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A relationship between carbon monoxide (CO) and hydrogen sulfide (H2S) has been described in different pathological conditions, but their interaction in modulating joint pain has not yet been investigated. In young female mice with monosodium acetate-induced joint degeneration and pain, we assessed: (1) the effects of CORM-2 (tricarbonyldichlororuthenium(II)dimer), a CO-releasing molecule, and CoPP (cobalt protoporphyrin IX), an inducer of heme oxygenase 1 (HO-1), administered alone and combined with low doses of two slow-releasing H2S donors, DADS (diallyl disulfide) and GYY4137 (morpholin-4-ium 4-methoxyphenyl(morpholino) phosphinodithioate dichloromethane complex) on the mechanical allodynia and loss of grip strength provoked by joint degeneration; (2) the role of Nrf2, NAD(P)H: quinone oxidoreductase 1 (NQO1) and HO-1 in the antinociceptive actions of H2S donors; (3) the impact of DADS and GYY4137 treatment on the expression of Nrf2 and several antioxidant proteins in dorsal root ganglia (DRG) and periaqueductal gray matter (PAG). Our data showed that treatment with H2S donors inhibited allodynia and functional deficits, while CORM-2 and CoPP only prevented allodynia. The Nrf2 pathway is implicated in the analgesic actions of DADS and GYY4137 during joint degeneration. Moreover, the co-administration of low doses of CORM-2 or CoPP with DADS or GYY4137 produced higher antiallodynic effects and greater recovery of grip strength deficits than those produced by each of these compounds alone. The activation of the antioxidant system caused by H2S donors in DRG and/or PAG might explain the enhancement of antinociceptive effects. These data reveal a positive interaction between H2S and CO in modulating joint pain in female mice.

Chemotherapy-induced peripheral neuropathy constitutes an unresolved clinical problem that severely decreases the quality of the patient's life. It is characterized by somatosensory alterations, including chronic pain, and a high risk of suffering mental disorders such as depression and anxiety. Unfortunately, an effective treatment for this neuropathology is yet to be found. We investigated the therapeutic potential of cobalt protoporphyrin IX (CoPP), a heme oxygenase 1 inducer, and morpholin-4-ium 4-methoxyphenyl(morpholino) phosphinodithioate dichloromethane complex (GYY4137), a slow hydrogen sulfide (HS) donor, in a preclinical model of paclitaxel (PTX)-induced peripheral neuropathy (PIPN) in mice. At three weeks after PTX injection, we evaluated the effects of the repetitive administration of 5 mg/kg of CoPP and 35 mg/kg of GYY4137 on PTX-induced nociceptive symptoms (mechanical and cold allodynia) and on the associated emotional disturbances (anxiety- and depressive-like behaviors). We also studied the mechanisms that could mediate their therapeutic properties by evaluating the expression of key proteins implicated in the development of nociception, oxidative stress, microglial activation, and apoptosis in prefrontal cortex (PFC) and dorsal root ganglia (DRG) of mice with PIPN. Results demonstrate that CoPP and GYY4137 treatments inhibited both the nociceptive symptomatology and the derived emotional alterations. These actions were mainly mediated through potentiation of antioxidant responses and inhibiting oxidative stress in the DRG and/or PFC of mice with PIPN. Both treatments normalized some plasticity changes and apoptotic reactions, and GYY4137 blocked microglial activation induced by PTX in PFC. In conclusion, this study proposes CoPP and GYY4137 as good candidates for treating neuropathic pain, anxiety- and depressive-like effects of PTX.

Chronic osteoarthritis pain is accompanied by several comorbidities whose treatment has not been completely resolved. The anti-inflammatory, analgesic, and antidepressant effects of slow-releasing hydrogen sulfide (H2S) donors during osteoarthritic pain have been shown, but their actions in the accompanying memory impairment and anxious-like behaviors have not yet been demonstrated. Using female mice with chronic osteoarthritic pain, the effects of natural, diallyl di-sulfide (DADS) or synthetic, morpholin-4-ium 4-methoxyphenyl(morpholino) phosphinodithioate dichloromethane complex (GYY4137) slow-releasing H2S donors, on associated cognitive and grip strength deficits and anxiodepressive-like behaviors, were assessed. Their effects on specific brain areas implicated in the modulation of pain and emotional responses were also determined. Results demonstrated an improvement in memory and grip strength deficits, as well as in the anxious-like behaviors associated with chronic pain in GYY4137 and/or DADS treated mice. The painkiller and antidepressant properties of both treatments were also established. Treatment with DADS and/or GYY4137 inhibited: oxidative stress in the amygdala; phosphoinositide 3-kinase overexpression in the amygdala, periaqueductal gray matter, and anterior cingulate cortex; protein kinase B activation in the amygdala and infralimbic cortex; up-regulation of inducible nitric oxide synthase in the amygdala, periaqueductal gray matter and infralimbic cortex and apoptotic responses in the amygdala. These results might explain the recovery of memory and grip strength and the inhibition of allodynia and associated anxiodepressive-like behaviors by these treatments. In conclusion, this study revealed new properties of slow-releasing H2S donors in cognitive impairment and affective disorders linked with chronic osteoarthritis pain and their effects on the central nervous system.

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 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 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 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.