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

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.

Download Full-text

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

Anesthesiology ◽

10.1097/aln.0b013e31828fc7e7 ◽

2013 ◽

Vol 119 (1) ◽

pp. 142-155 ◽

Cited By ~ 14

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.

Download Full-text

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

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x16684355 ◽

2016 ◽

Vol 37 (9) ◽

pp. 3135-3149 ◽

Cited By ~ 9

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.

Download Full-text

Neural plasticity and emotional memory

Development and Psychopathology ◽

10.1017/s0954579498001898 ◽

1998 ◽

Vol 10 (4) ◽

pp. 829-855 ◽

Cited By ~ 47

Author(s):

R. M. POST ◽

S. R. B. WEISS ◽

H. LI ◽

M. A. SMITH ◽

L. X. ZHANG ◽

...

Keyword(s):

Neural Plasticity ◽

Molecular Mechanisms ◽

Emotional Memory ◽

Neonatal Rat ◽

Prior History ◽

Rat Pups ◽

Life Threatening ◽

History Of ◽

And Behavior

Posttraumatic stress disorder is the pathological replay of emotional memory formed in response to painful, life-threatening, or horrifying events. In contrast, depression is often precipitated by more social context-related stressors. New data suggest that different types of life experiences can differentially impact biochemistry, physiology, anatomy, and behavior at the level of changes in gene expression. Repeated separation of neonatal rat pups from their mother results in many long-lasting alterations in biology and behavior paralleling that in depression, including hypercortisolism. The role of the amygdala in modulating emotional memory is highlighted, as well as some of its unique properties such as metaplasticity (i.e., the differential direction of long-term adaptation, either potentiation or depression) in response to the same input as a function of the prior history of stimulation. The implications of these emerging data on the physiological and molecular mechanisms underlying emotional memory emphasize the particular importance of prevention and early intervention.

Download Full-text

Long term neurological and behavioral effects of graded perinatal asphyxia in the rat

Life Sciences ◽

10.1016/s0024-3205(99)00678-5 ◽

2000 ◽

Vol 66 (10) ◽

pp. 947-962 ◽

Cited By ~ 43

Author(s):

Harald Hoeger ◽

Mario Engelmann ◽

Guenther Bernert ◽

Rainer Seidl ◽

Hermann Bubna-Littitz ◽

...

Keyword(s):

Perinatal Asphyxia ◽

Behavioral Effects

Download Full-text

Behavioral Components of Milk-Induced Activation in Neonatal Rat Pups

Perceptual and Motor Skills ◽

10.2466/pms.1996.82.3.903 ◽

1996 ◽

Vol 82 (3) ◽

pp. 903-911 ◽

Cited By ~ 2

Author(s):

Steven M. Specht ◽

Richard G. Burright ◽

Linda Patia Spear

Keyword(s):

Brain Stimulation ◽

Principal Components ◽

Behavioral Activation ◽

Neural Substrates ◽

Neonatal Rat ◽

Exact Nature ◽

Electrical Brain Stimulation ◽

Global Pattern ◽

Rat Pups ◽

Components Analysis

Neonatal rat pups exhibit a complex constellation of behaviors in response to a variety of salient stimuli such as the odor of milk or maternal saliva, stroking with a soft brush, electrical brain stimulation, and intraoral infusions of milk. Although psychobiologists have used the term “behavioral activation” to refer to such behavioral displays, the exact nature of “behavioral activation” and its underlying neural substrates have yet to be elucidated. This study was undertaken to characterize “behavioral activation” quantitatively to describe and define this apparently global pattern of response in terms of possible underlying components. Principal components analysis suggested that “behavioral activation” may be comprised of separable ingestive, exploratory, and locomotor behavioral “assemblies.”

Download Full-text