Antinociceptive, anxiolytic, and depression‐like effects of hydrogen sulfide, nitric oxide, and carbon monoxide in rats and the role of opioidergic and serotonergic systems in antinociceptive activity

Abstract

l‐Arginine, a nitric oxide (NO) donor; sodium hydrosulfide (NaHS), a hydrogen sulfide (H2S) donor; and tricarbonyldichlororuthenium(II) dimer (CORM‐2), carbon monoxide (CO) donor, are characterized as bioactive gas mediators that have been researched for their roles in human physiology. This study aimed to compare the effects of these mediators on pain, anxiety, and depression. Ninety‐one adult male Sprague–Dawley rats were used for the experiments. Locomotor activity, elevated plus maze, forced swimming, tail clip, hot plate, and writhing tests were used for the assessments after the administration of l‐arginine (30–100 mg/kg), a NO donor; NaHS (5–10 mg/kg), a H2S donor; and CORM‐2 (5–10 mg/kg), CO donor. Intraperitoneal H2S, NO, malondialdehyde (MDA), glutathione (GSH), and tumor necrosis factor‐α (TNF‐α) levels were determined by enzyme‐linked immunosorbent assay (ELISA). No statistical significance was found in the locomotor activity. NO and CO significantly extended latency at high doses in tail clip test. No significant activity was observed at any dose of all three substances on a hot plate. Both doses of CO and high doses of NO and H2S showed an antinociceptive effect in the writhing test. While the opioidergic system plays a role in the spinal antinociceptive effect of l‐arginine, both serotonergic and opioidergic systems play a role in its peripheral antinociceptive effect. The serotonergic system plays a role in the peripheral antinociceptive effect of CORM‐2. The time spent in open arm increased significantly in all groups an elevated plus maze. High doses of all three substances significantly increased the duration of immobility in the forced swimming test. No statistical significance was observed in MDA, GSH, and TNF‐α levels. High doses of NO and CO showed a spinal antinociceptive effect. Both doses of CO and high doses of NO and H2S showed a peripheral antinociceptive effect. All three agents showed anxiolytic and depression‐like effects.

BPC 157, L-NAME, L-Arginine, NO-Relation, in the Suited Rat Ketamine Models Resembling “Negative-Like” Symptoms of Schizophrenia

“…In contrast, with L-NAME or L-arginine, there were in the ketamine rats the worsening, the anxiogenic effect of both L-NAME and L-arginine. These might be also ketamine-specific effect, and thereby particular circumstances aggravation, providing the elevated plus-maze test as an anxiolytic effect of L-arginine [ 27 ] as well as L-NAME induced anxiolytic while L-arginine produced anxiogenic effects in the 6-OHDA mouse model of Parkinson’s disease [ 28 ]. Consistently in the ketamine-rats treated with either L-arginine or L-NAME, there is the decreased number of the trajectories in the central area, anxiogenic effect, the parallel worsening L-NAME/L-arginine effect (L-NAME, worsening, L-arginine, worsening).…”

“…In a specific manner, it might affect serotonin release in several brain areas, especially in substantia nigra [ 24 ]. In addition, as it was implicated for the NO-agents [ 25 , 26 , 27 , 28 ], BPC 157 has particular anxiolytic, anticonvulsant, and anti-depressant activity (for review, see [ 9 , 10 ]).…”