scholarly journals Evaluation of Spinal Toxicity and Long-term Spinal Reflex Function after Intrathecal Levobupivaciane in the Neonatal Rat

2013 ◽  
Vol 119 (1) ◽  
pp. 142-155 ◽  
Author(s):  
Emre Hamurtekin ◽  
Bethany L. Fitzsimmons ◽  
Veronica I. Shubayev ◽  
Marjorie R. Grafe ◽  
Ronald Deumens ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Caspase 3 ◽  
Cauda Equina ◽  
Safety Data ◽  
Spinal Reflex ◽  
Neonatal Rat ◽  
Spinal Cord Tissue ◽  
Drug Induced ◽  
Rat Pups

Abstract Background: Neuraxial anesthesia is utilized in children of all ages. Local anesthetics produce dose-dependent toxicity in certain adult models, but the developing spinal cord may also be susceptible to drug-induced apoptosis. In postnatal rodents, we examined the effects of intrathecal levobupivacaine on neuropathology and long-term sensorimotor outcomes. Methods: Postnatal day 3 (P3) or P7 rat pups received intrathecal levobupivacaine 2.5 mg/kg (0.5%) or saline. Mechanical withdrawal thresholds and motor block were assessed. Spinal cord tissue analysis included apoptosis counts (activated caspase-3, Fluoro-Jade C) at 24 h, glial reactivity at 7 days, and histopathology in cord and cauda equina at 24 h and 7 days. Long-term spinal function in young adults (P35) was assessed by hind limb withdrawal thresholds, electromyography responses to suprathreshold stimuli, and gait analysis. Results: Intrathecal levobupivacaine produced spinal anesthesia at P3 and P7. No increase in apoptosis or histopathological change was seen in the cord or cauda equina. In the P3 saline group, activated caspase-3 (mean ± SEM per lumbar cord section 6.1 ± 0.3) and Fluoro-Jade C (12.1 ± 1.2) counts were higher than at P7, but were not altered by levobupivacaine (P = 0.62 and P = 0.11, two-tailed Mann–Whitney test). At P35, mechanical withdrawal thresholds, thermal withdrawal latency, and electromyographic reflex responses did not differ across P3 or P7 levobupivacaine or saline groups (one way ANOVA with Bonferroni comparisons). Intrathecal bupivacaine at P3 did not alter gait. Conclusion: Single dose intrathecal levobupivacaine 0.5% did not increase apoptosis or produce spinal toxicity in neonatal rat pups. This study provides preclinical safety data relevant to neonatal use of neuraxial local anesthesia.

Micturition reflexes in the in vitro neonatal rat brain stem-spinal cord-bladder preparation

1994 ◽  
Vol 266 (3) ◽  
pp. R658-R667 ◽  
Author(s):  
K. Sugaya ◽  
W. C. De Groat
Keyword(s):  
Spinal Cord ◽  
Electrical Stimulation ◽  
Brain Stem ◽  
Rat Brain ◽  
Bladder Wall ◽  
Spinal Reflex ◽  
Neonatal Rat ◽  
Evoked Contractions ◽  
Stimulation Of

An in vitro neonatal (1-7 day) rat brain stem-spinal cord-bladder (BSB) preparation was used to examine the central control of micturition. Isovolumetric bladder contractions occurred spontaneously or were induced by electrical stimulation of the ventrolateral brain stem, spinal cord, bladder wall (ES-BW), or by perineal tactile stimulation (PS). Transection of the spinal cord at the L1 segment increased the amplitude of ES-BW- and PS-evoked contractions, and subsequent removal of the spinal cord further increased spontaneous and ES-BW-evoked contractions but abolished PS-evoked contractions. Hexamethonium (1 mM), a ganglionic blocking agent, mimicked the effect of cord extirpation. Tetrodotoxin (1 microM) blocked ES-BW- and PS-evoked contractions but enhanced spontaneous contractions. Bicuculline methiodide (10-50 microM), a gamma-aminobutyric acid A receptor antagonist, increased the amplitude of spontaneous, ES-BW- and PS-evoked contractions. These results indicate that PS-evoked contractions are mediated by spinal reflex pathways, whereas spontaneous and ES-BW-evoked contractions that are elicited by peripheral mechanisms are subject to a tonic inhibition dependent on an efferent outflow from the spinal cord. PS-evoked micturition is also subject to inhibitory modulation arising from sites rostral to the lumbosacral spinal cord. Although electrical stimulation of bulbospinal excitatory pathways can initiate bladder contractions in the neonatal rat, these pathways do not appear to have an important role in controlling micturition during the first postnatal week.

Spinal cord stimulation for chronic refractory pain: Long‐term effectiveness and safety data from a multicentre registry

2019 ◽  
Vol 23 (5) ◽  
pp. 1031-1044 ◽  
Author(s):  
Andrei Brinzeu ◽  
Emmanuel Cuny ◽  
Denys Fontaine ◽  
Patrick Mertens ◽  
Pierre‐Philippe Luyet ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Stimulation ◽  
Safety Data ◽  
Refractory Pain

Serotonin Increases the Incidence of Primary Afferent-Evoked Long-Term Depression in Rat Deep Dorsal Horn Neurons

2001 ◽  
Vol 85 (5) ◽  
pp. 1864-1872 ◽  
Author(s):  
Sandra M. Garraway ◽  
Shawn Hochman
Keyword(s):  
Spinal Cord ◽  
Dorsal Horn ◽  
Long Term Potentiation ◽  
Neonatal Rat ◽  
Long Term Depression ◽  
Primary Afferent ◽  
Dorsal Horn Neurons ◽  
Sensory Evoked ◽  
Synaptic Responses

5-hydroxytryptamine (5-HT) is released in spinal cord by descending systems that modulate somatosensory transmission and can potently depress primary afferent-evoked synaptic responses in dorsal horn neurons. Since primary afferent activity-induced long-term potentiation (LTP) may contribute to central sensitization of nociception, we studied the effects of 5-HT on the expression of sensory-evoked LTP and long-term depression (LTD) in deep dorsal horn (DDH) neurons. Whole cell, predominantly current clamp, recordings were obtained from DDH neurons in transverse slices of neonatal rat lumbar spinal cord. The effect of 5-HT on dorsal-root stimulation-evoked synaptic responses was tested before, during, or after high-frequency conditioning stimulation (CS). In most cells (80%), 5-HT caused a depression of the naı̈ve synaptic response. Even though 5-HT depressed evoked responses, CS in the presence of 5-HT was not only still capable of inducing LTD but also increased its incidence from 54% in controls to 88% ( P < 0.001). Activation of ligands selective for 5-HT1A/1B and 5-HT1B, but not 5-HT2A/2C or 5-HT3receptors, best reproduced these actions. 5-HT also potently depressed postconditioning synaptic responses regardless of whether the induced plasticity was LTP or LTD. Our results demonstrate that in addition to depressing the amplitude of evoked sensory input, 5-HT can also control the direction of its long-term modifiability, favoring the expression of LTD. These findings demonstrate cellular mechanisms that may contribute to the descending serotonergic control of nociception.

Pharmacoepidemiology Methods for Identifying and Quantifying Behavioral Effects of Neuropharmacological Agents

1988 ◽  
Vol 22 (3) ◽  
pp. 260-266
Author(s):  
Julie Magno Zito ◽  
Thomas J. Craig
Keyword(s):  
Quantitative Methods ◽  
Psychiatric Patients ◽  
Safety Data ◽  
Drug Efficacy ◽  
Incidence Rates ◽  
Drug Usage ◽  
Drug Induced ◽  
Multiple Outcome ◽  
Large Populations

The possibilities and limitations of the pharmacoepidemiologic methods of determining neuropharmacologic drug efficacy and safety in psychiatric patients are discussed in this review. Such methods can improve both the scientific evaluation and clinical practice aspects of our knowledge of these drugs by providing: (1) incidence rates of drug usage and adverse events from computerized information on large populations; (2) quantitative methods for risk-to-benefit assessments that incorporate multiple outcome measures, provide long-term effectiveness and safety data, and use statistical methods to distinguish drug-induced from illness-based behaviors; and (3) systematic epidemiologic approaches to resolving dilemmas that involve the political and social context in which neuropharmacological drugs are used.

scholarly journals Effects of Intrathecal Ketamine in the Neonatal Rat

2010 ◽  
Vol 113 (1) ◽  
pp. 147-159 ◽  
Author(s):  
Suellen M. Walker ◽  
B. David Westin ◽  
Ronald Deumens ◽  
Marjorie Grafe ◽  
Tony L. Yaksh
Keyword(s):  
Spinal Cord ◽  
Calcium Binding ◽  
Dose Range ◽  
Intrathecal Injection ◽  
Neonatal Rat ◽  
Glial Fibrillary Acid Protein ◽  
Percutaneous Injection ◽  
Withdrawal Threshold ◽  
Rat Pups ◽  
Relative Safety

Background Systemic ketamine can trigger apoptosis in the brain of rodents and primates during susceptible developmental periods. Clinically, spinally administered ketamine may improve the duration or quality of analgesia in children. Ketamine-induced spinal cord toxicity has been reported in adult animals but has not been systematically studied in early development. Methods In anesthetized rat pups, intrathecal ketamine was administered by lumbar percutaneous injection. Changes in mechanical withdrawal threshold evaluated dose-dependent antinociceptive and carrageenan-induced antihyperalgesic effects in rat pups at postnatal day (P) 3 and 21. After intrathecal injection of ketamine at P3, 7, or 21, spinal cords were examined for apoptosis (Fluoro-Jade C and activated caspase-3), histopathologic change, and glial responses (ionized calcium-binding adapter molecule 1 and glial fibrillary acid protein). After maximal doses of ketamine or saline at P3 or P21, sensory thresholds and gait analysis were evaluated at P35. Results Intrathecal injection of 3 mg/kg ketamine at P3 and 15 mg/kg at P21 reverses carrageenan-induced hyperalgesia. Baseline neuronal apoptosis in the spinal cord was greater at P3 than P7, predominantly in the dorsal horn. Intrathecal injection of 3-10 mg/kg ketamine in P3 pups (but not 15 mg/kg at P21) acutely increased apoptosis and microglial activation in the spinal cord and altered spinal function (reduced mechanical withdrawal threshold and altered static gait parameters) at P35. Conclusions Because acute pathology and long-term behavioral change occurred in the same dose range as antihyperalgesic effects, the therapeutic ratio of intrathecal ketamine is less than one in the neonatal rat. This measure facilitates comparison of the relative safety of spinally administered analgesic agents.

scholarly journals The Effects of Exposure to Repeated Minor Pain During the Neonatal Period on Formalin Pain Behavior and Thermal Withdrawal Latencies

2003 ◽  
Vol 8 (4) ◽  
pp. 213-217 ◽  
Author(s):  
C Celeste Johnston ◽  
Claire-Dominique Walker
Keyword(s):  
Formalin Test ◽  
Thermal Stimulation ◽  
Neonatal Rat ◽  
Maternal Behaviour ◽  
Long Term Effects ◽  
Thermal Thresholds ◽  
Rat Pups ◽  
Short And Long Term ◽  
Repeated Pain

Preterm infants undergoing untreated, repeated painful procedures as part of their early experience are more likely to behave differently to pain as they mature than infants who were born at term and did not experience excessive exogenous pain. The neonatal rat model was used to investigate the short- and long-term effects of repeated pain in infancy on later development of pain responses. Newborn rat pups were randomly assigned by litter to be left unhandled (UH), handled by being removed from the dam for 15 min four times daily (H), and being handled and receiving pain from a paw prick with a 26G needle four times daily (P)on postnatal days (PD) 2 through 8 (PD2-PD8). Maternal behaviour and grooming of pups on their return to the nest were recorded at PD6 for H and P pups. At PD15, PD36 and PD65, animals were first tested for latency to thermal stimulation threshold using the Hargreaves test and then for inflammatory pain using the formalin test. Pups in the HP group received significantly more grooming from their mothers (359 s) than pups in the H group (295 s, P<0.0001). When accounting for differences in maternal grooming, a decreased thermal threshold in the P group compared with the H group (6.04 s versus 5.3 s, P<0.05) was found, although the correlations were not significant between maternal grooming and thermal thresholds. No group differences were seen with the formalin test. Interestingly, age was a significant factor in both tests, with younger animals showing fewer pain behaviours regardless of group or maternal grooming of the pup. Sex was significant at one age only in latency to thermal stimulation testing. The results suggest that changes in maternal care may be an important factor mediating the long-term effects of repeated neonatal experiences of pain.

scholarly journals Long-Term Behavioral Effects of Repetitive Pain in Neonatal Rat Pups

1999 ◽  
Vol 66 (4) ◽  
pp. 627-637 ◽  
Author(s):  
K.J.S Anand ◽  
V Coskun ◽  
K.V Thrivikraman ◽  
C.B Nemeroff ◽  
P.M Plotsky
Keyword(s):  
Behavioral Effects ◽  
Neonatal Rat ◽  
Rat Pups

scholarly journals Bumetanide Alleviates Epileptogenic and Neurotoxic Effects of Sevoflurane in Neonatal Rat Brain

2010 ◽  
Vol 112 (3) ◽  
pp. 567-575 ◽  
Author(s):  
David A. Edwards ◽  
Hina P. Shah ◽  
Wengang Cao ◽  
Nikolaus Gravenstein ◽  
Christoph N. Seubert ◽  
...  
Keyword(s):  
Caspase 3 ◽  
Epileptic Seizures ◽  
Long Term Potentiation ◽  
Neonatal Rat ◽  
Gamma Aminobutyric Acid ◽  
Arterial Blood Gas ◽  
Arterial Blood ◽  
Term Potentiation ◽  
Neurotoxic Effects

Background We tested the hypothesis that in newborn rats, sevoflurane may cause seizures, neurotoxicity, and impairment in synaptic plasticity-effects that may be diminished by the Na-K-2Cl cotransporter 1 inhibitor, bumetanide. Methods Electroencephalography, activated caspase-3, and hippocampal long-term potentiation were measured in rats exposed to 2.1% sevoflurane for 0.5-6 h at postnatal days 4-17 (P4-P17). Results Arterial blood gas samples drawn at a sevoflurane concentration of 2.1% showed no evidence of either hypoxia or hypoventilation in spontaneously breathing rats. Higher doses of sevoflurane (e.g., 2.9%) caused respiratory depression. During anesthesia maintenance, the electroencephalography exhibited distinctive episodes of epileptic seizures in 40% of P4-P8 rats. Such seizure-like activity was not detected during anesthesia maintenance in P10-P17 rats. Emergence from 3 h of anesthesia with sevoflurane resulted in tonic/clonic seizures in some P10-P17 rats but not in P4-P8 rats. Bumetanide (5 micromol/kg, intraperitoneally) significantly decreased seizures in P4-P9 rats but did not affect the emergence seizures in P10-P17 rats. Anesthesia of P4 rats with sevoflurane for 6 h caused a significant increase in activated caspase-3 and impairment of long-term potentiation induction measured at 1 and 14-17 days after exposure to sevoflurane, respectively. Pretreatment of P4 rats with bumetanide nearly abolished the increase in activated caspase-3 but did not alleviate impairment of long-term potentiation. Conclusion These results support the possibility that excitatory output of sevoflurane-potentiated gamma-aminobutyric acid type A/glycine systems may contribute to epileptogenic and neurotoxic effects in early postnatal rats.

scholarly journals Dabigatran ameliorates post-haemorrhagic hydrocephalus development after germinal matrix haemorrhage in neonatal rat pups

2016 ◽  
Vol 37 (9) ◽  
pp. 3135-3149 ◽  
Author(s):  
Damon Klebe ◽  
Jerry J Flores ◽  
Devin W McBride ◽  
Paul R Krafft ◽  
William B Rolland ◽  
...  
Keyword(s):  
Water Maze ◽  
Matrix Proteins ◽  
Neonatal Rat ◽  
Therapeutic Effects ◽  
Short Term ◽  
Nissl Staining ◽  
Germinal Matrix ◽  
Thrombin Inhibition ◽  
Rat Pups

We aim to determine if direct thrombin inhibition by dabigatran will improve long-term brain morphological and neurofunctional outcomes and if potential therapeutic effects are dependent upon reduced PAR-1 stimulation and consequent mTOR activation. Germinal matrix haemorrhage was induced by stereotaxically injecting 0.3 U type VII-S collagenase into the germinal matrix of P7 rat pups. Animals were divided into five groups: sham, vehicle (5% DMSO), dabigatran intraperitoneal, dabigatran intraperitoneal + TFLLR-NH2 (PAR-1 agonist) intranasal, SCH79797 (PAR-1 antagonist) intraperitoneal, and dabigatran intranasal. Neurofunctional outcomes were determined by Morris water maze, rotarod, and foot fault evaluations at three weeks. Brain morphological outcomes were determined by histological Nissl staining at four weeks. Expression levels of p-mTOR/p-p70s6k at three days and vitronectin/fibronectin at 28 days were quantified. Intranasal and intraperitoneal dabigatran promoted long-term neurofunctional recovery, improved brain morphological outcomes, and reduced intracranial pressure at four weeks after GMH. PAR-1 stimulation tended to reverse dabigatran's effects on post-haemorrhagic hydrocephalus development. Dabigatran also reduced expression of short-term p-mTOR and long-term extracellular matrix proteins, which tended to be reversed by PAR-1 agonist co-administration. PAR-1 inhibition alone, however, did not achieve the same therapeutic effects as dabigatran administration.

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