Wake-promoting actions of median nerve stimulation in TBI-induced coma: An investigation of orexin-A and orexin receptor 1 in the hypothalamic region
Open accessAbstract
A coma is a serious complication, which can occur following traumatic brain injury (TBI), for which no effective treatment has been established. Previous studies have suggested that neural electrical stimulation, including median nerve stimulation (MNS), may be an effective method for treating patients in a coma, and orexin‑A, an excitatory hypothalamic neuropeptide, may be involved in wakefulness. However, the exact mechanisms underlying this involvement remain to be elucidated. The present study aimed to examine the arousal‑promoting role of MNS in rats in a TBI‑induced coma and to investigate the potential mechanisms involved. A total of 90 rats were divided into three groups, comprising a control group, sham‑stimulated (TBI) group and a stimulated (TBI + MNS) group. MNS was performed on the animals, which were in a TBI‑induced comatose state. Changes in the behavior of the rats were observed following MNS. Subsequently, hypothalamic tissues were extracted from the rats 6, 12 and 24 h following TBI or MNS, respectively. The expression levels of orexin‑A and orexin receptor‑1 (OX1R) in the hypothalamus were examined using immunohistochemistry, western blotting and an enzyme‑linked immunosorbent assay. The results demonstrated that 21 rats subjected to TBI‑induced coma exhibited a restored righting reflex and response to pain stimuli following MNS. In addition, ignificant differences in the expression levels of orexin‑A and OXIR were observed among the three groups and among the time‑points. Orexin‑A and OX1R were upregulated following MNS. The rats in the stimulated group reacted to the MNS and exhibited a re‑awakening response. The results of the present study indicated that MNS may be a therapeutic option for TBI‑induced coma. The mechanism may be associated with increasing expression levels of the excitatory hypothalamic neuropeptide, orexin-A, and its receptor, OX1R, in the hypothalamic region.
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In another study, significantly more orexin was observed in injured animals compared to sham-injured animals at 6 h post-injury, but not at 12 or 24 h.
“They observed significantly more orexin in injured animals compared to sham-injured animals at 6 h post-injury, but not at 12 or 24 h.”
From Effects of Traumatic Brain Injury on the Orexin/Hypocretin System (2025) · cites this paper as [76]
The Animal model section defines the comparison groups as uninjured controls, rats with TBI but no stimulation, and rats with TBI given median nerve stimulation—not injured versus sham-injured animals. The ELISA results report significant differences in orexin-A among these groups at both 6 and 12 hours, but not at 24 hours, contrary to the claimed 6-hour-only result. Page numbers are unavailable in our copy. (LLM, conf=0.88)
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Experimental — accuracy not yet measuredSeveral studies found an increase of orexin receptors compared to sham-injured animals after TBI.
“Several studies found an increase of orexin receptors compared to sham-injured animals after TBI,75–79,89”
From Effects of Traumatic Brain Injury on the Orexin/Hypocretin System (2025) · cites this paper as [76]
The Animal model section describes the control rats as receiving no interventions, not a sham injury. The Western blotting section reports higher hypothalamic OX1R in the TBI-only group than in controls at 6 and 24 hours, but lower OX1R at 12 hours. Thus, the paper supports an increase at some time points, not an unqualified increase compared with sham-injured animals. (LLM, conf=0.86)
Experimental — accuracy not yet measuredOne study demonstrates an acute increase in orexin receptors followed by a decrease.
“One study of orexin receptors,76 demonstrates a similar trend to the orexin neuropeptide expression, that there is an acute increase in orexin receptors followed by a decrease.”
From Effects of Traumatic Brain Injury on the Orexin/Hypocretin System (2025) · cites this paper as [76]
The Discussion (page not provided) reports that hypothalamic OX1R expression in stimulated rats rose from 6 to 12 hours, then fell by 24 hours. But it reports orexin-A increasing across all three time points, so the claimed similarity to the neuropeptide trend is not supported. (LLM, conf=0.88)
Experimental — accuracy not yet measuredOther studies found a decrease of orexin receptors compared to sham-injured animals after TBI.
“while other studies found a decrease of orexin receptors compared to sham-injured animals after TBI.76,77,90,91”
From Effects of Traumatic Brain Injury on the Orexin/Hypocretin System (2025) · cites this paper as [76]
The Western blotting results report lower hypothalamic OX1R in the TBI-only group than in controls at 12 hours, but higher levels at 6 and 24 hours. The Animal model section defines controls as receiving no interventions, not as sham-injured animals. Thus, the paper supports a decrease only at one time point and with a different comparator. (LLM, conf=0.86)
Experimental — accuracy not yet measuredSeveral studies found an increase in orexin neuropeptide after TBI.
“Several studies found an increase in orexin neuropeptide after TBI.75,76”
From Effects of Traumatic Brain Injury on the Orexin/Hypocretin System (2025) · cites this paper as [76]
The Discussion (page unavailable) reports increased hypothalamic orexin-A in rats with TBI-induced coma after median nerve stimulation. It also says the difference between unstimulated TBI rats and controls was not statistically significant, so this paper does not establish a general increase after TBI alone. (LLM, conf=0.86)
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Cited by
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Kousi, C., Lampri, E., Voulgaris, S., Vougiouklakis, T., Galani, V., & Mitselou, A. (2021) · Forensic Science International · doi:10.1016/j.forsciint.2021.110961 · Cited by 10 · see citing works
Effects of Traumatic Brain Injury on the Orexin/Hypocretin System
Somach, R. T., Lim, M. M., & Cohen, A. S. (2025) · Neurotrauma Reports · doi:10.1089/neur.2024.0111 · Cited by 2 · see citing works
- Authors
- ZHONG, Y.-J., FENG, Z., WANG, L., & WEI, T.-Q.
- Affiliations
- First Affiliated Hospital of Nanchang University (CN)
- Venue
- Molecular Medicine Reports
- Publisher
- Spandidos Publications
- Published
- 2015-06-08
- Volume
- 12
- Issue
- 3
- Pages
- 4441-4447
- ISSN
- 1791-2997 (ISSN-L)
- 1791-3004
- OpenAlex
- W2105489768
- Cited by
- 23
- References
- 0
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 3 · 2023: 1 · 2022: 3 · 2021: 4 · 2019: 2 · 2018: 2 · 2016: 2
- FWCI
- 0.94
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular Medicine Reports (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81260295)
- Natural Science Foundation of Jiangxi Province
- Topics
- Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Health Sciences › Medicine › Epidemiology › Traumatic Brain Injury Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
- Keywords
- traumatic brain injury, coma, median nerve stimulation, electrotherapy, orexin-A, orexin-1 receptor, hypothalamus, arousal, wakefulness, righting reflex, pain response
- MeSH terms
- Orexins, Animals, Brain Injuries, Coma, Electric Stimulation Therapy, Female, Hypothalamus, Male, Median Nerve, Rats, Sprague-Dawley, Orexin Receptors
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