In three comorbid pain and depression animal models (genetic predisposition, chronic social stress, arthritis), we demonstrated 1) the reduced antidepressant and antihyperalgesic effects of fluoxetine during its maintenance treatment, 2) upregulation of 5-HT1A and IDO1 expression in the DRN following fluoxetine exposure, 3) inhibition or knockout of 5-HT1A receptors prevented the fluoxetine-induced upregulation of IDO1 expression, and 4) inhibition of either the 5-HT1A receptor or IDO1 activity maintained the fluoxetine’s antidepressant and antihyperalgesic effects. Here, HTR1A is linked to depressive disorder.