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. 1998 Sep 15;18(18):7285-95.
doi: 10.1523/JNEUROSCI.18-18-07285.1998.

Activity of the delta-opioid receptor is partially reduced, whereas activity of the kappa-receptor is maintained in mice lacking the mu-receptor

H W Matthes  1 , C Smadja, O Valverde, J L Vonesch, A S Foutz, E Boudinot, M Denavit-Saubié, C Severini, L Negri, B P Roques, R Maldonado, B L Kieffer
Affiliations

Activity of the delta-opioid receptor is partially reduced, whereas activity of the kappa-receptor is maintained in mice lacking the mu-receptor

H W Matthes et al. J Neurosci. .

Abstract

Previous pharmacological studies have indicated the possible existence of functional interactions between mu-, delta- and kappa-opioid receptors in the CNS. We have investigated this issue using a genetic approach. Here we describe in vitro and in vivo functional activity of delta- and kappa-opioid receptors in mice lacking the mu-opioid receptor (MOR). Measurements of agonist-induced [35S]GTPgammaS binding and adenylyl cyclase inhibition showed that functional coupling of delta- and kappa-receptors to G-proteins is preserved in the brain of mutant mice. In the mouse vas deferens bioassay, deltorphin II and cyclic[D-penicillamine2, D-penicillamine5] enkephalin exhibited similar potency to inhibit smooth muscle contraction in both wild-type and MOR -/- mice. delta-Analgesia induced by deltorphin II was slightly diminished in mutant mice, when the tail flick test was used. Deltorphin II strongly reduced the respiratory frequency in wild-type mice but not in MOR -/- mice. Analgesic and respiratory responses produced by the selective kappa-agonist U-50,488H were unchanged in MOR-deficient mice. In conclusion, the preservation of delta- and kappa-receptor signaling properties in mice lacking mu-receptors provides no evidence for opioid receptor cross-talk at the cellular level. Intact antinociceptive and respiratory responses to the kappa-agonist further suggest that the kappa-receptor mainly acts independently from the mu-receptor in vivo. Reduced delta-analgesia and the absence of delta-respiratory depression in MOR-deficient mice together indicate that functional interactions may take place between mu-receptors and central delta-receptors in specific neuronal pathways.

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Figures

Fig. 1.
Fig. 1.
Autoradiographic study of opioid receptor coupling to G-proteins, by agonist-stimulated [35S]GTPγS binding on brain sections. A, [35S]GTPγS labeling induced by a μ-agonist. Coronal sections of brains from wild-type (+/+) and MOR-deficient (−/−) mice are shown. Slices were incubated in the absence (Control) or presence of 3 μm DAMGO and sections are shown at the level of caudate-putamen (a) or thalamus (b).B, [35S]GTPγS labeling induced by δ- and κ-agonists. Coronal sections from brains are presented at the level of caudate-putamen of wild-type (+/+) and MOR-deficient (−/−) mice. Slices are incubated in the absence (Control) or presence of 3 μmpCl-DPDPE (δ1), 3 μm deltorphin II (δ2), or 1 μm CI-977 (κ). The signal increases as follows:black < blue <green < yellow <red.
Fig. 2.
Fig. 2.
Agonist-induced [35S]GTPγS binding on brain membrane preparations. Brain membranes were incubated in the absence or presence of the agonists DAMGO (0.3 μm, μ), DPDPE (0.3 μm, δ1), deltorphin II (0.3 μm, δ2), or CI-977 (0.1 μm, κ). Basal level (100%) represents the amount of specific [35S]GTPγS binding (see Materials and Methods) in the absence of agonist, and values on the y-axis indicate the stimulation obtained using the various agonists. Results are expressed as mean ± SEM of at least three experiments performed in triplicate and conducted on at least two distinct membrane preparations. DPDPE, deltorphin II, and CI-977 significantly increase [35S]GTPγS binding above basal levels in both wild-type and mutant mice (black stars, comparisons with basal levels for the same genotype; three stars,p < 0.001; two stars,p < 0.01). There is no significant difference between genotypes, except for DAMGO-induced [35S]GTPγS binding (white stars, comparisons between wild-type and mutant groups receiving the same treatment; three stars, p < 0.001).
Fig. 3.
Fig. 3.
δ- and κ-induced inhibition of adenylyl cyclase activity in brain. Adenylyl cyclase activity was measured in brain homogenates (see Materials and Methods) in the absence or presence of increasing concentrations of selective δ-agonists (DPDPE and deltorphin II) and κ-agonists (U-50,488H). Basal activity (100%) refers to the amount of cAMP generated in the absence of opioid agonist. Data are mean ± SEM values from three to four independent experiments, each performed in triplicate. Black stars, comparisons with cyclase inhibition level in the absence of agonist for the same genotype; p < 0.05. There is a significant dose-dependent inhibition of adenylyl cyclase activity for all three agonists in both MOR +/+ and MOR −/− mice, with no significant difference between mouse genotypes.
Fig. 4.
Fig. 4.
δ analgesia. A, Antinociceptive responses induced by the selective δ-opioid agonists deltorphin II (Delt II, 10 μg, i.c.v.) and DPDPE (15 μg, i.c.v.), in MOR-deficient (−/−) and wild-type (+/+) mice (8 animals per group). B, Reversal of deltorphin II (Delt II, 10 μg, i.c.v.) antinociception by the selective δ-opioid antagonist naltrindole (Naltr, 25 mg/kg, s.c.) in MOR-deficient (−/−) and wild-type (+/+) mice (6–8 animals per group). Tail-immersion (tail-withdrawal latency) and hot-plate (licking and jumping latencies) tests were used. Values ony-axis represent the latencies in seconds of different nociceptive thresholds expressed as mean ± SEM. Black stars indicate comparisons with saline-treated animals of the same genotype. White stars indicate comparisons between wild-type and mutant groups receiving the same treatment. Black triangles in B represent comparisons with deltorphin II-treated animals of the same genotype. One symbol, p < 0.05; two symbols, p < 0.01.
Fig. 5.
Fig. 5.
κ analgesia. A, Antinociceptive responses induced by the selective κ-opioid agonist U-50,488H (30 mg/kg, s.c.) in MOR-deficient (−/−) and wild-type (+/+) mice (8 animals per group). B, Reversal of U-50,488H (30 mg/kg, s.c.) antinociception by the selective κ-opioid antagonist norbinaltorphimine (NorBNI, 5 mg/kg, s.c.) in MOR-deficient (−/−) and wild-type (+/+) mice (10–12 animals per group, excepting groups receiving opioid antagonists alone, where the number of animals was 6). Tail-immersion (tail-withdrawal latency) and hot-plate (licking and jumping latencies) tests were used. Values on the y-axis represent the latencies in seconds of different nociceptive thresholds expressed as mean ± SEM.Black stars represent comparisons with saline-treated animals of the same genotype. White stars represent comparison between wild-type and mutant groups receiving the same treatment. Black triangles in B represent comparisons with U-50,488H-treated animals of the same genotype.One symbol, p < 0.05; two symbols, p < 0.01.
Fig. 6.
Fig. 6.
Respiratory depression. Respiratory responses induced by morphine (6 mg/kg, s.c.), the selective δ-opioid agonist deltorphin II (10 μg, i.c.v.), and the selective κ-opioid agonist U-50,488H (30 mg/kg, s.c.) in MOR-deficient (−/−) and wild-type (+/+) mice. Values on the y-axis represent respiratory frequency (A), inspiratory time (B), and minute volume (C) expressed as mean ± SEM. Black stars represent comparisons with the same animal before subcutaneous drug injection (controls for morphine and U-50,488H) or with saline-injected (intracerebroventricular) animals of the same genotype (controls for deltorphin II). White stars represent comparison between wild-type and mutant animals receiving the same treatment. One symbol, p < 0.05; two symbols, p < 0.01 (10–12 animals per group).
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