Direct evidence for the up-regulation of spinal micro-opioid receptor function after repeated stimulation of kappa-opioid receptors in the mouse.
The present study was designed to investigate the possible change in spinal micro -opioid receptor function after repeated administration of a selective kappa-opioid receptor agonist (1S-trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl) cyclohexyl]-benzeneacetamide hydrochloride [(-)U-50,488H] in the ICR mouse. A single s.c. or i.t. injection of (-)U-50,488H produced a dose-dependent antinociception. Repeated s.c. or i.t. administration of (-)U-50,488H resulted in the development of tolerance to (-)U-50,488H-induced antinociception. Under these conditions, we demonstrated here that repeated s.c. injection of (-)U-50,488H significantly enhanced the antinociceptive effect induced by the i.t. administration of a selective micro -opioid receptor agonist [d-Ala2,N-Me-Phe4,Gly5-ol] enkephalin (DAMGO). Using the guanosine-5'-o-(3-[35S]thio) triphosphate ([35S]GTPgammaS) binding assay, we found that (-)U-50,488H was able to produce a dose-dependent increase in [35S]GTPgammaS binding to membranes of the mouse spinal cord. Repeated administration of (-)U-50,488H caused a significant reduction in the (-)U-50,488H-stimulated [35S]GTPgammaS binding in this region, whereas repeated treatment with (-)U-50,488H exhibited an increase in the DAMGO-stimulated [35S]GTPgammaS binding in membranes of the spinal cord. Using a receptor binding assay, repeated treatment with (-)U-50,488H significantly increased the density of [3H]DAMGO binding sites in membranes of the mouse spinal cord. In contrast, the expression of micro -opioid receptor was not affected after repeated treatment with (-)U-50,488H. These results suggest that repeated stimulation of kappa-opioid receptors leads to the up-regulation of micro -opioid receptor functions in the spinal cord, which may be associated with an increase in the number of functional micro -opioid receptors in the mouse spinal cord.
Narita
Minoru
M
Department of Toxicology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan.
Khotib
Junaidi
J
Mizoguchi
Hirokazu
H
Suzuki
Masami
M
Ozaki
Satoru
S
Yajima
Yoshinori
Y
Tseng
Leon F
LF
Suzuki
Tsutomu
T
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000494:pharmacology*; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010146:Pain / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000819:agonists* / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000187:drug effects* / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
D018712:Analgesics, Non-Narcotic; D000701:Analgesics, Opioid; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer