Effects of multiple intrathecal administration of L-arginine with different doses on formalin-induced nociceptive behavioral responses in rats.
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ABSTRACT:
SUBMITTER: Li K
PROVIDER: S-EPMC5552487 | biostudies-other | 2010 Jun
REPOSITORIES: biostudies-other
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Project description:BACKGROUND AND PURPOSE:Kyotorphin (KTP; L-Tyr-L-Arg), an endogenous neuropeptide, is potently analgesic when delivered directly to the central nervous system. Its weak analgesic effects after systemic administration have been explained by inability to cross the blood-brain barrier (BBB) and detract from the possible clinical use of KTP as an analgesic. In this study, we aimed to increase the lipophilicity of KTP by amidation and to evaluate the analgesic efficacy of a new KTP derivative (KTP-amide - KTP-NH(2) ). EXPERIMENTAL APPROACH:We synthesized KTP-NH(2) . This peptide was given systemically to assess its ability to cross the BBB. A wide range of pain models, including acute, sustained and chronic inflammatory and neuropathic pain, were used to characterize analgesic efficacies of KTP-NH(2) . Binding to opioid receptors and toxicity were also measured. KEY RESULTS:KTP-NH(2) , unlike its precursor KTP, was lipophilic and highly analgesic following systemic administration in several acute and chronic pain models, without inducing toxic effects or affecting motor responses and blood pressure. Binding to opioid receptors was minimal. KTP-NH(2) inhibited nociceptive responses of spinal neurons. Its analgesic effects were prevented by intrathecal or i.p. administration of naloxone. CONCLUSIONS AND IMPLICATIONS:Amidation allowed KTP to show good analgesic ability after systemic delivery in acute and chronic pain models. The indirect opioid-mediated actions of KTP-NH(2) may explain why this compound retained its analgesic effects although the usual side effects of opioids were absent, which is a desired feature in next-generation pain medications.
| S-EPMC3130928 | biostudies-literature
Project description:ObjectiveThis phase I/II study sought to explore intrathecal administration of mesenchymal stem cells (MSCs) as therapeutic approach to multiple system atrophy (MSA).MethodsUtilizing a dose-escalation design, we delivered between 10 and 200 million adipose-derived autologous MSCs intrathecally to patients with early MSA. Patients were closely followed with clinical, laboratory, and imaging surveillance. Primary endpoints were frequency and type of adverse events; key secondary endpoint was the rate of disease progression assessed by the Unified MSA Rating Scale (UMSARS).ResultsTwenty-four patients received treatment. There were no attributable serious adverse events, and injections were generally well-tolerated. At the highest dose tier, 3 of 4 patients developed low back/posterior leg pain, associated with thickening/enhancement of lumbar nerve roots. Although there were no associated neurologic deficits, we decided that dose-limiting toxicity was reached. A total of 6 of 12 patients in the medium dose tier developed similar, but milder and transient discomfort. Rate of progression (UMSARS total) was markedly lower compared to a matched historical control group (0.40 ± 0.59 vs 1.44 ± 1.42 points/month, p = 0.004) with an apparent dose-dependent effect.ConclusionsIntrathecal MSC administration in MSA is safe and well-tolerated but can be associated with a painful implantation response at high doses. Compelling dose-dependent efficacy signals are the basis for a planned placebo-controlled trial.Classification of evidenceThis phase I/II study provides Class IV evidence that for patients with early MSA, intrathecal MSC administration is safe, may result in a painful implantation response at high doses, and is associated with dose-dependent efficacy signals.
| S-EPMC6659003 | biostudies-literature
Project description:Substantial evidence from preclinical models of pain suggests that basal and noxious nociceptive sensitivity, as well as antinociceptive responses to drugs, show significant heritability. Individual differences to these responses have been observed across species from rodents to humans. The use of closely related C57BL/6 inbred mouse substrains can facilitate gene mapping of acute nociceptive behaviors in preclinical pain models. In this study, we investigated behavioral differences between C57BL/6 J (B6 J) and C57BL/6 N (B6 N) substrains in the formalin test, a widely used tonic inflammatory pain model, using a battery of pain-related phenotypes, including reflexive tests, nesting, voluntary wheel running, sucrose preference and anxiety-like behavior in the light/dark test at two different time points (1-h and 24-h). Our results show that these substrains did not differ in reflexive thermal and mechanical responses at the 1-h time point. However, B6 N substrain mice showed increased sensitivity to spontaneous pain-like behaviors. In addition, B6 N substrain continued to show higher levels of mechanical hypersensitivity compared to controls at 24-h. indicating that mechanical hypersensitivity is a more persistent pain-related phenotype induced by formalin. Finally, no sex differences were observed in our outcome measures. Our results provide a comprehensive behavioral testing paradigm in response to an inflammatory agent for future mouse genetic studies in pain.
| S-EPMC7375808 | biostudies-literature
Project description:In patients suffering from multiple sclerosis (MS), intrathecal injection of triamcinolone acetonide (TCA) has been shown to improve symptoms of spasticity. Although repeated intrathecal injection of TCA has been used in a number of studies in late-stage MS patients with spinal cord involvement, no clinical-chemical data are available on the distribution of TCA in cerebrospinal fluid (CSF) or serum. Moreover, the effects of intrathecal TCA administration on the concentrations of endogenous steroids remain poorly understood. Therefore, we have quantified TCA and selected endogenous steroids in CSF and serum of TCA-treated MS patients suffering from spasticity. Concentrations of steroids were quantified by LC-MS, ELISA, or ECLIA and compared with the blood-brain barrier status, diagnosed with the Reibergram. The concentration of TCA in CSF significantly increased during each treatment cycle up to >5 μg/ml both in male and female patients (p < 0.001). Repeated TCA administration also evoked serum concentrations of TCA up to >30 ng/ml (p < 0.001) and severely depressed serum levels of cortisol and corticosterone (p < 0.001). In addition, concentrations of circulating estrogen were significantly suppressed (p < 0.001). Due to the potent suppressive effects of TCA on steroid hormone concentrations both in the brain and in the periphery, we recommend careful surveillance of adrenal function following repeated intrathecal TCA injections in MS patients.
| S-EPMC7481359 | biostudies-literature
Project description:Understanding the effects of environmental change on natural ecosystems is a major challenge, particularly when multiple stressors interact to produce unexpected "ecological surprises" in the form of complex, nonadditive effects that can amplify or reduce their individual effects. Animals often respond behaviorally to environmental change, and multiple stressors can have both population-level and community-level effects. However, the individual, not combined, effects of stressors on animal behavior are commonly studied. There is a need to understand how animals respond to the more complex combinations of stressors that occur in nature, which requires a systematic and rigorous approach to quantify the various potential behavioral responses to the independent and interactive effects of stressors. We illustrate a robust, systematic approach for understanding behavioral responses to multiple stressors based on integrating schemes used to quantitatively classify interactions in multiple-stressor research and to qualitatively view interactions between multiple stimuli in behavioral experiments. We introduce and unify the two frameworks, highlighting their conceptual and methodological similarities, and use four case studies to demonstrate how this unification could improve our interpretation of interactions in behavioral experiments and guide efforts to manage the effects of multiple stressors. Our unified approach: (1) provides behavioral ecologists with a more rigorous and systematic way to quantify how animals respond to interactions between multiple stimuli, an important theoretical advance, (2) helps us better understand how animals behave when they encounter multiple, potentially interacting stressors, and (3) contributes more generally to the understanding of "ecological surprises" in multiple stressors research.
| S-EPMC5214703 | biostudies-other
Project description:Objective:In this study, we aim to investigate the effect of different doses of dexmedetomidine as an adjuvant to hyperbaric ropivacaine in spinal anesthesia for cesarean section. Methods:Seventy-five parturients with American Society of Anesthesiologists (ASA) I or II were anesthetized with intrathecal ropivacaine (12.5 mg) alone (R group) or in combination with dexmedetomidine 3 ?g (RD3 group) and 5 ?g (RD5 group) to undergo a cesarean section. The anesthetic parameters, postoperative analgesia, stress responses and neonates outcomes were monitored. Results:The onset time of sensory block to T10, T4, and peak level in the RD3 group and RD5 group were significantly shorter than those in the R group (p < 0.05). The time of the level of sensory block to descend two segments and to T10 in the RD3 group(57.28 ± 16.65 min, 3.87 ± 1.60 h) and RD5 group (71.92 ± 10.10 min, 3.99 ± 1.06 h) were longer than that in the R group (40.64 ± 12.06 min, 1.98 ± 1.01 h) (p < 0.05). The median time of motor blockade to both legs score 3 on the Bromage scale (B3B3) in the RD3 group and RD5 group was shorter than that in the R group (p < 0.001). The time of motor blockade recovery to both legs score 0 on the Bromage scale (B0B0) in the RD5 group (3.6 h) was longer than that in the R group (2 h) or RD3 group (2.2 h) (p < 0.001). Visceral traction response and abdominal muscle relaxation during the operation in the RD3 group and the RD5 group were better than that in the R group. The Visual Analogue Score (VAS) in the 12 h after the operation in the RD3 group (3.30 ± 1.17) and RD5 group (2.80 ± 0.87) was smaller than that in the R group (3.80 ± 1.47) (p < 0.05). The incidence of shivering in the RD3 group and RD5 group was significantly lower than that in the R group (p < 0.05). The postoperative concentrations of c-reactive protein (CRP), interleukin-6 (IL-6) and cortisol in the RD3 and RD5 groups were lower than that in the R group (p < 0.05). Conclusion:3 µg intrathecal dexmedetomidine as an adjuvant to ropivacaine improved intraoperative somato-visceral sensory block characteristics and postoperative analgesia, alleviated shivering in parturients, and did not prolong the time of motor block or produce any side effects, which makes this dose appropriate for cesarean delivery. Cinical Trial Registration:ChiCTR, identifier ChiCTR1800014454. Registered 15 January 2018, http://www.chictr.org.cn/edit.aspx?pid=24613&htm=4.
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Project description:Melanopsin (OPN4) is a retinal photopigment that mediates a wide range of non-image-forming (NIF) responses to light including circadian entrainment, sleep induction, the pupillary light response (PLR), and negative masking of locomotor behavior (the acute suppression of activity in response to light). How these diverse NIF responses can all be mediated by a single photopigment has remained a mystery. We reasoned that the alternative splicing of melanopsin could provide the basis for functionally distinct photopigments arising from a single gene. The murine melanopsin gene is indeed alternatively spliced, producing two distinct isoforms, a short (OPN4S) and a long (OPN4L) isoform, which differ only in their C terminus tails. Significantly, both isoforms form fully functional photopigments. Here, we show that different isoforms of OPN4 mediate different behavioral responses to light. By using RNAi-mediated silencing of each isoform in vivo, we demonstrated that the short isoform (OPN4S) mediates light-induced pupillary constriction, the long isoform (OPN4L) regulates negative masking, and both isoforms contribute to phase-shifting circadian rhythms of locomotor behavior and light-mediated sleep induction. These findings demonstrate that splice variants of a single receptor gene can regulate strikingly different behaviors.
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Project description:Somatosensory neurons (SSNs) that detect and transduce mechanical, thermal, and chemical stimuli densely innervate an animal’s skin. However, although epidermal cells provide the first point of contact for sensory stimuli. our understanding of roles that epidermal cells play in SSN function, particularly nociception, remains limited. Here, we show that stimulating Drosophila epidermal cells elicits activation of SSNs including nociceptors and triggers a variety of behavior outputs, including avoidance and escape. Further, we find that epidermal cells are intrinsically mechanosensitive and that epidermal mechanically evoked calcium responses require the store-operated calcium channel Orai. Epidermal cell stimulation augments larval responses to acute nociceptive stimuli and promotes prolonged hypersensitivity to subsequent mechanical stimuli. Hence, epidermal cells are key determinants of nociceptive sensitivity and sensitization, acting as primary sensors of noxious stimuli that tune nociceptor output and drive protective behaviors.
2024-12-19 | GSE284380 | GEO
Project description:Enzyme replacement therapy with intravenous idursulfase (recombinant iduronate-2-sulfatase) is approved for the treatment of Hunter syndrome. Intravenous administration does not, however, treat the neurological manifestations, due to its low central nervous system bioavailability. Using intrathecal-lumbar administration, iduronate-2-sulfatase is delivered directly to the central nervous system. This study investigates the central nervous system biodistribution of intrathecal-lumbar administered iduronate-2-sulfatase in cynomolgus monkeys. Twelve monkeys were administered iduronate-2-sulfatase in one 30 mg intrathecal-lumbar injection. Brain, spinal cord, liver, and kidneys were collected for iduronate-2-sulfatase concentration (measured by an enzyme linked immunosorbent assay) and enzyme activity measurement (via a method utilizing 4-methylumbelliferyl-?-iduronate-2-sulfate) at 1, 2, 5, 12, 24, and 48 hours following administration. The tissue enzyme linked immunosorbent assay confirmed iduronate-2-sulfatase uptake to the brain, spinal cord, kidneys, and liver in a time-dependent manner. In spinal cord and brain, iduronate-2-sulfatase appeared as early as 1 hour following administration, and peak concentrations were observed at ~2 and ~5 hours. Iduronate-2-sulfatase appeared in liver and kidneys 1 hour post intrathecal-lumbar dose with peak concentrations between 5 and 24 hours. Liver iduronate-2-sulfatase concentration was approximately 10-fold higher than kidney. The iduronate-2-sulfatase localization and enzyme activity in the central nervous system, following intrathecal administration, demonstrates that intrathecal-lumbar treatment with iduronate-2-sulfatase may be considered for further investigation as a treatment for Hunter syndrome patients with neurocognitive impairment.
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Project description:Preclinical studies have demonstrated that a single injection of an adeno-associated virus (AAV) vector into the cerebrospinal fluid (CSF) can achieve widespread gene transfer throughout the central nervous system. Successfully translating this approach to humans requires identifying factors that influence AAV distribution in the CSF so that optimal parameters can be replicated in the clinic. In the context of developing a motor neuron-targeted gene therapy for spinal muscular atrophy, we conducted studies in nonhuman primates to evaluate the impact of injection volume on spinal cord transduction after AAV delivery via lumbar puncture. Lumbar injection of an AAVhu68 vector targeted motor neurons throughout the spinal cord, but only in juvenile nonhuman primates administered large injection volumes, equivalent to about half of the total CSF volume. Upon repeating this study with clinically relevant injection volumes and larger animals, we found that lumbar puncture failed to achieve significant transduction of the spinal cord. In contrast, vector administered into the cisterna magna distributed reproducibly throughout the spinal cord in both juvenile and adult animals. These findings highlight the challenges of translating AAV delivery via lumbar puncture to humans and suggest that delivery into the cisterna magna may represent a more feasible alternative.
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