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

Abstract

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 (H2S) 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 H2S 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 H2S 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.

Hydrogen Sulfide Inhibits Inflammatory Pain and Enhances the Analgesic Properties of Delta Opioid Receptors

“…In the first set of experiments, the antinociceptive effects produced by the acute administration of different doses of DADS (25–200 µmols/kg), P-ITC (18.6–29 µmols/kg), or vehicle at 10 days after CFA-injection were evaluated ( n = 6 animals per dose). Mice were tested at 1 h after DADS or P-ITC injection in accordance with our previous studies [ 8 , 10 ].…”

“…In this context, recent studies proved that the exogenous administration of slow-releasing H 2 S donors, such as phenyl isothiocyanate (P-ITC) or allyl isothiocyanate (A-ITC), attenuated osteoarthritis and neuropathic pain, thus turning these compounds into potential therapeutical targets for the treatment of inflammatory pain [ 6 , 7 , 8 ]. Other investigations also demonstrated the antinociceptive effects of other slow-releasing H 2 S compounds, such as diallyl disulfide (DADS) and morpholin-4-ium 4-methoxyphenyl (morpholino) phosphinodithioate dichloromethane complex (GYY4137), in models of osteoarthritis or nerve injury-induced neuropathic pain [ 9 , 10 ]. These and other studies further revealed that the possible mechanisms involved in H 2 S-mediated antinociceptive actions in nociceptive, osteoarthritis, and neuropathic pain might be produced by opening the voltage-gated potassium channels, such as the Kv7 [ 6 , 7 , 10 ] and the ATP-sensitive (KATP) potassium channels [ 11 , 12 ].…”

“…Other investigations also demonstrated the antinociceptive effects of other slow-releasing H 2 S compounds, such as diallyl disulfide (DADS) and morpholin-4-ium 4-methoxyphenyl (morpholino) phosphinodithioate dichloromethane complex (GYY4137), in models of osteoarthritis or nerve injury-induced neuropathic pain [ 9 , 10 ]. These and other studies further revealed that the possible mechanisms involved in H 2 S-mediated antinociceptive actions in nociceptive, osteoarthritis, and neuropathic pain might be produced by opening the voltage-gated potassium channels, such as the Kv7 [ 6 , 7 , 10 ] and the ATP-sensitive (KATP) potassium channels [ 11 , 12 ]. However, the participation of these potassium channels in the possible antinociceptive effects of slow-releasing H 2 S donors during inflammatory pain has not been elucidated.…”

The Recovery of Cognitive and Affective Deficiencies Linked with Chronic Osteoarthritis Pain and Implicated Pathways by Slow-Releasing Hydrogen Sulfide Treatment

“…In the first experiments, we evaluated the effects of repetitive intraperitoneal administration, twice daily, of 200 µmol/kg of DADS and 32 µmol/kg of GYY4137, over 3 and 4 consecutive days, on the cognitive and grip strength losses and mechanical allodynia caused by osteoarthritis (n = 6-8 animals for each group). The doses of DADS and GYY4137 were chosen in conformity with another research [47]. The effects of the same treatments on associated depressive-and anxiety-like behaviors were further assessed (n = 8 animals for each group).…”

“…DADS and GYY4137 were purchased from Sigma-Aldrich (St. Louis, MO, USA) and dissolved in SS. Both drugs were intraperitoneally administered 1 h before testing, in a final volume of 10 mL/kg, in accordance with our previous pilot studies and other work [47]. Both drugs were prepared before use, and for each group treated with a drug, the respective control group received the same volume of corresponding vehicle.…”