagawa-ku, Tokyo, Japan.
Satoru
S
Ozaki
Minoru
M
Narita
Michiko
M
Narita
Masahiko
M
Ozaki
Junaidi
J
Khotib
Tsutomu
T
Suzuki
D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D003600:Cytosol / Q000201:enzymology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006930:Hyperalgesia / Q000188:drug therapy / Q000201:enzymology / Q000209:etiology; D008026:Ligation; D008297:Male; D008636:Mesencephalon / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D008813:Mice, Inbred ICR; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009020:Morphine / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000201:enzymology; D010766:Phosphorylation; D017450:Receptors, Opioid, mu / Q000819:agonists; D012201:Reward; D020426:Sciatic Neuropathy / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013037:Spatial Behavior / Q000187:drug effects; D014446:Tyrosine 3-Monooxygenase / Q000096:biosynthesis; D017557:Ventral Tegmental Area / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D048051:p38 Mitogen-Activated Protein Kinases
D000701:Analgesics, Opioid; D004791:Enzyme Inhibitors; D017450:Receptors, Opioid, mu; D009020:Morphine; D014446:Tyrosine 3-Monooxygenase; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases