Implication of endogenous beta-endorphin in the inhibition of the morphine-induced rewarding effect by the direct activation of spinal protein kinase C in mice.
It has often been proposed that opioid addiction does not arise as a consequence of opioid treatment for pain. Recently, we demonstrated that activated protein kinase C (PKC) in the spinal cord associated with chronic pain-like hyperalgesia suppressed the morphine-induced rewarding effect in mice. In the present study, we investigated whether a gene deletion for an endogenous mu-opioid peptide beta-endorphin could affect pain-like behavior and the suppression of the morphine-induced rewarding effect by the direct activation of PKC in the spinal cord. We found that activation of spinal PKC by intrathecal (i.t.) treatment with phorbol 12,13-dibutyrate (PDBu), a specific PKC activator, caused thermal hyperalgesia, pain-like behaviors and suppression of the morphine-induced rewarding effect. This suppression of morphine reward was eliminated in mice that lacked beta-endorphin. In contrast, thermal hyperalgesia and pain-like behaviors were not affected in beta-endorphin knockout mice. These results suggest that the activation of PKC in the spinal cord may play an essential role in the suppression of the morphine-induced rewarding effect in mice with neuropathic pain through the constant release of beta-endorphin.
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
Okutsu
Daiki
D
Tsurukawa
Yuri
Y
Nanjo
Kana
K
Kurahashi
Kana
K
Kobayashi
Yasuhisa
Y
Suzuki
Tsutomu
T
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D004789:Enzyme Activation / Q000235:genetics; D020536:Enzyme Activators / Q000494:pharmacology; D005260:Female; D006930:Hyperalgesia / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009020:Morphine / Q000494:pharmacology; D009021:Morphine Dependence / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D009294:Narcotics / Q000494:pharmacology; D009433:Neural Inhibition / Q000187:drug effects / Q000235:genetics; D010146:Pain / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D011493:Protein Kinase C / Q000378:metabolism*; D012201:Reward; D013116:Spinal Cord / Q000187:drug effects* / Q000201:enzymology; D001615:beta-Endorphin / Q000235:genetics*
D020536:Enzyme Activators; D009294:Narcotics; D001615:beta-Endorphin; D009020:Morphine; D011493:Protein Kinase C