Investigation of the relationship between antinociceptive mechanism of antidepressant and descending noradrenergic inhibitory pathway

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Findings to date indicate that tricyclic antidepressants, such as amitriptyline, have an antinociceptive effect It is supposed that descending inhibitory neurons are involved in the antinociceptive action of antidepressants. The mechanism whereby descending inhibitory neurons, including noradrenergic neurons, produce antinociception remains unclear Recent electrophysiological studies have shown that noradrenalin activates GABAergic interneurons in the spinal cord, suggesting its role in mediating the antinociceptive effect In the present study, we investigated whether amitriptyline activates GABAergic interneurons in the spinal cord using c-Fos protein as a marker for neuronal activation.Adult male Wistar rats were administered 0 (control), 15, 30, 60 or 90 pg of amitriptyline intrathecally. After 4 hours, animals were anesthetized with intraperitoneal injection of pentobarbital and perfused with paraformaldehyde for fixation. The spinal cords were dissected at the lumbar level and fro … More zen-sectioned Sections were then stained for c-Fos protein using cliaminobenzicline and the number of c-Fos positive cells was counted Sections also double stained for c-Fos and glutamic acid decarboxylase (GAD ; a rate-limiting enzyme for GABA synthesis) using fluorescent conjugated secondary antibodies. In the following study, rats were injected with prazosin (alpha 1 adrenoceptor antagonist) or yohimbine (alpha 2 adrenoceptor antagonist) intrathecally and, 15 min later were injected 60 μg of amitriptyline intrathecally.Amitriptyline administration increased c-Fos positive cells in the dorsal horn of the spinal cord in a dose-dependent manner The number of c-Fos positive cells per section was 40.8 (mean) in control group, while 89.2 in 90 μg group. Amitriptyline-induced c-Fos protein expression was localized within the laminae I, II, III and IV Analysis by double staining indicated that approximately 80% of c-Fos positive cells were colocalized with GAD positive cells. Amitriptyline-induced c-Fos was blocked by prazosin but not by yohimbine.Results from the present study indicate that amitriptyline activates GABAergic interneurons through alpha 1 adrenoceptor in the dorsal horn of the spinal cord. Our finding suggests that GABAergic interneurons and their downstream effectors play at least a part in the antinociceptive action of amitriptyline in the spinal cord. Less