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.