Direct evidence for the involvement of endogenous beta-endorphin in the suppression of the morphine-induced rewarding effect under a neuropathic pain-like state.
Recent clinical studies have demonstrated that when opioids are used to control pain, psychological dependence is not a major problem. In this study, we further investigated the mechanisms that underlie the suppression of opioid reward under neuropathic pain in rodents. Sciatic nerve ligation suppressed a place preference induced by the selective mu-opioid receptor agonist [d-Ala(2), N-MePhe(4), Gly-ol(5)] enkephalin (DAMGO) and reduced both the increase in the level of extracellular dopamine by s.c. morphine in the nucleus accumbens and guanosine-5'-o-(3-[(35)S]thio) triphosphate ([(35)S]GTPgammaS) binding to membranes of the ventral tegmental area (VTA) induced by DAMGO. These effects were eliminated in mice that lacked the beta-endorphin gene. Furthermore, intra-VTA injection of a specific antibody to the endogenous mu-opioid peptide beta-endorphin reversed the suppression of the DAMGO-induced rewarding effect by sciatic nerve ligation in rats. These results provide molecular evidence that nerve injury results in the continuous release of endogenous beta-endorphin to cause the dysfunction of mu-opioid receptors in the VTA. This phenomenon could explain the mechanism that underlies the suppression of opioid reward under a neuropathic pain-like state.
Niikura
Keiichi
K
Department of Toxicology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.
Narita
Minoru
M
Narita
Michiko
M
Nakamura
Atsushi
A
Okutsu
Daiki
D
Ozeki
Ayumi
A
Kurahashi
Kana
K
Kobayashi
Yasuhisa
Y
Suzuki
Masami
M
Suzuki
Tsutomu
T
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003216:Conditioning, Operant / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000627:therapeutic use; D005260:Female; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009020:Morphine / Q000008:administration & dosage*; D009294:Narcotics / Q000008:administration & dosage*; D010147:Pain Measurement; D011485:Protein Binding / Q000187:drug effects; D011930:Reaction Time / Q000187:drug effects; D012201:Reward; D012585:Sciatica / Q000188:drug therapy* / Q000235:genetics / Q000523:psychology*; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D001615:beta-Endorphin / Q000172:deficiency / Q000502:physiology*
D009294:Narcotics; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D001615:beta-Endorphin; D009020:Morphine; D014446:Tyrosine 3-Monooxygenase