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1.
Figure 1

Figure 1. From: A Novel G??-Subunit Inhibitor Selectively Modulates ?-Opioid-Dependent Antinociception and Attenuates Acute Morphine-Induced Antinociceptive Tolerance and Dependence.

Chemical structure of the novel Gβγ inhibitor M119, which was obtained from the NCI diversity set (reference number NSC 119910).

Jennifer L. Mathews, et al. J Neurosci. ;28(47):12183-12189.
2.
Figure 7

Figure 7. From: A Novel G??-Subunit Inhibitor Selectively Modulates ?-Opioid-Dependent Antinociception and Attenuates Acute Morphine-Induced Antinociceptive Tolerance and Dependence.

Effect of M119 on morphine-induced physical dependence. In a measure of acute morphine dependence, mice were administered morphine (100 mg/kg, s.c., −4 h) and withdrawal was precipitated by injection of naloxone (10 mg/kg, i.p.). Withdrawal jumping was counted for 15 min after antagonist injection. Injection of M119 (100 nmol, i.c.v.) 30 min before the injection of naloxone resulted in significantly less vertical jumps than naloxone alone (*p < 0.05).

Jennifer L. Mathews, et al. J Neurosci. ;28(47):12183-12189.
3.
Figure 4

Figure 4. From: A Novel G??-Subunit Inhibitor Selectively Modulates ?-Opioid-Dependent Antinociception and Attenuates Acute Morphine-Induced Antinociceptive Tolerance and Dependence.

Effect of systemic administration of M119 on morphine-induced antinociception. Systemic administration of M119 (100 mg/kg, i.p.) with graded doses of morphine (1–10 mg/kg, s.c.) resulted in a potentiation of antinociception as measured by a fourfold leftward shift in the ED50 value compared with morphine alone (p < 0.01). All data points are the mean of 7–10 mice, with SEM represented by error bars. Antinociception was assessed 20 min after agonist injection in the 55°C warm-water tail-flick test.

Jennifer L. Mathews, et al. J Neurosci. ;28(47):12183-12189.
4.
Figure 2

Figure 2. From: A Novel G??-Subunit Inhibitor Selectively Modulates ?-Opioid-Dependent Antinociception and Attenuates Acute Morphine-Induced Antinociceptive Tolerance and Dependence.

Effect of M119 on antinociception mediated by the μ-opioid receptor. Coadministration of M119 (100 nmol, i.c.v.) with morphine (0.01–3 nmol, i.c.v.) resulted in a 10-fold potentiation of morphine-induced antinociception (p < 0.001) (A). The graph was reproduced with permission from Bonacci et al. (2006), their Figure 4. Concomitant administration of M119 (100 nmol) with the μ-selective agonist, DAMGO (0.01–0.1 nmol), resulted in a sevenfold leftward shift in ED50 value compared with DAMGO alone (p < 0.001) (B). All data points are the mean of 7–10 mice, with SEM represented by error bars. Antinociception was assessed 20 min after agonist and M119 injection in the 55°C warm-water tail-flick test.

Jennifer L. Mathews, et al. J Neurosci. ;28(47):12183-12189.
5.
Figure 8

Figure 8. From: A Novel G??-Subunit Inhibitor Selectively Modulates ?-Opioid-Dependent Antinociception and Attenuates Acute Morphine-Induced Antinociceptive Tolerance and Dependence.

Effect of M119 on [3H]DAMGO binding to the μ-opioid receptor ( A) and on DAMGO-induced inhibition of cAMP levels (B). hMOR-CHO membranes were incubated with 0.25 nm [3H]DAMGO and varying concentrations of M119 as described in Materials and Methods. M119 did not significantly inhibit [3H]DAMGO binding to the hMOR (A). DAMGO inhibited forskolin-stimulated cAMP production and this effect was not potentiated by the addition of the βγ inhibitor, M119 (B). hMOR-CHO cells were treated with varying concentrations of DAMGO along with 10 µm forskolin and 100 mm IBMX, with and without 10 µm M119. DAMGO dose-dependently inhibited cAMP (IC50 = 24 ± 3.6 nm), and concomitant treatment of cells with DAMGO and 10µm M119 did not potentiate this effect (IC50 = 26 ± 2.9 nm).

Jennifer L. Mathews, et al. J Neurosci. ;28(47):12183-12189.
6.
Figure 3

Figure 3. From: A Novel G??-Subunit Inhibitor Selectively Modulates ?-Opioid-Dependent Antinociception and Attenuates Acute Morphine-Induced Antinociceptive Tolerance and Dependence.

Effect of M119 on antinociception mediated by the κ- and δ-opioid receptors. A moderate, twofold, leftward shift in ED50 value was observed with coadministration of M119 (100 nmol, i.c.v.) and the κ-selective, agonist, U50,488 (10–60 nmol, i.c.v.) compared with U50,488 alone (p < 0.01) (A). Coadministration of M119 with either the δ1-selective agonist, DPDPE (3–30 nmol, i.c.v.) (B) or the δ2-selective agonist, Deltorphin II (1–10 nmol, i.c.v.) (C), did not result in a shift of the ED50 value compared with either agonist alone. Antinociception was assessed 20 min after agonist and M119 injection in the 55°C tail-flick test. All data points are the mean of 7–10 mice, with SEM represented by error bars.

Jennifer L. Mathews, et al. J Neurosci. ;28(47):12183-12189.
7.
Figure 6

Figure 6. From: A Novel G??-Subunit Inhibitor Selectively Modulates ?-Opioid-Dependent Antinociception and Attenuates Acute Morphine-Induced Antinociceptive Tolerance and Dependence.

Effect of M119 on acute morphine antinociceptive tolerance. In an acute model of morphine antinociceptive tolerance, morphine was administered at times 0, 2, 4, 6 h(A). At 4 h, significant tolerance (p < 0.01) had developed as measured by an eightfold shift in the ED50 value and by 6 h, a 16-fold shift in the ED50 value was measured (p < 0.001). Concomitant administration of M119 (100 nmol, i.c.v.) and graded doses of morphine attenuated acute morphine antinociceptive tolerance at all time points tested (B). Both compounds were administered at times 0, 2, 4, 6 h. No significant change in the ED50 values was determined. Antinociception was assessed 20 min after each injection in the 55°C tail-flick test. Control mice had no change from baseline tail-withdrawal latencies at any of the time points tested (data not shown).

Jennifer L. Mathews, et al. J Neurosci. ;28(47):12183-12189.
8.
Figure 5

Figure 5. From: A Novel G??-Subunit Inhibitor Selectively Modulates ?-Opioid-Dependent Antinociception and Attenuates Acute Morphine-Induced Antinociceptive Tolerance and Dependence.

The effects of μ-, δ-, and κ-selective opioid agonists and M119 on IP production in CHO cells stably expressing one of the human opioid receptors. IP levels were measured as described in Materials and Methods. The μ agonists, DAMGO (10 µm) and morphine (10 µm), both significantly increased the total inositol phosphates measured in hMOR-CHO cells (**p < 0.01) compared with control (A). The μ-selective antagonist β-FNA (10 µm) attenuated this response (*p < 0.05) compared with the agonist alone. M119 inhibition of DAMGO-stimulated IP generation was concentration dependent [10 µm (*p < 0.05) and 30 µm (**p < 0.01), compared with DAMGO alone] (B). In the hDOR-CHO cells, neither δ-selective agonist, DPDPE (10 µm) nor Deltorphin II (10 µm) significantly increased IP generation over control treated cells (C). M119 and naltrindole (NTI) also had no effect in the hDOR-CHO cells. The κ-selective agonist, U50,488 (10 µm), had no significant effect on IP generation with or without M119 (10 µm) or nor-BNI (10 µm) in the hKOR-CHO cells (D).

Jennifer L. Mathews, et al. J Neurosci. ;28(47):12183-12189.

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