Involvement of kappa opioid receptors in the formalin-induced inhibition of analgesic tolerance to morphine via suppression of conventional protein kinase C activation.
OBJECTIVE
Repeated morphine treatment results in a decreased analgesic effect or the development of analgesic tolerance. However, we reported that some inflammatory chronic pain may inhibit morphine tolerance via kappa opioid receptor (KOR) activation. In this study, we further investigated the role of KOR in the inhibition of morphine tolerance in a chronic pain condition with a focus on the regulation of protein kinase C (PKC) activity.


METHODS
Chronic pain was induced by formalin treatment into the dorsal part of the left hind paws of mice. The analgesic effect of morphine was measured by the tail flick method. We analysed the protein expression of PKC and its activity, and G-protein activity of mu opioid receptor (MOR) under repeated morphine treatment with or without formalin treatment.


RESULTS
We found that conventional subtypes of PKC (cPKC) were up-regulated by repeated morphine treatment. Also, antisense oligonucleotide (AS-ODN) targeting cPKC completely suppressed the development of morphine tolerance. The disappearance of the repeated morphine-induced up-regulation of cPKC was completely reversed by treatment with AS-ODN targeting KOR. In addition, AS-ODN targeting KOR significantly reversed the chronic pain-induced down-regulation of PKC activity or up-regulation of MOR [(35)S]GTPgammaS binding activity after repeated morphine treatment.


CONCLUSIONS
These results indicate that KOR plays an important role in the inhibition of repeated morphine-induced cPKC up-regulation under chronic pain condition. Furthermore, this may result in the increase of MOR activity and in the inhibition of morphine tolerance under chronic pain condition.
Fujita-Hamabe
Wakako
W
Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Kobe, Japan.
Nagae
Ryuji
R
Nawa
Ayaka
A
Harada
Shinichi
S
Nakamoto
Kazuo
K
Tokuyama
Shogo
S
D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000201:enzymology; D002908:Chronic Disease; D004195:Disease Models, Animal; D015536:Down-Regulation; D004361:Drug Tolerance; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000378:metabolism; D004789:Enzyme Activation; D005557:Formaldehyde; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D008297:Male; D051379:Mice; D009020:Morphine / Q000494:pharmacology*; D009281:Naphthalenes / Q000494:pharmacology; D016376:Oligonucleotides, Antisense / Q000378:metabolism; D010146:Pain / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control*; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects*; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017473:Receptors, Opioid, kappa / Q000187:drug effects* / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors
D000701:Analgesics, Opioid; D009281:Naphthalenes; D016376:Oligonucleotides, Antisense; D047428:Protein Kinase Inhibitors; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D005557:Formaldehyde; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D009020:Morphine; D011493:Protein Kinase C; C058819:calphostin C