The Anxiolytic and Antidepressant Effects of Diallyl Disulfide and GYY4137 in Animals with Chronic Neuropathic Pain

When neuropathic pain is maintained long term, it can also lead to the development of emotional disorders that are even more intense than pain perception and difficult to treat. Hydrogen sulfide (H(2)S) donors relieve chronic pain, but their effects on the associated mood disorders are not completely elucidated. We evaluated if treatment with DADS (diallyl disulfide) or GYY4137 (morpholin-4-ium 4-methoxyphenyl(morpholino) phosphinodithioate dichloromethane complex), two slow-releasing H(2)S donors, inhibits the anxiety- and depressive-like behaviors that concur with chronic neuropathic pain generated by sciatic nerve injury in mice. The modulatory role of these drugs in the inflammatory, apoptotic, and oxidative processes implicated in the development of the affective disorders was assessed. Our results revealed the anxiolytic, antidepressant, and antinociceptive properties of DADS and GYY4137 during neuropathic pain by inhibiting microglial activation and the up-regulation of phosphoinositide 3-kinase/phosphorylated protein kinase B and BAX in the amygdala (AMG) and/or periaqueductal gray matter (PAG). Both treatments also normalized and/or activated the endogenous antioxidant system, but only DADS blocked ERK 1/2 phosphorylation. Both H(2)S donors decreased allodynia and hyperalgesia in a dose-dependent manner by activating the Kv7 potassium channels and heme oxygenase 1 signaling pathways. This study provides evidence of the anxiolytic and antidepressant properties of DADS and GYY4137 during neuropathic pain and reveals their analgesic actions, suggesting that these therapeutic properties may result from the inhibition of the inflammatory, apoptotic, and oxidative responses in the AMG and/or PAG. These findings support the use of these treatments for the management of affective disorders accompanying chronic neuropathic pain.