Inhibition of the morphine-induced rewarding effect by direct activation of spinal protein kinase C in mice.
BACKGROUND
We previously demonstrated that the morphine-induced rewarding effect was attenuated under a neuropathic pain-like state following partial sciatic nerve ligation in rodents. Furthermore, the up-regulation of protein kinase C (PKC) activity in the spinal cord is considered to be the key factor for induction of hyperalgesia following sciatic nerve ligation. However, little direct evidence is available for the involvement of activated PKC in the spinal cord in reduction of rewarding effects induced by morphine under chronic pain-like state.


OBJECTIVE
The present study was to investigate whether direct activation of spinal PKC by intrathecal (IT) administration of a specific PKC activator, phorbol 12,13-dibutyrate (PDBu) could produce hyperalgesia and suppress the place preference induced by morphine in mice.


METHODS
The morphine-induced rewarding effect was investigated using the conditioned place preference method. Conditioning sessions (three for morphine, three for saline) were started 24 h after IT injection of PDBu or saline and conducted once daily for 6 days. On the day after the final conditioning session, a post-conditioning test was performed.


RESULTS
IT-administered PDBu produced a long-lasting thermal hyperalgesia. Under these conditions, the place preference induced by morphine was abolished by a single IT pretreatment with PDBu. The effect was reversed by concomitant IT treatment with the specific PKC inhibitor Ro-32-0432. In contrast, IT-administered PDBu failed to affect the hyperlocomotion and supraspinal antinociception induced by morphine.


CONCLUSIONS
The present findings suggest that activated PKC in the spinal cord with chronic pain-like hyperalgesia may play a substantial role in the suppression of the morphine-induced rewarding effect in mice with chronic pain-like hyperalgesia.
Oe
Kousei
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
Imai
Satoshi
S
Shibasaki
Masahiro
M
Kubota
Chiharu
C
Kasukawa
Akiko
A
Hamaguchi
Mami
M
Yajima
Yoshinori
Y
Yamazaki
Mitsuaki
M
Suzuki
Tsutomu
T
D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009020:Morphine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D011493:Protein Kinase C / Q000378:metabolism*; D012201:Reward; D013116:Spinal Cord / Q000187:drug effects* / Q000201:enzymology*
D009020:Morphine; D011493:Protein Kinase C