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- Title
Direct evidence for the up-regulation of spinal µ-opioid receptor function after repeated stimulation of κ-opioid receptors in the mouse.
- Authors
Narita, Minoru; Khotib, Junaidi; Mizoguchi, Hirokazu; Suzuki, Masami; Ozaki, Satoru; Yajima, Yoshinori; Tseng, Leon F.; Suzuki, Tsutomu
- Abstract
The present study was designed to investigate the possible change in spinal µ-opioid receptor function after repeated administration of a selective κ-opioid receptor agonist (1 S- 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 µ-opioid receptor agonist [ d-Ala2, N-Me-Phe4,Gly5-ol] enkephalin (DAMGO). Using the guanosine-5′- o-(3-[35S]thio) triphosphate ([35S]GTPγS) binding assay, we found that (−)U-50,488H was able to produce a dose-dependent increase in [35S]GTPγS 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]GTPγS binding in this region, whereas repeated treatment with (−)U-50,488H exhibited an increase in the DAMGO-stimulated [35S]GTPγS 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 µ-opioid receptor was not affected after repeated treatment with (−)U-50,488H. These results suggest that repeated stimulation of κ-opioid receptors leads to the up-regulation of µ-opioid receptor functions in the spinal cord, which may be associated with an increase in the number of functional µ-opioid receptors in the mouse spinal cord.
- Subjects
SPINAL cord; OPIOID receptors; RADIOLIGAND assay; MICE
- Publication
European Journal of Neuroscience, 2003, Vol 18, Issue 9, p2498
- ISSN
0953-816X
- Publication type
Article
- DOI
10.1046/j.1460-9568.2003.02980.x