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![| Environmental enrichment (EE) and ketamine (K) reduced nociceptive responses in hindpaws after spinal cord injury (SCI). (A-C) EE (n = 14), K (n = 8), and their combination EEK (n = 9) treatments alleviated SCI-induced mechanical allodynia [paw withdrawal threshold (PWT)]. n = 6 in sham and n = 8 in the SCI group. Two-way repeated-measures ANOVA (effect vs. group × time interaction) followed by Tukey's post hoc test. F ketamine (10,95) = 13.78, F ee (10,125) = 13.65, F eek (10,100) = 16.84. *P < 0.05, **P < 0.01, ***P < 0.001 vs. SCI. (D) Comparison between treatment effects over time by measuring area under the curve (AUC) demonstrated a higher efficacy of the joint treatment than individual ones in combating allodynia. One-way ANOVA (effect vs. group) followed by Tukey's post hoc test. F(3,33) = 78.27. *P < 0.05, **P < 0.01, ***P < 0.001. (E-G) SCI-induced thermal hyperalgesia [paw withdrawal latency (PWL)] was reduced by either ketamine (n = 8) or EE (n = 14) and was reversed by the EEK group (n = 9). n = 6 in sham and n = 7 in the SCI group. Two-way repeated-measures ANOVA (effect vs. group × time interaction) followed by Tukey's post hoc test. F ketamine (10,90) = 5.665, F ee (10,120) = 2.166, F eek (10,95) = 4.218. *P < 0.05, **P < 0.01, ***P < 0.001 vs. SCI. (H) Between-treatment comparison over time (AUC) demonstrated an added benefit of the combined treatment EEK in hyperalgesia relief. AUC is computed from timepoints day 10 to 28, which are after treatment started. One-way ANOVA (effect vs. group) followed by Tukey's post hoc test. F(3,33) = 27.72. *P < 0.05, **P < 0.01, ***P < 0.001. Data are presented as mean ± standard deviation (SD). Double-end line in bold indicates the 10-day period of ketamine administration (day 8 to 17). Sham, sham-operated group; BL, baseline.](publication/350279408/figure/fig2/AS:1010719231332356@1617985651674/Environmental-enrichment-EE-and-ketamine-K-reduced-nociceptive-responses-in.png)
| Environmental enrichment (EE) and ketamine (K) reduced nociceptive responses in hindpaws after spinal cord injury (SCI). (A-C) EE (n = 14), K (n = 8), and their combination EEK (n = 9) treatments alleviated SCI-induced mechanical allodynia [paw withdrawal threshold (PWT)]. n = 6 in sham and n = 8 in the SCI group. Two-way repeated-measures ANOVA (effect vs. group × time interaction) followed by Tukey's post hoc test. F ketamine (10,95) = 13.78, F ee (10,125) = 13.65, F eek (10,100) = 16.84. *P < 0.05, **P < 0.01, ***P < 0.001 vs. SCI. (D) Comparison between treatment effects over time by measuring area under the curve (AUC) demonstrated a higher efficacy of the joint treatment than individual ones in combating allodynia. One-way ANOVA (effect vs. group) followed by Tukey's post hoc test. F(3,33) = 78.27. *P < 0.05, **P < 0.01, ***P < 0.001. (E-G) SCI-induced thermal hyperalgesia [paw withdrawal latency (PWL)] was reduced by either ketamine (n = 8) or EE (n = 14) and was reversed by the EEK group (n = 9). n = 6 in sham and n = 7 in the SCI group. Two-way repeated-measures ANOVA (effect vs. group × time interaction) followed by Tukey's post hoc test. F ketamine (10,90) = 5.665, F ee (10,120) = 2.166, F eek (10,95) = 4.218. *P < 0.05, **P < 0.01, ***P < 0.001 vs. SCI. (H) Between-treatment comparison over time (AUC) demonstrated an added benefit of the combined treatment EEK in hyperalgesia relief. AUC is computed from timepoints day 10 to 28, which are after treatment started. One-way ANOVA (effect vs. group) followed by Tukey's post hoc test. F(3,33) = 27.72. *P < 0.05, **P < 0.01, ***P < 0.001. Data are presented as mean ± standard deviation (SD). Double-end line in bold indicates the 10-day period of ketamine administration (day 8 to 17). Sham, sham-operated group; BL, baseline.
Source publication
Spinal cord injury (SCI) impairs mobility and often results in complications like intractable neuropathic pain. A multi-approach management of this chronic pain condition has been encouraged, but little has been explored of the field. Here, we focus on the effect and underlying mechanism of environmental enrichment (EE), which promotes voluntary so...
Contexts in source publication
Context 1
... developed mechanical allodynia after SCI that persisted for at least 28 days, which was demonstrated by significantly lower PWT in the ipsilateral hindpaws of SCI rats than that in sham (all P < 0.001, n = 8, Figures 2A-C). In contrast to the SCI group, 10 days' injection of subanesthetic ketamine (30 mg kg −1 day −1 , intramuscular; Figure 2A) significantly increased PWT by 2 days after initial injection. ...
Context 2
... developed mechanical allodynia after SCI that persisted for at least 28 days, which was demonstrated by significantly lower PWT in the ipsilateral hindpaws of SCI rats than that in sham (all P < 0.001, n = 8, Figures 2A-C). In contrast to the SCI group, 10 days' injection of subanesthetic ketamine (30 mg kg −1 day −1 , intramuscular; Figure 2A) significantly increased PWT by 2 days after initial injection. Although a slight drop in PWT was seen after ketamine discontinued on POD 17, the remaining drug effect continued to relieve pain-like behavior till experiment end point (POD 10 to 28; all P < 0.01). ...
Context 3
... a slight drop in PWT was seen after ketamine discontinued on POD 17, the remaining drug effect continued to relieve pain-like behavior till experiment end point (POD 10 to 28; all P < 0.01). EE housing took effect later than ketamine did but in a progressive manner ( Figure 2B). It first increased PWT by a week after housing began and continued to further elevate PWT progressively (POD 14 to 28; all P < 0.001). ...
Context 4
... first increased PWT by a week after housing began and continued to further elevate PWT progressively (POD 14 to 28; all P < 0.001). In comparison, the combination of ketamine and EE markedly increased PWT starting from POD 10 (all P < 0.001; Figure 2C) and reversed the threshold to basal level by POD 28 (P = 0.438, EEK: 49.629 ± 3.270 g vs. sham: 52.645 ± 2.332 g). To evaluate differences in the therapeutic effects between treatment groups overtime, we compared the AUC of PWT of treated groups, which is a measure of both magnitude and duration. ...
Context 5
... evaluate differences in the therapeutic effects between treatment groups overtime, we compared the AUC of PWT of treated groups, which is a measure of both magnitude and duration. Over the experiment time course, the joint treatment conferred significantly better relief of allodynia than that by ketamine or EE alone (P < 0.01; Figure 2D). Thermal hyperalgesia manifested as significant decrease of ipsilateral PWL in response to noxious heat stimulus after SCI compared with sham (POD 7 to 28, all P < 0.01; Figures 2E- G). ...
Context 6
... the experiment time course, the joint treatment conferred significantly better relief of allodynia than that by ketamine or EE alone (P < 0.01; Figure 2D). Thermal hyperalgesia manifested as significant decrease of ipsilateral PWL in response to noxious heat stimulus after SCI compared with sham (POD 7 to 28, all P < 0.01; Figures 2E- G). After 2 days of ketamine injection (Figure 2E), PWL spiked as observed on POD 10 (P < 0.001, K: 9.987 ± 0.702 s vs. SCI: 5.442 ± 0.713 s) and returned to the basal level from POD 10 to 21 (all P > 0.05 vs. sham). ...
Context 7
... hyperalgesia manifested as significant decrease of ipsilateral PWL in response to noxious heat stimulus after SCI compared with sham (POD 7 to 28, all P < 0.01; Figures 2E- G). After 2 days of ketamine injection (Figure 2E), PWL spiked as observed on POD 10 (P < 0.001, K: 9.987 ± 0.702 s vs. SCI: 5.442 ± 0.713 s) and returned to the basal level from POD 10 to 21 (all P > 0.05 vs. sham). After ketamine cessation (POD 17), such analgesia lasted at least 4 days (POD 21: P < 0.001) and their combination EEK (n = 9) treatments alleviated SCI-induced mechanical allodynia [paw withdrawal threshold (PWT)]. ...
Context 8
... the other hand, EE gradually increased PWL, which reached a significant level by POD 14 (P < 0.05, EE: 7.452 ± 1.535 s vs. SCI: 5.432 ± 0.724 s). This effect was maintained throughout the experiment where PWL returned to the basal level from POD 14 to 21 (all P > 0.05 vs. sham, Figure 2F). In contrast, combined regimen EEK took effect early and reversed hyperalgesia-like behavior by 6 days after treatment commenced and returned PWL to the basal level from POD 10 to 28 (all P > 0.05 vs. sham). ...
Context 9
... contrast, combined regimen EEK took effect early and reversed hyperalgesia-like behavior by 6 days after treatment commenced and returned PWL to the basal level from POD 10 to 28 (all P > 0.05 vs. sham). The observed significant analgesia lasted through the experiment time course (POD 14 to 28: all P < 0.001 vs. SCI, Figure 2G). Overtime, the combination treatment demonstrated a strong efficacy against thermal hyperalgesia, surpassing the effects of ketamine or EE significantly (P < 0.001; Figure 2H). ...
Context 10
... observed significant analgesia lasted through the experiment time course (POD 14 to 28: all P < 0.001 vs. SCI, Figure 2G). Overtime, the combination treatment demonstrated a strong efficacy against thermal hyperalgesia, surpassing the effects of ketamine or EE significantly (P < 0.001; Figure 2H). ...
Citations
... Glutamate receptor antagonists have been assessed in EAE, primarily in the context of neuroprotection, prevention of demyelination, and improvement of motor deficits (144)(145)(146)(147)(148). Although glutamate receptor antagonists, including memantine (149)(150)(151) or modulators of the glutamatergic system such as ketamine (152,153) have been used for the relief of chronic pain in various diseases or injuries, their effectiveness in the alleviation of neuropathic pain during EAE/MS has not been adequately investigated. ...
Multiple sclerosis (MS) is a multifaceted, complex and chronic neurological disease that leads to motor, sensory and cognitive deficits. MS symptoms are unpredictable and exceedingly variable. Pain is a frequent symptom of MS and manifests as nociceptive or neuropathic pain, even at early disease stages. Neuropathic pain is one of the most debilitating symptoms that reduces quality of life and interferes with daily activities, particularly because conventional pharmacotherapies do not adequately alleviate neuropathic pain. Despite advances, the mechanisms underlying neuropathic pain in MS remain elusive. The majority of the studies investigating the pathophysiology of MS-associated neuropathic pain have been performed in animal models that replicate some of the clinical and neuropathological features of MS. Experimental autoimmune encephalomyelitis (EAE) is one of the best-characterized and most commonly used animal models of MS. As in the case of individuals with MS, rodents affected by EAE manifest increased sensitivity to pain which can be assessed by well-established assays. Investigations on EAE provided valuable insights into the pathophysiology of neuropathic pain. Nevertheless, additional investigations are warranted to better understand the events that lead to the onset and maintenance of neuropathic pain in order to identify targets that can facilitate the development of more effective therapeutic interventions. The goal of the present review is to provide an overview of several mechanisms implicated in neuropathic pain in EAE by summarizing published reports. We discuss current knowledge gaps and future research directions, especially based on information obtained by use of other animal models of neuropathic pain such as nerve injury.
... Moreover, the release of proinflammatory cytokines by spinal glial cells might be indirectly modulated by SCS. It is known that astrogliosis occurs and microglial GluN2B increases after SCI in rats [48], and the local astroglial scar is proven to hamper the neuroregeneration in the injured spinal cord. Additionally, the proinflammatory cytokines and chemokines released from activated microglia due to SCI contribute to the central sensitization in neuropathic pain. ...
Spinal cord stimulation (SCS) as an evidence-based interventional treatment has been used and approved for clinical use in a variety of pathological states including peripheral neuropathic pain; however, until now, it has not been used for the treatment of spinal cord injury- (SCI-) induced central neuropathic pain. This paper reviews the underlying mechanisms of SCS-induced analgesia and its clinical application in the management of peripheral and central neuropathic pain. Evidence from recent research publications indicates that nociceptive processing at peripheral and central sensory systems is thought to be modulated by SCS through (i) inhibition of the ascending nociceptive transmission by the release of analgesic neurotransmitters such as GABA and endocannabinoids at the spinal dorsal horn; (ii) facilitation of the descending inhibition by release of noradrenalin, dopamine, and serotonin acting on their receptors in the spinal cord; and (iii) activation of a variety of supraspinal brain areas related to pain perception and emotion. These insights into the mechanisms have resulted in the clinically approved use of SCS in peripheral neuropathic pain states like Complex Regional Pain Syndrome (CRPS) and Failed Back Surgery Syndrome (FBSS). However, the mechanisms underlying SCS-induced pain relief in central neuropathic pain are only partly understood, and more research is needed before this therapy can be implemented in SCI patients with central neuropathic pain.
... We also looked at the dorsal horn as activation of these fibers are known to contribute to chronic pain (Mohammadi et al., 2018). Also, the literature suggests that EE can inhibit activity in the dorsal horn to relieve neuropathic pain (Tai et al., 2021), leading us to investigate whether it can produce the same effects for visceral pain. We showed that exposure to EE inhibits neuronal activation to colorectal distension at the dorsal horn. ...
Introduction
Stress is a known trigger for the symptoms of irritable bowel syndrome (IBS), a gastrointestinal (GI) disorder that presents with abnormal bowel habits and abdominal pain due to visceral hypersensitivity. While behavioral therapies have been used to attenuate IBS symptoms, the underlying mechanisms by which these therapies interact with stress-induced pathology remains to be delineated. Here we use a rat model to test the hypothesis that exposure to environmental enrichment (EE) inhibits stress-induced changes within the brain-gut axis to prevent visceral and somatic hypersensitivity and colonic hyperpermeability.
Methods
Female rats (n = 8/group) were housed in EE one week before and one week during exposure to water avoidance stress (WAS) while controls were housed in standard cages (SH). One day after the final WAS exposure, colonic and somatic sensitivity were assessed by the visceromotor response (VMR) to colorectal distension (CRD) and withdrawal threshold elicited by an electronic von Frey on the hind paw of the rats respectively. All rats were returned to SH for 3 weeks before colonic and somatic sensitivity were reassessed on day 28. The rats were then immediately euthanized and the spinal cord was collected to assess changes in neuronal activation (assessed via ERK phosphorylation) in response to noxious CRD. A separate cohort of animals (n = 8/group) that did not undergo behavioral assessments was euthanized the day after the final WAS exposure and the central nucleus of the amygdala (CeA) was collected to investigate WAS and EE induced epigenetic changes at the glucocorticoid receptor (GR) and corticotrophin releasing hormone (CRH) promoter. The colon from these rats was also collected to assess colonic permeability via changes in transepithelial electrical resistance (TEER) in vitro.
Results
Exposure to stress persistently increased VMR to CRD (P < 0.01) and decreased the hind paw withdrawal threshold (P < 0.001) in female rats. WAS also decreased TEER in the colon tissue of female rats (p = 0.05). In the CeA, WAS induced a decrease in histone acetylation at the GR promoter but increased histone acetylation at the CRH promoter and reduced GR-CRH interactions in the CeA. Analysis of the spinal cord showed that WAS increased CRD-evoked ERK phosphorylation in the dorsal horn. Exposure to EE prevented WAS-induced changes in the CeA, dorsal horn and colon respectively to prevent visceral and somatic hypersensitivity.
Conclusion
Our data reveals that behavioral therapies can produce long lasting molecular and epigenetic changes that can prevent stress-induced pathologies even after completion of the therapy. These results highlight the potential mechanisms by which behavioral therapies may ameliorate visceral pain associated stress-related pathologies such as the irritable bowel syndrome.
Mammalian target of rapamycin (mTOR) is an important molecule that regulates cell metabolism, growth, and proliferation in the nervous system. This study aimed to present the current study hot spots and predict the future development trend of the mTOR pathway in neurologic diseases using bibliometrics. We referred to the publications in the Web of Science Core Collection database. VOSviewer and CiteSpace programs were used to evaluate countries/regions, institutions, authors, journals, keywords, and citations showing the current study focus and predicting the future trend of mTOR in neuroscience. The search date ended on 19 June 2022, and there were 3,029 articles on mTOR in neuroscience from 2002 to 2021. Visual analysis showed that although the number of publications declined slightly in some years, the number of publications related to mTOR generally showed an upward trend, reaching its peak in 2021. It had the largest number of publications in the United States. Keywords and literature analysis showed that protein synthesis regulation, ischemia, mitochondrial dysfunction, oxidative stress, and neuroinflammation may be hot spots and future directions of the nervous system in mTOR studies. Recently, the most studied neurological diseases are Alzheimer’s disease (AD), tuberous sclerosis complex (TSC), and depression, which are still worthy of further studies by researchers in the future. This can provide a useful reference for future researchers to study mTOR further in the field of neuroscience.
Objective: Spinal cord injury (SCI) causes motor deficits, urinary incontinence, and neuropathic pain. This study was designed to optimize a photobiomodulation therapy (PBMT) protocol using a continuous wave (CW) 660 nm laser in rats with SCI. Specifically, the number of days of irradiation and the daily dose of PBMT were investigated. Methods: The study was performed in two steps. In the first step, a comparison between the effects of PBMT (45 sec) daily for 2 and 4 weeks on pain and movement [Basso, Beattie, and Brenham (BBB) score] was made. In the second step, a comparison between different durations of irradiation (27, 45, 90, and 117 sec) was performed. PBMT used a 100 mW laser delivered to 9 points on and around the lesion site. Oxidative stress, fibroblast invasion, and time to achieve spontaneous urination were also assessed. Results: The improvement in movement and pain stopped with discontinuation of radiation at week 2 and fibroblast invasion resumed. No improvement was seen in movement and pain in the group receiving PBMT for 27 sec compared with the groups receiving higher doses of laser radiation. Animals receiving 117 sec of photobiomodulation showed a higher BBB score even in the first 3 days. Conclusions: The number of days is an important factor for improving mobility; however, the daily dose of radiation is more important for pain relief.
