Repeated Administration of Duloxetine Suppresses Neuropathic Pain by Accumulating Effects of Noradrenaline in the Spinal Cord

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Abstract

BACKGROUND:

Antidepressants are used to treat neuropathic pain and although the detailed mechanisms of their effects are unclear, the descending noradrenergic inhibitory system might play an important role. We tested our hypothesis that repeated administration of duloxetine suppresses neuropathic pain by restoring the descending noradrenergic inhibitory system in rats 6 weeks after spinal nerve ligation (SNL).

METHODS:

We subcutaneously injected SNL rats with duloxetine (10 mg kg−1 day−1) daily for 3 consecutive days and assessed behavioral hypersensitivity and noxious stimulus–induced analgesia (NSIA) activated by subcutaneous injection of capsaicin. We also performed microdialysis studies of the spinal cord, noradrenaline measurements of homogenized lumbar spinal tissue, and immunohistochemistry of the locus coeruleus.

RESULTS:

Three daily injections of duloxetine attenuated the mechanical hyperalgesia induced by SNL (SNL treated with vehicle: 88 ± 9.4 g versus SNL treated with duloxetine: 148 ± 13 g, P < .001; estimated treatment effect of duloxetine [95% confidence interval {CI}], 65 [50.6–79.4]; n = 6/group, on day 4) and recovered the decreased NSIA (vehicle: 154 ± 10 g versus duloxetine: 213 ± 33 g, P < .001; 71.3 [57.4–85.2]; n = 6/group, 30 minutes after injection). The noradrenaline content in the dorsal spinal cord increased bilaterally (SNL treated with vehicle: 946.7 ± 203.6 pg/g versus SNL treated with duloxetine: 1593.5 ± 181.4 pg/g, P < .001; 646.79 pg/g [481.61–811.97] on the ipsilateral side; SNL treated with vehicle: 845.0 ± 164.7 pg/g versus SNL treated with vehicle: 1557.2 ± 237.4 pg/g, P < .001; 712.17 pg/g [449.31–975.02] on the contralateral side). Intrathecal injection (IT) of the α2-adrenoceptor antagonist idazoxan reversed both the antihyperalgesic effect (before IT: 133 ± 5.7 g versus 30 minutes after IT: 85.8 ± 6.5 g, P < .001, −47 [−39.1 to −54.8], n = 6/group, and NSIA; vehicle-IT: 219 ± 7.4 g versus idazoxan-IT: 153 ± 10 g, P < .001; −65.8 g [−25.2 to −77.4] n = 6/group, 30 minutes after forepaw injection of capsaicin). Duloxetine treatment did not alter the noradrenaline release in the spinal cord after capsaicin injection (P = .415), or the fraction of nuclei positive for phosphorylated cyclic adenosine monophosphate response element binding protein in the locus coeruleus (P = 1.00 duloxetine versus vehicle 120 minutes after forepaw injection of vehicle and P = 1.00 duloxetine versus vehicle 120 minutes after forepaw injection of capsaicin).

CONCLUSIONS:

These findings suggest that 3 daily injections of duloxetine suppressed hyperalgesia and recovered impaired NSIA in rats 6 weeks after nerve injury. Both effects of duloxetine were reversed by IT of an α2-adrenoceptor antagonist. These findings suggest the inhibitory effects of duloxetine against neuropathic pain depend on recovery of the noradrenergic descending inhibitory system, especially in the spinal cord.

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