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.
Highlights
Several studies have demonstrated that the prevalence of neuropathic pain in the general population is around 6.9–10% [1]
The results show that both diallyl disulfide (DADS) and GYY4137 normalized the diminished number of entries into the open arms (p < 0.013; one-way ANOVA followed by the Student–Newman–Keuls test, as compared with their respective sham-operated mice treated with vehicle; Figures 1A and 2A) and the percentage of time spend in its
We further assessed the effects of DADS and GYY4137 in the open file (OF) test to verify their anxiolytic effects during neuropathic pain
Summary
Several studies have demonstrated that the prevalence of neuropathic pain in the general population is around 6.9–10% [1]. It is well known that, when neuropathic pain is maintained long term, in addition to the symptoms of the pain itself, it is very common to develop emotional disorders that are even more intense than pain perception, making their treatment a challenge [2]. Current treatments reduce pain symptoms but have limited efficacy in reducing the mood disorders that co-occur with neuropathic pain; new therapies are urgently needed. Hydrogen sulfide (H2 S) is a gaseous neurotransmitter that regulates numerous physiological and pathophysiological processes [3]. It is highly implicated in modulating the cellular redox state and protects cells from oxidative stress [4,5]. The antidepressant effects of H2 S donors that could release H2 S in a more controlled manner, such
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