Atomoxetine exhibited antinociceptive synergy with morphine using a fixed-dose design in the rat formalin model.

<p>(A) Both 3 and 10 mg/kg atomoxetine (Atx, IP) shifted the morphine (Mor) dose-response curve leftward in the rat formalin model (n = 6–16). Morphine alone: ED₅₀ = 2.3 mg/kg (95% CI: 2.0–2.5); morphine+atomoxetine (IP, 3 mg/kg): ED₅₀ = 1.1 mg/kg (95% CI: 0.8–1.6); and morphine+atomoxetine (IP, 10 mg/kg): ED₅₀ = 0.6 mg/kg (95% CI: 0.4–0.8). All data points are shown as mean ± SEM for each group and are expressed as percentage of controls. Inset (A) Atomoxetine (IP) at 3 and 10 mg/kg was associated with 67±10% and 84±3% for NET and 35±9% and 64±5% for SERT occupancy measured <i>ex vivo</i> at 75 min post-dose, respectively. All occupancy data represent mean (± SEM) for each group. (B) A subefficacious dose of morphine 1 mg/kg (SC) left-shifted the atomoxetine dose-response curve (n = 6–16). Atomoxetine alone: ED₅₀ = 27.8 mg/kg (95% CI: 22–36); and atomoxetine+morphine (SC, 1 mg/kg): ED₅₀ = 2.5 mg/kg (95% CI: 1.3–4.7). (C) A fixed combination of NET selective inhibitor esreboxetine (Esrbx, IP, 10 mg/kg) and SERT selective inhibitor fluoxetine (Flx, IP, 1 mg/kg) left-shifted the morphine dose-response curve (n = 6–12). Morphine alone: ED₅₀ = 2.3 mg/kg (95% CI: 2.0–2.5); morphine+esreboxetine (IP, 10 mg/kg)+fluoxetine (IP, 1 mg/kg): ED₅₀ = 0.3 mg/kg (95% CI: 0.2–0.7).</p

Atomoxetine exhibited antinociceptive synergy with morphine using a fixed-ratio design in the rat formalin model.

<p>(A) The dose-response curve of a fixed-ratio of 3 parts atomoxetine (Atx, IP) to 1 part morphine (Mor, SC) leftward shifted relative to the atomoxetine dose-response curve alone (n = 6–12). All data points are shown as mean ± SEM for each group and are expressed as percentage of controls. (B) An isobologram for the combined effects of atomoxetine and morphine in a fixed ratio combination 3∶1. The ED₅₀ value for morphine is plotted on the abscissa, and the ED₅₀ value for atomoxetine is plotted on the ordinate. The solid line represents the line of additivity and the isobol point (observed ED₅₀ value) is located to the left and below the theoretical additive ED₅₀ value (with non-overlapping 95% CI). (C) The dose-response curve of a fixed-ratio of concomitant administration of 10 part atomoxetine (IP) to 1 part morphine (SC) leftward shifted relative to the atomoxetine dose-response curve alone (n = 6–16). All data points are shown as mean ± SEM for each group and are expressed as percentage of controls. (D) An isobologram for the combined effects of atomoxetine and morphine in a fixed ratio combination 10∶1. The isobol point (observed ED₅₀ value) is located to the left and below the theoretical additive ED₅₀ value (without overlapping 95% CI).</p

Antinociceptive synergy between atomoxetine and morphine did not reflect impaired motor coordination.

<p>The white bars represent the % reduction in the flinching behavior compared to vehicle-treatment in the rat formalin model (n = 10–22), and the grey bars represent the change in latency for rats to fall from an accelerating rotating rod compared to vehicle treatment in the rat RotaRod test (n = 8). All data points are shown as mean ± SEM for each group and are expressed as percentage of controls. Data from one-way ANOVA are as follows: rat formalin model: F _{(4, 53)} = 36.12, p<0.0001; RotaRod: F _{(4, 34)} = 4.604, p = 0.004. Data from the <i>post hoc</i> Dunnett’s test follows: **p<0.01, q = 3.265; ***p<0.001, q = 9.258–9.370, compared to vehicle treatment.</p

Plasma _unbound and brain_unbound concentrations of atomoxetine in absence or presence of morphine; esreboxetine in absence or presence of morphine and/or fluoxetine; fluoxetine in absence or presence of morphine and/or esreboxetine; and duloxetine in absence or presence of morphine and ondansetron - at 75 min post-dosing.

<p>n = 3–6 for each group. Data are presented as mean ± standard deviation.</p

<i>In vitro</i> uptake inhibitory potency (pIC₅₀) and apparent binding affinity (pK_i) of fluoxetine, duloxetine, atomoxetine and esreboxetine in rat cortical membrane or synaptosomal preparations, respectively (n = 3–12).

<p><i>In vitro</i> uptake inhibitory potency (pIC₅₀) and apparent binding affinity (pK_i) of fluoxetine, duloxetine, atomoxetine and esreboxetine in rat cortical membrane or synaptosomal preparations, respectively (n = 3–12).</p

Duloxetine failed to exhibit antinociceptive synergy with morphine in the rat formalin model.

<p>(A) Duloxetine (Dlx) at 5 mg/kg failed to shift the morphine (Mor) dose-response curve leftward. Morphine alone: ED₅₀ = 2.3 mg/kg (95% CI: 2.0–2.5); morphine+duloxetine (IP, 5 mg/kg): ED₅₀ = 2.0 mg/kg (95% CI: 1.3–3.0). All data points are shown as mean ± SEM for each group and are expressed as percentage of controls. Inset (A) Duloxetine (IP) at 5 mg/kg was associated with 62±5% for NET and 92±3% for SERT occupancy measured <i>ex vivo</i> at 75 min post-dose. All occupancy data represent mean (± SEM) for each group. (B) A subefficacious dose of morphine 1 mg/kg (SC) failed to left-shift the duloxetine dose-response curve (n = 6–12). Duloxetine alone: ED₅₀ = 10.9 mg/kg (95% CI: 8–15); and duloxetine+morphine (SC, 1 mg/kg): ED₅₀ = 7.7 mg/kg (95% CI: 4–16).</p

The antinociceptive activity of atomoxetine in the rat formalin model was independent of µ-opioid receptor activation.

<p>The µ-opioid receptor antagonist naloxone (Nal, IP, 5 mg/kg), at a dose which effectively blocked morphine (Mor)-induced analgesia in the rat formalin model, did not inhibit atomoxetine (Atx)-induced antinociception (n = 5–7). All values are shown as mean ± SEM for each group and are expressed as percentage of controls. Student’s <i>t</i> test, t ₍₁₀₎ = 7.668, ***p<0.001.</p