Functional reduction in mu-opioidergic system in the spinal cord under a neuropathic pain-like state following chronic ethanol consumption in the rat.
Chronic ethanol consumption produces a painful peripheral neuropathy. The aim of this study was then to investigate the mechanism underlying the neuropathic pain-like state induced by chronic ethanol treatment in rats. Mechanical hyperalgesia was clearly observed during ethanol consumption and even after ethanol withdrawal, and it lasted for, at least, 14 weeks. At 24 days after ethanol withdrawal, antinociception of morphine was significantly suppressed and the increased guanosine-5'-o-(3-thio) triphosphate ([(35)S]GTPgammaS) binding to membranes of the spinal cord induced by the selective mu-opioid receptor (MOR) agonist, [D-Ala(2),N-MePhe(4),Gly(5)-ol]enkephalin (DAMGO), was significantly decreased under the ethanol-dependent neuropathic pain-like state, whereas the increased [(35)S]GTPgammaS binding to membranes of the spinal cord induced by either the selective delta-opioid receptor (DOR) agonist or kappa-opioid receptor (KOR) agonist was not changed under the ethanol-dependent neuropathic pain-like state. Furthermore, total-MOR immunoreactivity was not changed in the spinal cord of ethanol-fed rats. Under these conditions, immunoblotting showed a robust increase in phosphorylated-cPKC immunoreactivity (p-cPKC-IR) in the spinal cord from chronic ethanol fed-rats, whereas phosphorylated-protein kinase A (PKA), dynamin II and G protein-coupled receptor kinase 2 (GRK2) were not affected in the spinal cord of ethanol-fed rats. These findings suggest that the dysfunction of MOR, but not DOR and KOR, linked to cPKC activation in the spinal cord may be, at least in part, involved in the reduced sensitivity to antinociception induced by morphine under the ethanol-dependent neuropathic pain-like state.
Narita
M
M
Department of Toxicology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan. narita@hoshi.ac.jp
Miyoshi
K
K
Narita
M
M
Suzuki
T
T
D020268:Alcohol-Induced Disorders, Nervous System / Q000378:metabolism* / Q000503:physiopathology; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D002492:Central Nervous System Depressants / Q000009:adverse effects; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D000431:Ethanol / Q000009:adverse effects; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006930:Hyperalgesia / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D009020:Morphine / Q000494:pharmacology; D009437:Neuralgia / Q000378:metabolism / Q000503:physiopathology; D018847:Opioid Peptides / Q000378:metabolism*; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000378:metabolism* / Q000503:physiopathology; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D013116:Spinal Cord / Q000378:metabolism* / Q000503:physiopathology
D000701:Analgesics, Opioid; D002492:Central Nervous System Depressants; D018847:Opioid Peptides; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D000431:Ethanol; D009020:Morphine; D011493:Protein Kinase C