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Nitric Oxide in the Spinal Cord Is Involved in the Hyperalgesia Induced by Tetrahydrobiopterin in Chronic Restraint Stress Rats.

ABSTRACT: It has been well recognized that exposure to chronic stress could increase pain responding and exacerbate pain symptoms, resulting in stress-induced hyperalgesia. However, the mechanisms underlying stress-induced hyperalgesia are not yet fully elucidated. To this end, we observed that restraint as a stressful event exacerbated mechanical and thermal hyperalgesia, accompanied with up-regulation of nitric oxide (NO) (P < 0.001), GTP cyclohydrolase 1 (GCH1) (GCH1 mRNA: P = 0.001; GCH1 protein: P = 0.001), and tetrahydrobiopterin (BH4) concentration (plasma BH4: P < 0.001; spinal BH4: P < 0.001) on Day 7 in restraint stress (RS) rats. Intrathecal injection of N ^ω-nitro-L-arginine methyl ester (L-NAME), a non-specific NO synthase inhibitor, or N-([3-(aminomethyl)phenyl]methyl) ethanimidamide, a special inhibitor of inducible NO synthase (iNOS), for seven consecutive days attenuated stress-induced hyperalgesia and decreased the production of NO (P < 0.001). Interestingly, 7-nitro indazole, a special inhibitor of neuronal NO synthase, alleviated stress-induced hyperalgesia but did not affect spinal NO synthesis. Furthermore, intrathecal injection of BH4 not only aggravated stress-induced hyperalgesia but also up-regulated the expression of spinal iNOS (iNOS mRNA: P = 0.015; iNOS protein: P < 0.001) and NO production (P < 0.001). These findings suggest that hyperalgesia induced by RS is associated with the modulation of the GCH1-BH4 system and constitutively expressed spinal iNOS. Thus, the GCH1-BH4-iNOS signaling pathway may be a new novel therapeutic target for pain relief in the spinal cord.

SUBMITTER: Huang Y

PROVIDER: S-EPMC8044835 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionMales with acute spinal cord injury (SCI) frequently exhibit testosterone deficiency and reproductive dysfunction. While such incidence rates are high in chronic patients, the underlying mechanisms remain elusive.Methods and resultsHerein, we generated a rat SCI model, which recapitulated complications in human males, including low testosterone levels and spermatogenic disorders. Proteomics analyses showed that the differentially expressed proteins were mostly enriched in lipid metabolism and steroid metabolism and biosynthesis. In SCI rats, we observed that testicular nitric oxide (NO) levels were elevated and lipid droplet-autophagosome co-localization in testicular interstitial cells was decreased. We hypothesized that NO impaired lipophagy in Leydig cells (LCs) to disrupt testosterone biosynthesis and spermatogenesis. As postulated, exogenous NO donor (S-nitroso-N-acetylpenicillamine (SNAP)) treatment markedly raised NO levels and disturbed lipophagy via the AMPK/mTOR/ULK1 pathway, and ultimately impaired testosterone production in mouse LCs. However, such alterations were not fully observed when cells were treated with an endogenous NO donor (L-arginine), suggesting that mouse LCs were devoid of an endogenous NO-production system. Alternatively, activated (M1) macrophages were predominant NO sources, as inducible NO synthase inhibition attenuated lipophagic defects and testosterone insufficiency in LCs in a macrophage-LC co-culture system. In scavenging NO (2-4-carboxyphenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (CPTIO)) we effectively restored lipophagy and testosterone levels both in vitro and in vivo, and importantly, spermatogenesis in vivo. Autophagy activation by LYN-1604 also promoted lipid degradation and testosterone synthesis.DiscussionIn summary, we showed that NO-disrupted-lipophagy caused testosterone deficiency following SCI, and NO clearance or autophagy activation could be effective in preventing reproductive dysfunction in males with SCI.

Project description:The number of elderly patients with spinal cord injury without radiographic abnormalities (SCIWORA) has been increasing in recent years and common of most cervical spinal cord injuries. Basic research has shown the effectiveness of early decompression after spinal cord injury on the spinal cord without stenosis; no studies have reported the efficacy of decompression in models with spinal cord compressive lesions. The purpose of this study was to evaluate the effects of decompression surgery after acute spinal cord injury in rats with chronic spinal cord compressive lesions, mimicking SCIWORA. A water-absorbent polymer sheet (Aquaprene DX, Sanyo Chemical Industries) was inserted dorsally into the 4-5th cervical sublaminar space in 8-week-old Sprague Dawley rats to create a rat model with a chronic spinal compressive lesion. At the age of 16 weeks, 30 mildly myelopathic or asymptomatic rats with a Basso, Beattie, and Bresnahan score (BBB score) of 19 or higher were subjected to spinal cord compression injuries. The rats were divided into three groups: an immediate decompression group (decompress immediately after injury), a sub-acute decompression group (decompress 1 week after injury), and a non-decompression group. Behavioral and histological evaluations were performed 4 weeks after the injury. At 20 weeks of age, the BBB score and FLS (Forelimb Locomotor Scale) of both the immediate and the sub-acute decompression groups were significantly higher than those of the non-decompression group. There was no significant difference between the immediate decompression group and the sub-acute decompression group. TUNEL (transferase-mediated dUTP nick end labeling) staining showed significantly fewer positive cells in both decompression groups compared to the non-decompression group. LFB (Luxol fast blue) staining showed significantly more demyelination, and GAP-43 (growth associated protein-43) staining tended to show fewer positive cells in the non-decompression group. Decompression surgery in the acute or sub-acute phase of injury is effective after mild spinal cord injury in rats with chronic compressive lesions. There was no significant difference between the immediate decompression and sub-acute decompression groups.

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Nitric Oxide in the Spinal Cord Is Involved in the Hyperalgesia Induced by Tetrahydrobiopterin in Chronic Restraint Stress Rats.

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