The efficacy of duloxetine depends on spinal cholinergic plasticity in neuropathic pain model rats

Antidepressants, such as duloxetine, are widely used to treat chronic pain, including neuropathic pain; however, their efficacy is unsatisfactory. In our previous studies, we showed that in a spinal nerve ligation (SNL) rat model, the descending noradrenergic inhibitory system, which involves in the anti-hypersensitivity mechanism of antidepressants, decrease its activity over time following peripheral nerve injury. In this study, we hypothesized that the analgesic effects of duloxetine may diminish following the attenuation of the descending noradrenergic inhibitory system. The analgesic effects of duloxetine in SNL model rats at the early (SNL2W) and chronic (SNL6W) phases following spinal nerve ligation were compared. Male Sprague-Dawley rats were randomly assigned to the SNL2W or SNL6W groups and used to evaluate the anti-allodynic effects of duloxetine using the von Frey filament test. The anti-allodynic effects of duloxetine at a dose of 10 mg/kg were lower in SNL6W rats than in SNL2W rats. Basal noradrenaline concentrations in rat spinal dorsal horns were higher in the SNL6W group than in the SNL2W group, and there was no difference in the increase in spinal noradrenaline concentrations between the 2 groups following duloxetine administration. In addition, we found that duloxetine-induced acetylcholine (ACh) release and choline acetyltransferase (ChAT) expression in the spinal dorsal horn decreased in SNL6W rats. At a dose of 30 mg/kg, duloxetine showed anti-allodynic effects even in SNL6W rats and induced ACh release in the spinal cord. Furthermore, these anti-allodynic effects were completely inhibited by intrathecal atropine (muscarinic antagonist) administration. Moreover, 5 daily intraperitoneal injections of the TrkB agonist, 7,8-dihydroxyflavone (5 mg/kg), not only restored ChAT expression, but also decreased the anti-allodynic effects of duloxetine. These findings suggest that the attenuation of the anti-allodynic effects of duloxetine at the chronic phase of SNL may be due to impaired spinal acetylcholine-mediated analgesia. In addition, the activation of BDNF-TrkB signaling may be beneficial in reversing this impairment.