The Interaction between Carbon Monoxide and Hydrogen Sulfide during Chronic Joint Pain in Young Female Mice

Abstract

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.

Hydrogen-Rich Water as a Novel Therapeutic Strategy for the Affective Disorders Linked with Chronic Neuropathic Pain in Mice

“…The fact that all of them reversed the antiallodynic and antihyperalgesic effects of HRW revealed the participation of the antioxidant enzymes (HO-1 and NQO1) and the K ATP channels in the analgesic actions of HRW during neuropathic pain. These data agreed with other findings showing the reversion of the analgesic effects induced by HRS with SnPP in rats with neuropathic pain [ 11 ] as well as with the contribution of the NQO1 enzyme and K ATP channels in the pain reliever effects of H 2 S donors in animals with chronic joint or inflammatory pain [ 14 , 31 ].…”

“…Thus, revealing a positive interaction between HO-1 and H 2 systems in inhibiting CNP. In line with these data, a positive interaction between HO-1/CO with other gases, for example H 2 S or nitric oxide, has been also proved in other pain models [ 13 , 14 ]. Our data suggested the combination of CoPP with HRW as a good antinociceptive strategy for CNP.…”

“…The major endogenous antioxidant system is initiated by the translocation of the nuclear erythroid factor 2-related factor 2 (Nrf2) from the cytoplasm to the nucleus and the subsequent transcription of several antioxidant proteins, including heme oxygenase 1 (HO-1), superoxide dismutase 1 (SOD-1) and NAD(P)H: quinone oxidoreductase 1 (NQO1). The upregulation of these enzymes triggered by Nrf2 has exhibited a positive relationship with antinociceptive and anti-inflammatory responses in several pain models [ 11 , 12 ], as for example that induced by cobalt protoporphyrin IX (CoPP), an HO-1 inductor in animals with inflammatory and osteoarthritic pain [ 13 , 14 ]. The enzyme HO-1 catalysis the heme group into biliverdin, iron and carbon monoxide (CO) which acts as a gaseous neurotransmitter with antiapoptotic, antiproliferative and anti-inflammatory properties [ 12 , 15 ].…”

“…Thereby, the outstanding effects of hydrogen sulfide (H 2 S) in treating CNP through the administration of slow-releasing H 2 S donors, are mainly produced by activating the endogenous HO-1 expression [ 17 , 18 ]. A close interaction between H 2 S and CO as well as among nitric oxide and the HO-1/CO system in modulating chronic osteoarthritis and inflammatory pain in rodents has been also demonstrated [ 14 , 19 ]. Consequently, the combination of different gases constitutes a potential therapeutic target for chronic pain.…”

Local delivery of gaseous signaling molecules for orthopedic disease therapy

“…The latest study revealed that the combined application of CO and H 2 S gaseous signaling molecules portrayed a synergistic effect in the treatment of chronic joint pain, producing higher anti-pain and grip strength restoration effects at equal doses [ 162 ]. And the p65 subunit of NF-κB was first sulfated by H 2 S produced by CSE and later S-nitrosylated by NO produced by iNOS in TNF-α-induced inflammation and apoptosis.…”