| الملخص: | (1) Background: Fibromyalgia syndrome (FMS) is a chronic pain condition with widespread pain and multiple comorbidities, for which conventional therapies offer limited benefits. The reserpine-induced myalgia (RIM) model is an efficient animal model of FMS in rodents. This study aimed to develop a pharmacokinetic–pharmacodynamic (PK–PD) model of reserpine in rats, linking to its impact on monoamines (MAs). (2) Methods: Reserpine was administered daily for three consecutive days at dose levels of 0.1, 0.5, and 1 mg/kg. A total of 120 rats were included, and 120 PK and 828 PD observations were collected from 48 to 96 h after the first dose of reserpine. Non-linear mixed-effect data analysis was applied for structural PK–PD model definition, variability characterization, and covariate analysis. (3) Results: A one-compartment model best described reserpine in rats (V = 1.3 mL/kg and CL = 4.5 × 10<sup>−1</sup> mL/h/kg). A precursor-pool PK–PD model (k<sub>in</sub> = 6.1 × 10<sup>−3</sup> mg/h, k<sub>p</sub> = 8.6 × 10<sup>−4</sup> h<sup>−1</sup> and k<sub>out</sub> = 2.7 × 10<sup>−2</sup> h<sup>−1</sup>) with a parallel transit chain (k<sub>0</sub> = 1.9 × 10<sup>−1</sup> h<sup>−1</sup>) characterized the longitudinal levels of MA in the prefrontal cortex, spinal cord, and amygdala in rats. Reserpine stimulates the degradation of MA from the pool compartment (Slope<sub>1</sub> = 1.1 × 10<sup>−1</sup> h) and the elimination of MA (Slope<sub>2</sub> = 1.25 h) through the transit chain. Regarding the reference dose (1 mg/kg) of the RIM model, the administration of 4 mg/kg would lead to a mean reduction of 65% (C<sub>max</sub>), 80% (C<sub>min</sub>), and 70% (AUC) of MA across the brain regions tested. (4) Conclusions: Regional brain variations in neurotransmitter depletion were identified, particularly in the amygdala, offering insights for therapeutic strategies and biomarker identification in FMS research.
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