Publications by authors named "Gordon Barr"

42 Publications

Maternal continuous oral oxycodone self-administration alters pup affective/social communication but not spatial learning or sensory-motor function.

Drug Alcohol Depend 2021 Apr 17;221:108628. Epub 2021 Feb 17.

Department of Anesthesiology and Critical Care Medicine, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA, United States; Department of Psychology, University of Pennsylvania, Philadelphia, PA, United States. Electronic address:

Background: The broad use/misuse of prescription opioids during pregnancy has resulted in a surge of infants with Neonatal Opioid Withdrawal Syndrome (NOWS). Short-term irritability and neurological complications are its hallmarks, but the long-term consequences are unknown.

Methods: A newly-developed preclinical model of oxycodone self-administration enables adult female rats to drink oxycodone (∼10/mg/kg/day) before and during pregnancy, and after delivery, and to maintain normal liquid intake, titrate dosing, and avoid withdrawal.

Results: Oxycodone was detected in the serum of mothers and pups. Growth parameters in dams and pups and litter mass and size were similar to controls. There were no differences in paw retraction latency to a thermal stimulus between Oxycodone and Control pups at postnatal (PN) 2 or PN14. Oxycodone and Control pups had similar motor coordination, cliff avoidance, righting time, pivoting, and olfactory spatial learning from PN3 through PN13. Separation-induced ultrasonic vocalizations at PN8 revealed higher call frequency in Oxycodone pups relative to Control pups (p<0.031; Cohen's d=1.026). Finally, Oxycodone pups displayed withdrawal behaviors (p's<0.029; Cohen's d's>0.806), and Oxycodone males only vocalized more than Control pups in the first minute of testing (p's<0.050; Cohen's d's>.866). Significant effects were corroborated by estimation plots.

Conclusions: Our rat model of oral oxycodone self-administration in pregnancy shows exacerbated affect/social communication in pups in a sex-dependent manner but spared cognition and sensory-motor behaviors. This preclinical model reproduces selective aspects of human opioid use during pregnancy, enabling longitudinal analysis of how maternal oxycodone changes emotional behavior in the offspring.
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http://dx.doi.org/10.1016/j.drugalcdep.2021.108628DOI Listing
April 2021

Female and male rats readily consume and prefer oxycodone to water in a chronic, continuous access, two-bottle oral voluntary paradigm.

Neuropharmacology 2020 05 27;167:107978. Epub 2020 Jan 27.

Department of Anesthesiology and Critical Care, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA; Department of Neuroscience, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA. Electronic address:

The increasing abuse of opioids - such as oxycodone - poses major challenges for health and socioeconomic systems. Human prescription opioid abuse is marked by chronic, voluntary, oral intake and sex differences. To develop interventions, the field would benefit from a preclinical paradigm that similarly provides rodents with chronic, continuous, oral, voluntary and free-choice access to oxycodone. Here we show female and male rats voluntarily ingest and choose oxycodone over water and show both dependence and motivation to take oxycodone during a chronic oral voluntary, two-bottle choice, continuous access paradigm. Adult female and male Long-Evans rats were given unlimited, continuous homecage access to two bottles containing water (Control) or one bottle of water and one bottle of oxycodone dissolved in water (Experimental). Virtually all experimental rats voluntarily drank oxycodone (~10 mg/kg/day) and escalated their intake over 22 weeks. Females self-administered twice as much oxycodone by body weight (leading to higher blood levels of oxycodone) and engaged in more gnawing behavior of wooden blocks relative to males. Precipitated withdrawal revealed high levels of dependence in both sexes. Reflecting motivation to drink oxycodone, ascending concentrations of citric acid suppressed the intake of oxycodone (Experimental) and the intake of water (Control); however, Experimental rats returned to pre-citric acid preference levels whereas Controls rats did not. Pre-screening behaviors of rats on open field exploration predicted oxycodone intake. Thus, rats consumed and preferred oxycodone over time in this chronic two-bottle oral choice paradigm and both sexes displayed many features of human oxycodone abuse.
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http://dx.doi.org/10.1016/j.neuropharm.2020.107978DOI Listing
May 2020

Effects of plant-derived analgesic compounds sinomenine and salvinorin A in infant rats.

J Integr Med 2020 Mar 8;18(2):174-180. Epub 2020 Jan 8.

Department of Anesthesiology and Critical Care, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Anesthesiology and Critical Care, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Psychology, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address:

Objective: Premature and ill neonates undergo painful but medically necessary procedures while hospitalized. Although opiate drugs are administered as analgesics, problems associated with their side effects, tolerance, and potential dependence necessitate research into alternative pain-relieving medications. Here we test two plant-derived compounds in infant rats: sinomenine, which targets the Mas-related G-protein-coupled receptor member X2 opioid receptor; and salvinorin A, which is a κ opioid receptor agonist. In adult animals both sinomenine and salvinorin A are analgesic, but neither has been tested in infants.

Methods: We used the formalin and thermal plantar tests in rats 7 and 21 days of age (PN7 and PN21) for behavioral signs of pain. In addition, brain sections were stained using Fos immunohistochemistry to examine patterns of brain activation in the midbrain periaqueductal gray and the paraventricular nucleus of the hypothalamus.

Results: Sinomenine was analgesic in both the formalin and thermal tests on animals 21 days of age. At PN7 only the highest dose elevated response latencies in the thermal test and there were no effects of sinomenine in the formalin test. Analysis of Fos expression in the sinomenine-treated animals showed no drug effect, in contrast to the behavioral results. Salvinorin A was analgesic in the formalin test only at the highest dose at 21 days of age but not in the thermal test at either age.

Conclusion: The increased modest effectiveness of sinomenine in older animals and the minimum salvinorin A drug effect suggest that the compounds act on sites that develop during the preweaning period (sinomenine) or after weaning (salvinorin A).
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http://dx.doi.org/10.1016/j.joim.2020.01.002DOI Listing
March 2020

Trigeminal Pain Responses in Obese ob/ob Mice Are Modality-Specific.

Neuroscience 2019 09 8;415:121-134. Epub 2019 Jul 8.

Department of Neurology, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA, USA; Department of Neurology, University of Iowa, Iowa City, IA, USA. Electronic address:

How obesity exacerbates migraine and other pain disorders remains unknown. Trigeminal nociceptive processing, crucial in migraine pathophysiology, is abnormal in mice with diet induced obesity. However, it is not known if this is also true in genetic models of obesity. We hypothesized that obese mice, regardless of the model, have trigeminal hyperalgesia. To test this, we first evaluated trigeminal thermal nociception in leptin deficient (ob/ob) and control mice using an operant thermal assay. Unexpectedly, we found significant hypoalgesia in ob/ob mice. Because thermal hypoalgesia also occurs in mice lacking the transient receptor potential vanilloid 1 channel (TRPV1), we tested capsaicin-evoked trigeminal nociception. Ob/ob and control mice had similar capsaicin-evoked nocifensive behaviors, but ob/ob mice were significantly less active after a facial injection of capsaicin than were diet-induced obese mice or lean controls. Conditioned place aversion in response to trigeminal stimulation with capsaicin was similar in both genotypes, indicating normal negative affect and pain avoidance. Supporting this, we found no difference in TRPV1 expression in the trigeminal ganglia of ob/ob and control mice. Finally, we assessed the possible contribution of hyperphagia, a hallmark of leptin deficiency, to the behavior observed in the operant assay. Ob/ob and lean control mice had similar reduction of intake when quinine or capsaicin was added to the sweetened milk, excluding a significant contribution of hyperphagia. In summary, ob/ob mice, unlike mice with diet-induced obesity, have trigeminal thermal hypoalgesia but normal responses to capsaicin, suggesting specificity in the mechanisms by which leptin acts in pain processing.
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http://dx.doi.org/10.1016/j.neuroscience.2019.06.043DOI Listing
September 2019

Differences Between the Prenatal Effects of Fluoxetine or Buspirone Alone or in Combination on Pain and Affective Behaviors in Prenatally Stressed Male and Female Rats.

Front Behav Neurosci 2019 11;13:125. Epub 2019 Jun 11.

Department of Anesthesiology and Critical Care Medicine, The Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States.

The selective serotonin reuptake inhibitor fluoxetine and the 5-HT1A receptor agonist buspirone are used to treat depression and anxiety. Previously we demonstrated that chronic stress during pregnancy (prenatal stress) in rats, used as a model of maternal depression risk, increased inflammatory pain and depressive-like behavior in the offspring; buspirone injected to pregnant dams was protective. Clinically, the addition of buspirone to fluoxetine increases the latter's efficacy in treating depression in patients. Here, we investigated the influence of repeated prenatal injections of fluoxetine, buspirone or their combination on pain- and depressive-like behaviors in prenatally stressed young male and female rats. Prenatal stress augmented depressive-like behavior and both thermal and inflammatory pain (formalin test), replicating our prior findings, and increased basal levels of corticosterone in the blood plasma. Both drugs and their combination reduced the effects of prenatal stress on thermal pain and depressive-like behavior independently of sex. The combination of fluoxetine and buspirone, compared with fluoxetine, was more antinociceptive in the hot plate test in both sexes, and when compared with buspirone, was more antinociceptive only in males. A detailed study of the time-course of formalin-induced pain showed a nuanced effect of these drugs that was sex-dependent. The combination of the two drugs was less effective in females than males during the initial acute phase of nociceptive behavior in flexing + shaking behaviors, whereas that combination was more effective than fluoxetine alone in the first acute phase of licking behavior in females. The antinociceptive effect of buspirone dominated that of the drug combination and of fluoxetine alone, especially during the interphase of the formalin test in both sexes for both flexing + shaking and licking, suggesting a more effective prenatal action of buspirone on the development of a descending serotonergic inhibitory system modulating pain in the spinal cord dorsal horn neurons. Our results indicate that inflammatory pain-like responses integrated at the spinal level in males were more vulnerable to prenatal stress than females. In licking, the antinociceptive effect of fluoxetine and drug combination in the interphase was more in males than females. The data underscore the importance of considering sexual dimorphism when using drug therapy.
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http://dx.doi.org/10.3389/fnbeh.2019.00125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6579839PMC
June 2019

Long-Term Effects of Chronic Buspirone during Adolescence Reduce the Adverse Influences of Neonatal Inflammatory Pain and Stress on Adaptive Behavior in Adult Male Rats.

Front Behav Neurosci 2017 26;11:11. Epub 2017 Jan 26.

Department of Anesthesiology and Critical Care Medicine, The Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania Philadelphia, PA, USA.

Neonatal pain and stress induce long-term changes in pain sensitivity and behavior. Previously we found alterations in pain sensitivity in adolescent rats exposed to early-life adverse events. We tested whether these alterations have long-lasting effects and if those effects can be improved by the 5-hydroxytryptamine 1A (5-HT1A) receptor agonist buspirone injected chronically during the adolescent period. This study investigates: (1) effects of inflammatory pain (the injection of formalin into the pad of a hind paw) or stress (short maternal deprivation-isolation, MI), or their combination in 1-2-day-old rats on the adult basal pain, formalin-induced pain, anxiety and depression; (2) effects of adolescent buspirone in adult rats that experienced similar early-life insults. Changes in nociceptive thresholds were evaluated using the hot plate (HP) and formalin tests; levels of anxiety and depression were assessed with the elevated plus maze and forced swim tests respectively. Both neonatal painful and stressful treatments induced long-term alterations in the forced swim test. Other changes in adult behavioral responses were dependent on the type of neonatal treatment. There was a notable lack of long-term effects of the combination of early inflammatory pain and stress of MI on the pain responses, anxiety levels or on the effects of adolescent buspirone. This study provides the first evidence that chronic injection of buspirone in adolescent rats alters antinociceptive and anxiolytic effects limited to adult rats that showed behavioral alterations induced by early-life adverse treatments. These data highlight the role of 5-HT1A receptors in long-term effects of neonatal inflammatory pain and stress of short MI on adaptive behavior and possibility of correction of the pain and psychoemotional behavior that were altered by adverse pain/stress intervention using buspirone during critical adolescent period.
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http://dx.doi.org/10.3389/fnbeh.2017.00011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5266710PMC
January 2017

Developmental Changes in Pain and Spinal Immune Gene Expression after Radicular Trauma in the Rat.

Front Neurol 2016 15;7:223. Epub 2016 Dec 15.

Spine Pain Research Laboratory, Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania , Philadelphia, PA , USA.

Neuropathic pain is chronic pain that develops after nerve injury and is less frequent in infants and children than in adults. Likewise, in animal models of neuropathic pain, allodynia and hyperalgesia are non-existent or attenuated in the infant, with a "switch" during development by which acute nerve injury transitions to chronic pain. Concomitant with the delay in neuropathic pain, there is a parallel delay in the ability of nerve injury to activate the immune system. Models of neuropathic pain in the infant have used various ligation methods and find that neuropathic pain does not occur under after postnatal days 21-28 (PN21-PN28), linked to activation of immune processes and developmental regulation of anti-inflammatory cytokines. We applied a model of neuropathic pain in the adult using a transient compression of the cervical nerve or nerve root in infant rats (injured at 10, 14, 21, or 28 days of age) to define transition periods during which injury results in no change in thermal and mechanical pain sensitivity or in short-term changes in pain. There was little to no hyperalgesia when the injury was imposed at PN10, but significant thermal hyperalgesia and mechanical allodynia 1 day after compression injury when performed at PN14, 21, or 28. Thermal withdrawal latencies returned to near baseline by 7 days postsurgery when the injuries were at PN14, and lasted up to 14 days when the injury was imposed at PN28. There was mechanical allodynia following injury at 1 day postinjury and at 14 days after injury at PN14. Measurements of mRNA from spinal cord at 1, 7, and 14 days postinjury at PN14, 21, and 28 showed that both the magnitude and duration of elevated immune markers and chemokines/cytokines were greater in the older animals, corresponding to the development of hyperalgesia. Thus, we confirm the late onset of neuropathic pain but found no evidence of emergent hyperalgesia if the injury was before PN21. This may be due to the use of a transient, and not sustained, compression ligation model.
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http://dx.doi.org/10.3389/fneur.2016.00223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5156703PMC
December 2016

Repeated recall and PKMζ maintain fear memories in juvenile rats.

Learn Mem 2016 12 15;23(12):710-713. Epub 2016 Nov 15.

Division of Developmental Neuroscience, New York State Psychiatric Institute, New York, New York 10032, USA.

We examined the neural substrates of fear memory formation and maintenance when repeated recall was used to prevent forgetting in young animals. In contrast to adult rats, juveniles failed to show contextual fear responses at 4 d post-fear conditioning. Reconsolidation sessions 3 and 6 d after conditioning restored contextual fear responses in juveniles 7 d after initial training. In juveniles that received reconsolidation sessions, protein kinase M zeta (PKMζ) increased in the amygdala, but not in the hippocampus. These data suggest that repeated reminders and increased PKMζ maintain fear responses in juvenile animals that otherwise would not exhibit this behavior.
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http://dx.doi.org/10.1101/lm.042549.116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5110988PMC
December 2016

Enduring good memories of infant trauma: rescue of adult neurobehavioral deficits via amygdala serotonin and corticosterone interaction.

Proc Natl Acad Sci U S A 2015 Jan 5;112(3):881-6. Epub 2015 Jan 5.

Emotional Brain Institute, Nathan Kline Institute, Orangeburg, NY 10962; Neuroscience and Physiology, Sackler Institute, New York University School of Medicine, New York, NY 10016; Child and Adolescent Psychiatry, The Child Study Center, New York University Langone Medical Center, NY 10016;

Children form a strong attachment to their caregiver--even when that caretaker is abusive. Paradoxically, despite the trauma experienced within this relationship, the child develops a preference for trauma-linked cues--a phenomenon known as trauma bonding. Although infant trauma compromises neurobehavioral development, the mechanisms underlying the interaction between infant trauma bonding (i.e., learned preference for trauma cues) and the long-term effects of trauma (i.e., depressive-like behavior, amygdala dysfunction) are unknown. We modeled infant trauma bonding by using odor-shock conditioning in rat pups, which engages the attachment system and produces a life-long preference for the odor that was paired with shock. In adulthood, this trauma-linked odor rescues depressive-like behavior and amygdala dysfunction, reduces corticosterone (CORT) levels, and exerts repair-related changes at the molecular level. Amygdala microarray after rescue implicates serotonin (5-HT) and glucocorticoids (GCs), and a causal role was verified through microinfusions. Blocking amygdala 5-HT eliminates the rescue effect; increasing amygdala 5-HT and blocking systemic CORT mimics it. Our findings suggest that infant trauma cues share properties with antidepressants and safety signals and provide insight into mechanisms by which infant trauma memories remain powerful throughout life.
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http://dx.doi.org/10.1073/pnas.1416065112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4311810PMC
January 2015

Effects of COX inhibition and LPS on formalin induced pain in the infant rat.

Dev Neurobiol 2015 Oct 13;75(10):1068-79. Epub 2014 Sep 13.

Department of Developmental Neuroscience, New York State Psychiatric Institute, Columbia University College of Physicians and Surgeons, New York.

In the adult, immune and neural processes jointly modulate pain. During development, both are in transition and little is known about the role that the immune system plays in pain processing in infants and children. The objective of this study was to determine if inhibition or augmentation of the immune system would alter pain processing in the infant rat, as it does in the adult. In Experiment 1, rat pups aged 3, 10, or 21 (PN3, PN10, and PN21) days of age were pretreated with NS398 (selective cyclooxygenase (COX)-2 inhibitor) or SC560 (selective COX-1 inhibitor) and tested in the intraplantar formalin test to assess effects of COX inhibition on nociception. Neither drug had an effect on the behavioral response at PN3 or PN10 pups but both drugs attenuated nociceptive scores in PN21 pups. cFos expression in the spinal cord likewise was reduced only at PN21. In Experiment 2, pups were injected with lipopolysaccharide (LPS) prior to the formalin test at PN3 or PN21. LPS increased the nociceptive response more robustly at PN21 than at PN3, while increasing cytokine mRNA equally at both ages. The augmentation of pain responding at PN21 was largely during the late stages of the formalin test, as reported in the adult. These data support previous findings demonstrating late maturing immune modulation of nociceptive behaviors.
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http://dx.doi.org/10.1002/dneu.22230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4362925PMC
October 2015

Interactions between glia, the immune system and pain processes during early development.

Dev Psychobiol 2014 Dec 9;56(8):1698-710. Epub 2014 Jun 9.

Department of Anesthesiology and Critical Care Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, 19104.

Pain is a serious problem for infants and children and treatment options are limited. Moreover, infants born prematurely or hospitalized for illness likely have concurrent infection that activates the immune system. It is now recognized that the immune system in general and glia in particular influence neurotransmission and that the neural bases of pain are intimately connected to immune function. We know that injuries that induce pain activate immune function and suppressing the immune system alleviates pain. Despite this advance in our understanding, virtually nothing is known of the role that the immune system plays in pain processing in infants and children, even though pain is a serious clinical issue in pediatric medicine. This brief review summarizes the existing data on immune-neural interactions in infants, providing evidence for the immaturity of these interactions.
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http://dx.doi.org/10.1002/dev.21229DOI Listing
December 2014

Medial prefrontal cortex processes threatening stimuli in juvenile rats.

Neuropsychopharmacology 2014 Jul 19;39(8):1924-32. Epub 2014 Feb 19.

1] Department of Psychiatry, Columbia University, New York, NY, USA [2] Division of Developmental Neuroscience, New York State Psychiatric Institute, New York, NY, USA.

To survive, all mammalian species must recognize and respond appropriately to threatening stimuli. In adults, the prelimbic medial prefrontal cortex (mPFC) appears to be involved in fear expression, whereas the infralimbic mPFC mediates fear extinction. In juvenile rats (PN26), the mPFC receives information on potential predators but does not act on it. To test whether the prefrontal cortex is capable of fear regulation in the young organism, we exposed juvenile rats to a threatening or nonthreatening stimulus and assessed fear and brain Fos activation of the mPFC subdivisions, amygdala and periaqueductal gray (PAG). In response to the threat, juveniles froze more, spent more time far from the threat, and had elevated numbers of Fos-positive cells in the prelimbic mPFC, the medial amygdala, and ventral PAG. To test the hypothesis that the mPFC has a dual role in modulating the amygdala and PAG in juveniles, we pharmacologically disinhibited each of the two subdivisions of the mPFC and assessed freezing and downstream activation to the threat. Juvenile rats infused with picrotoxin into the prelimbic mPFC and exposed to a threatening stimulus froze less, spent less time far from the threat, and increased Fos expression. Infusion of picrotoxin into the infralimbic mPFC also reduced fear responding to the threatening stimulus but had no effect on Fos expression. In sum, it appears that the mPFC can process threatening stimuli in juveniles at this age, even though it is normally not involved in the fear responses.
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http://dx.doi.org/10.1038/npp.2014.40DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4059901PMC
July 2014

Peripheral nerve graft with immunosuppression modifies gene expression in axotomized CNS neurons.

J Comp Neurol 2011 Dec;519(17):3433-55

Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, Pennsylvania 19129, USA.

Adult central nervous system (CNS) neurons do not regenerate severed axons unaided but may regenerate axons into apposed predegenerated peripheral nerve grafts (PNGs). We examined gene expression by using microarray technology in laser-dissected lateral vestibular (LV) neurons whose axons were severed by a lateral hemisection at C3 (HX) and in lateral vestibular nucleus (LVN) neurons that were hemisected at C3 and that received immunosuppression with cyclosporine A (CsA) and a predegenerated PNG (termed I-PNG) into the lesion site. The results provide an expression analysis of temporal changes that occur in LVN neurons in nonregenerative and potentially regenerative states and over a period of 42 days. Axotomy alone resulted in a prolonged change in regulation of probe sets, with more being upregulated than downregulated. Apposition of a PNG with immunosuppression muted gene expression overall. Axotomized neurons (HX) upregulated genes commonly associated with axonal growth, whereas axotomized neurons whose axons were apposed to the PNG showed diminished expression of many of these genes but greater expression of genes related to energy production. The results suggest that axotomized LVN neurons express many genes thought to be associated with regeneration to a greater extent than LVN neurons that are apposed to a PNG. Thus the LVN neurons remain in a regenerative state following axotomy but the conditions provided by the I-PNG appear to be neuroprotective, preserving or enhancing mitochondrial activity, which may provide required energy for regeneration. We speculate that the graft also enables sufficient axonal synthesis of cytoskeletal components to allow axonal growth without marked increase in expression of genes normally associated with regeneration.
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http://dx.doi.org/10.1002/cne.22714DOI Listing
December 2011

The role of the medial prefrontal cortex in innate fear regulation in infants, juveniles, and adolescents.

J Neurosci 2011 Mar;31(13):4991-9

Department of Psychiatry, Columbia University, New York, New York 10032, USA.

In adult animals, the medial prefrontal cortex (mPFC) plays a significant role in regulating emotions and projects to the amygdala and periaqueductal gray (PAG) to modulate emotional responses. However, little is known about the development of this neural circuit and its relevance to unlearned fear in pre-adulthood. To address these issues, we examined the mPFC of 14-d-old (infants), 26-d-old (juveniles), and 38- to 42-d-old (adolescents) rats to represent different developmental and social milestones. The expression patterns of the neuronal marker FOS were used to assess neurological activity. Muscimol, a GABA agonist, was used to inactivate the prelimbic and infralimbic mPFC subdivisions (400 ng in 200 nl). Animals were exposed to either a threatening or nonthreatening stimulus that was ecologically relevant and age specific. Freezing was measured as an indicator of innate fear behavior. The data indicated that the mPFC is neither active nor responsive to innate fear in infant rats. In juveniles, the prelimbic mPFC became responsive in processing aversive sensory stimulation but did not regulate freezing behavior. Finally, during adolescence, inactivation of the prelimbic mPFC significantly attenuated freezing and decreased FOS expression in the ventral PAG. Surprisingly, across all ages, there were no significant differences in FOS levels in the medial and basolateral/lateral amygdala when either mPFC subdivision was inactivated. Together, unlearned fear has a unique developmental course with different brain areas involved in unlearned fear in the immature animal than the adult. In particular, the mPFC neural circuitry is different in young animals and progressively develops more capacities as the animal matures.
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http://dx.doi.org/10.1523/JNEUROSCI.5216-10.2011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3108443PMC
March 2011

Interactions of estradiol and NSAIDS on carrageenan-induced hyperalgesia.

Brain Res 2011 Mar 31;1382:181-8. Epub 2011 Jan 31.

Hunter College and The Graduate Center, The City University of New York, NY, 10065, USA; New York State Psychiatric Institute, New York, NY, 10032, USA.

How exogenous estrogen affects inflammatory responses is poorly understood despite the large numbers of women receiving estrogen-alone hormone therapy. The aim of this study was to determine if estradiol alters injury- or inflammation-induced nociceptive responses after carrageenan administration in females and whether its effects are mediated through cyclo-oxygenase (COX) and prostaglandins (PG). To this end, paw withdrawal latencies and serum levels of PGE2 and PGD2 were measured in rats treated with estradiol (0, 10, 20, and 30%) and/or SC560 (COX-1 inhibitor) or NS398 (COX-2 inhibitor) after intraplantar carrageenan administration. Estradiol significantly increased withdrawal latencies before (baseline condition) and after carrageenan administration to one hindpaw. NS398 was anti-nociceptive only in carrageenan treated animals. SC560 increased withdrawal latencies in both paws at 1 and 5hours after carrageenan administration. Co-administration of estradiol and NS398, but not SC560, was additive except for a prolonged anti-nociceptive effects of estradiol combined with NS398. The anti-nociceptive effect extended beyond that observed with either drug or estradiol alone at the 5-hour time point. Estradiol had no significant effect on PGE2 serum levels, but both COX antagonists decreased them. Although neither estradiol nor the COX inhibitors alone had an effect on PGD2 serum levels, co-administration of NS398 and estradiol significantly elevated PGD2 levels. Taken together, our results suggest that estradiol is anti-nociceptive in the thermal test and reduces carrageenan-induced hyperalgesia. These effects are minimally altered through PG-mediated mechanisms.
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http://dx.doi.org/10.1016/j.brainres.2011.01.075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3068478PMC
March 2011

Changing mechanisms of opiate tolerance and withdrawal during early development: animal models of the human experience.

ILAR J 2011 ;52(3):329-41

Human infants may be exposed to opiates through placental transfer from an opiate-using mother or through the direct administration of such drugs to relieve pain (e.g., due to illness or neonatal surgery). Infants of many species show physical dependence and tolerance to opiates. The magnitude of tolerance and the nature of withdrawal differ from those of the adult. Moreover, the mechanisms that contribute to the chronic effects of opiates are not well understood in the infant but include biological processes that are both common to and distinct from those of the adult. We review the animal research literature on the effects of chronic and acute opiate exposure in infants and identify mechanisms of withdrawal and tolerance that are similar to and different from those understood in adults. These mechanisms include opioid pharmacology, underlying neural substrates, and the involvement of other neurotransmitter systems. It appears that brain circuitry and opioid receptor types are similar but that NMDA receptor function is immature in the infant. Intracellular signaling cascades may differ but data are complicated by differences between the effects of chronic versus acute morphine treatment. Given the limited treatment options for the dependent infant patient, further study of the biological functions that are altered by chronic opiate treatment is necessary to guide evidenced-based treatment modalities.
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http://dx.doi.org/10.1093/ilar.52.3.329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6040919PMC
April 2016

Formalin-induced c-fos expression in the brain of infant rats.

Authors:
Gordon A Barr

J Pain 2011 Feb 13;12(2):263-71. Epub 2010 Dec 13.

Department of Psychology, Biopsychology Doctoral Program, City University of New York, Hunter College, New York, NY, USA.

Unlabelled: In the fetal, infant, and adult rat, injury induces a well-defined behavioral response and induces c-fos expression in the spinal cord dorsal horn. There is more limited information about the processing of noxious stimulation in the infant brain. We describe here the appearance of the Fos protein in the brain of fetal and infant rats following formalin-induced injury. Regions were chosen for analysis with a special focus on brain loci that express c-fos in the adult. No Fos positive cells were found in the brains of fetuses; newborns did not show increased Fos expression after formalin injection in any structure examined. At 3 and 14 days of age, there was a significant increase in Fos staining induced by formalin in the ventral lateral medulla. In contrast, paraventricular and medial dorsal nuclei of the thalamus, the paraventricular nucleus of the hypothalamus, and periaqueductal gray of the midbrain showed increased levels of Fos protein only at 14 days of age. We hypothesize that this developmental pattern is related not only to the maturation of pain perception but also to development of autonomic and defensive reactions to pain in the infant.

Perspective: Because the infant processes pain differently than the adult, knowledge of those differences informs pediatric clinical practice. Using Fos expression as a marker of neural activity in the rat, we show that the pattern of brain activation is immature at birth but is in place by 14 days of age.
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http://dx.doi.org/10.1016/j.jpain.2010.09.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3062261PMC
February 2011

Estradiol-induced antinociceptive responses on formalin-induced nociception are independent of COX and HPA activation.

Synapse 2011 Jul 25;65(7):643-51. Epub 2011 Feb 25.

Hunter College and The Graduate Center, The City University of New York, New York 10065, USA.

Estrogen modulates pain perception but how it does so is not fully understood. The aim of this study was to determine if estradiol reduces nociceptive responses in part via hypothalamic-pituitary-adrenal (HPA) axis regulation of cyclooxygenase (COX)-1/COX-2 activity. The first study examined the effects of estradiol (20%) or vehicle with concurrent injection nonsteroidal antiinflammatory drugs (NSAIDs) on formalin-induced nociceptive responding (flinching) in ovariectomized (OVX) rats. The drugs were ibuprofen (COX-1 and COX-2 inhibitor), SC560 (COX-1 inhibitor), or NS398 (COX-2 inhibitor). In a second study, estradiol's effects on formalin-induced nociception were tested in adrenalectomized (ADX), OVX, and ADX+OVX rats. Serum levels of prostaglandins (PG) PGE(2) and corticosterone were measured. Estradiol significantly decreased nociceptive responses in OVX rats with effects during both the first and the second phase of the formalin test. The nonsteroidal antiinflammatory drugs (NSAIDs) did not alter nociception at the doses used here. Adrenalectomy neither altered flinching responses in female rats nor reversed estradiol-induced antinociceptive responses. Estradiol alone had no effect on corticosterone (CORT) or prostaglandin levels after the formalin test, dissociating the effects of estradiol on behavior and these serum markers. Ibuprofen and NS398 significantly reduced PGE2 levels. CORT was not decreased by OVX surgery or by estradiol below that of ADX. Only IBU significantly increased corticosterone levels. Taken together, our results suggest that estradiol-induced antinociception in female rats is independent of COX activity and HPA axis activation.
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http://dx.doi.org/10.1002/syn.20890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3075311PMC
July 2011

Proteomic analysis of a noninvasive human model of acute inflammation and its resolution: the twenty-one day gingivitis model.

J Proteome Res 2010 Sep;9(9):4732-44

Periodontal Research Group, School of Dentistry, College of Medical and Dental Sciences, University of Birmingham, St. Chads Queensway, Birmingham, B4 6NN, United Kingdom.

The 21-day experimental gingivitis model, an established noninvasive model of inflammation in response to increasing bacterial accumulation in humans, is designed to enable the study of both the induction and resolution of inflammation. Here, we have analyzed gingival crevicular fluid, an oral fluid comprising a serum transudate and tissue exudates, by LC-MS/MS using Fourier transform ion cyclotron resonance mass spectrometry and iTRAQ isobaric mass tags, to establish meta-proteomic profiles of inflammation-induced changes in proteins in healthy young volunteers. Across the course of experimentally induced gingivitis, we identified 16 bacterial and 186 human proteins. Although abundances of the bacterial proteins identified did not vary temporally, Fusobacterium outer membrane proteins were detected. Fusobacterium species have previously been associated with periodontal health or disease. The human proteins identified spanned a wide range of compartments (both extracellular and intracellular) and functions, including serum proteins, proteins displaying antibacterial properties, and proteins with functions associated with cellular transcription, DNA binding, the cytoskeleton, cell adhesion, and cilia. PolySNAP3 clustering software was used in a multilayered analytical approach. Clusters of proteins that associated with changes to the clinical parameters included neuronal and synapse associated proteins.
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http://dx.doi.org/10.1021/pr100446fDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2950674PMC
September 2010

Transitions in infant learning are modulated by dopamine in the amygdala.

Nat Neurosci 2009 Nov 27;12(11):1367-9. Epub 2009 Sep 27.

Department of Anesthesiology and Critical Care Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

Behavioral transitions characterize development. Young infant rats paradoxically prefer odors that are paired with shock, but older pups learn aversions. This transition is amygdala and corticosterone dependent. Using microarrays and microdialysis, we found downregulated dopaminergic presynaptic function in the amygdala with preference learning. Corticosterone-injected 8-d-old pups and untreated 12-d-old pups learned aversions and had dopaminergic upregulation in the amygdala. Dopamine injection into the amygdala changed preferences to aversions, whereas dopamine antagonism reinstated preference learning.
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http://dx.doi.org/10.1038/nn.2403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2783302PMC
November 2009

Regional Fos expression induced by morphine withdrawal in the 7-day-old rat.

Dev Psychobiol 2009 Nov;51(7):544-52

Department of Psychology, Hunter College and the Graduate Center, City University of New York, New York, NY 10016, USA.

Human infants are often exposed to opiates chronically but the mechanisms by which opiates induce dependence in the infant are not well studied. In the adult the brain regions involved in the physical signs of opiate withdrawal include the periaqueductal gray area, the locus coeruleus, amygdala, ventral tegmental area, nucleus accumbens, hypothalamus, and spinal cord. Microinjection studies show that many of these brain regions are involved in opiate withdrawal in the infant rat. Our goal here was to determine if these regions become metabolically active during physical withdrawal from morphine in the infant rat as they do in the adult. Following chronic morphine or saline treatment, withdrawal was precipitated in 7-day-old pups with the opiate antagonist naltrexone. Cells positive for Fos-like immunoreactivity were quantified within select brain regions. Increased Fos-like labeled cells were found in the periaqueductal gray, nucleus accumbens, locus coeruleus, and spinal cord. These are consistent with other studies showing that the neural circuits underlying the physical signs of opiate withdrawal are similar in the infant and adult.
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http://dx.doi.org/10.1002/dev.20392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6040917PMC
November 2009

A quick method for the quantitative analysis of mixtures. 1. Powder X-ray diffraction.

J Pharm Sci 2008 Jun;97(6):2260-76

WestCHEM, Department of Chemistry, University of Glasgow, Glasgow G12 8QQ, UK.

A method of analyzing mixtures of APIs and excipients using X-ray powder diffraction is described. It uses a simple algorithm based on linear regression in which the pure component phases are fitted to the mixture pattern using linear least squares. Unlike many methods that use only the peaks in the powder pattern, this technique uses all the measured data points in the 2theta scan with minimal data processing. In practice, using 33 different samples on three diffractometers, the method can be shown to work well for mixtures with up to three components, giving mean errors between 1.7% and 3.9% for two-phase mixtures, and 4.0% and 8.6% for three-phase mixtures. These results compare favorably to those given by traditional Rietveld refinement. It is also shown that the Bruker GADDS system, which is designed for high throughput crystallization experiments, is capable of giving results of comparable accuracy to those derived from traditional, single sample diffractometers. It is possible to identify those mixtures for which one or more pure phase X-ray powder patterns are not available with a detection limit around 10%. The techniques are implemented in the PolySNAP computer program. The method requires very little computer time or user interaction.
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http://dx.doi.org/10.1002/jps.21142DOI Listing
June 2008

Using cluster analysis to study transition-metal geometries: four-coordinate complexes with two salicylaldiminato or related ligands.

Acta Crystallogr B 2007 Aug 17;63(Pt 4):612-20. Epub 2007 Jul 17.

WestCHEM, Department of Chemistry, University of Glasgow, Glasgow G12 8QQ, Scotland.

Cluster analysis is shown to be an effective method to analyse and classify metal coordination geometry in a very large number of four-coordinate bis-salicylaldimato (or bis-beta-iminoketonate) transition-metal complexes available in the Cambridge Structural Database. The methods described require no prior knowledge of chemistry to be input; retrieved structures are automatically clustered into groups based purely on the geometric similarity of the fragments and these groupings can then be interpreted by the structural chemist.
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http://dx.doi.org/10.1107/S0108768107021969DOI Listing
August 2007

The application of cluster analysis to identify conformational preferences in enones and enimines from crystal structural data.

Acta Crystallogr B 2007 Jun 16;63(Pt 3):469-76. Epub 2007 May 16.

WestCHEM, Department of Chemistry, University of Glasgow, Glasgow G12 8QQ, Scotland.

Cluster analysis can be an effective tool for analysing large quantities of data. Here it has been applied to the conformational analysis of enones and enimines in the crystalline solid state, using structural information mined from the Cambridge Structural Database. The forms that are common in the gaseous state and in solution are already known from spectroscopic studies. These forms are also found to be the most common conformations observed in the solid state; however, the clustering method highlights those structures that do not conform to the expected geometries. The study is supported by ab initio gas phase calculations on simple enone and enimine fragments.
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http://dx.doi.org/10.1107/S0108768107006969DOI Listing
June 2007

Sex differences in formalin-induced pain in prenatally stressed infant rats.

Eur J Pain 2007 Nov 26;11(8):888-94. Epub 2007 Mar 26.

Laboratory of Ontogeny of Nervous System, I.P. Pavlov Institute of Physiology, The Russian Academy of Sciences, St. Petersburg 199034, Russia.

The aim of this work was to study the effects of prenatal stress on nociceptive responses in the formalin test in female and male infant (7-day-old) Long-Evans hooded rats. Prenatally stressed infant rats displayed biphasic flinching+ shaking behavior whereas non-stressed animals showed only a weak second phase. Pain sensitivity in prenatally stressed males was significantly greater than that of prenatally non-stressed males during the second phase only; there were no differences in pain sensitivity between prenatally stressed and non-stressed females. Moreover prenatally stressed male rats pups demonstrated that the second phase of the response to formalin was enhanced relative to the second phase in stressed females. The current and previous data [Butkevich IP, Barr GA, Mikhailenko VA, Otellin VA. Increased formalin-induced pain and expression of fos neurons in the lumbar spinal cord of prenatally stressed infants rats. Neurosci Lett 2006a;403:222-226] show increased tonic pain in prenatally stressed infant rats and a large increase in the number of formalin-induced fos-like immunoreactivity in the spinal cord dorsal horn. There is a concomitant decrease in serotonin-like immunoreactivity in the lumbar spinal cord dorsal horn [Butkevich IP, Barr GA, Otellin VA. Effect of prenatal stress on behavioral and neural indices of formalin-induced pain in infant rats. Abstracts, 35th Annual Meeting of Soc. For Neurosci. 2005a. Program No. 512.4 Washington, DC: Society for Neuroscience]. Given the decreased level of perinatal testosterone in prenatally stressed rats to which infant males are more sensitive than females, we suggest that these hormonal, behavioral and neuronal indices are strongly interrelated in prenatally stressed 7-day-old rat pups and that the decreased surge of testosterone may contribute to the increased behavioral response in the second phase in male rat pups. Mechanisms underlying the behavioral pain response induced by inflammation in prenatally stressed rat pups are characterized by sexual dimorphism even prior to the activational effects of sex hormones.
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http://dx.doi.org/10.1016/j.ejpain.2007.02.001DOI Listing
November 2007

Spinal cord ionotropic glutamate receptors function in formalin-induced nociception in preweaning rats.

Psychopharmacology (Berl) 2007 Jul 14;192(4):489-98. Epub 2007 Mar 14.

Department of Psychiatry, Columbia University, 1051 Riverside Drive, New York, NY 10032, USA.

Rationale: Neonates respond to noxious stimuli at or before birth, but the organization of nociceptive systems changes well into postnatal life. It is unknown how nociceptive information is processed in the immature animal and, specifically, whether noxious stimulation is transmitted by glutamatergic circuits, known to play an important role in nociception in the adult. Both N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are found within the neonatal spinal cord, but in immature form, and when they become involved in pain processing in vivo is not known.

Objectives: The objective was to determine the age-related changes in the involvement of spinal NMDA and AMPA receptors in formalin-induced nociception during early life. Because the formalin test provides a measure of immediate nociceptive responding (first phase) and of peripheral and central sensitization (second phase), a second aim was to determine if there is specificity of the effects to either phase.

Materials And Methods: NMDA antagonists (MK801, AP5) or an AMPA antagonist (YM872) was administered intrathecally, and pups were assessed in the formalin test behaviorally and by Fos expression within the spinal cords of 3-, 10-, and 21-day-old rats.

Results: The NMDA antagonists attenuated formalin-induced behavioral responses at the youngest age tested with some selectivity for the second phase of responding. MK-801 did not induce motor impairment at any age. YM872 also attenuated formalin-induced nociceptive responses at all ages throughout the test session, although there was some motor impairment in the 3-day-old subjects. Spinal administration of either YM872 or MK-801 reduced Fos expression in the spinal cord at all ages.

Conclusions: These data suggest that spinal NMDA and AMPA receptor are functional and involved in formalin-induced nociception throughout development.
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http://dx.doi.org/10.1007/s00213-007-0735-xDOI Listing
July 2007

Increased formalin-induced pain and expression of fos neurons in the lumbar spinal cord of prenatally stressed infant rats.

Neurosci Lett 2006 Aug 19;403(3):222-6. Epub 2006 Jun 19.

Laboratory of Ontogeny of Nervous System, I.P. Pavlov Institute of Physiology, The Russian Academy of Sciences, St. Petersburg 199034, Russia.

When pregnant dams are stressed, there is a resultant alteration in brain development and behavior in their offspring. Prior work has shown increased nociceptive responses in adolescent or adult rats born of stressed dams. However, the age at which those changes first occur is not known. The aim of the present study was to evaluate the effect of prenatal stress on pain sensitivity in the formalin test in 7-day-old rats, behaviorally and by fos-like immunoreactivity (Fos-LI) in the lumbar spinal cord dorsal horn. The behavioral response to intraplantar injection of formalin is represented by two nociceptive phases separated by an interphase during which nociceptive responses decrease; the interphase is not seen until the start of the third postnatal week and appears as descending inhibitory monoaminergic systems develop. Prenatally stressed infants showed increased nociceptive responses in the second, tonic phase and a large increase in the number of formalin-induced Fos-LI neurons in the lumbar dorsal horn, a result consistent with the behavioral data. The increased nociception in prenatally stressed 7-day-old pups may be associated with the decrease in the intensity of serotonin-like immunoreactivity and density of serotonergic cells in the lumbar spinal cord dorsal horn and the dorsal raphe nucleus reported earlier.
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http://dx.doi.org/10.1016/j.neulet.2006.04.059DOI Listing
August 2006

Estradiol and progesterone differentially regulate formalin-induced nociception in ovariectomized female rats.

Horm Behav 2006 Apr 27;49(4):441-9. Epub 2005 Oct 27.

Department of Psychology, Hunter College and The Graduate Center of the City University of New York, 695 Park Avenue, New York, NY 10021, USA.

Clinical and preclinical studies have found sex-specific differences in the discrimination and perception of inflammatory stimuli. The emerging picture suggests that the biological basis of these differences resides in the regulatory activity of gonadal hormones in the central nervous system. This study describes the effects of ovarian hormones in inflammatory pain processes. Ovariectomized rats received estradiol and/or progesterone, and the number of paw flinches was measured after 1, 2.5 or 5% formalin administration. Both estradiol and progesterone altered the number of flinches only after 1% formalin administration. Estradiol significantly reduced the overall number of flinches during Phase II of the formalin nociceptive response while progesterone attenuated Phase I of the response. After co-administration of estradiol and progesterone, progesterone reversed estradiol's analgesic effect in Phase II, however, estradiol did not reverse progesterone's analgesic activity in Phase I. To determine if estradiol effects are receptor-mediated, tamoxifen (selective estrogen receptor mediator, 15 mg/kg) or alpha-estradiol (an inactive isomer of estradiol, 20 microg) were utilized. Tamoxifen decreased the number of formalin-induced flinches during Phase II while alpha-estradiol did not affect any formalin-induced responses. When co-administered with estradiol, tamoxifen failed to reverse estradiol's effect, suggesting both tamoxifen and estradiol activate similar intracellular mechanisms. Although Western blot analysis detected the presence of estradiol alpha and beta and progesterone B receptors in the spinal cord, hormone replacement treatments had no effects on the levels of these receptors. We postulate that the mechanisms by which estradiol and progesterone induce analgesia occur through the activation of their receptor at the spinal cord level.
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http://dx.doi.org/10.1016/j.yhbeh.2005.09.007DOI Listing
April 2006

Microarray analysis of gene expression following the formalin test in the infant rat.

Pain 2005 Sep;117(1-2):6-18

Department of Developmental Psychobiology, New York State Psychiatric Institute, New York, NY, USA.

Injury and pain experienced by the infant results in immediate changes in pain sensitivity that last into adulthood. These long-term changes are likely initiated by altered gene expression. Here we measured how injury alters gene expression in the lumbar spinal cord early and late in the preweaning period of the rat. The expression of large numbers of genes was altered significantly at 3 days of age, when injury has long-term consequences. The functional classes of altered genes included transcription factors, cell death related and metal ion genes. The intensity of the stimulus in the 3-day-old pups induced changes in different classes of genes. Fewer changes were noted at 21 days of age. The increased expression of transcription factors and decreased expression of genes whose products are protective against cell death are hypothesized to underlie the long-term changes that are seen after injury in the neonate.
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http://dx.doi.org/10.1016/j.pain.2005.04.024DOI Listing
September 2005

Issues for consideration in the analysis of microarray data in behavioural studies.

Addict Biol 2005 Mar;10(1):15-21

Department of Developmental Psychobiology, New York State Psychiatry Institute, NY 10032, USA.

Microarrays are one of several technologies that allow for measurement the expression of thousands of genes simultaneously. This technological advance provides a challenge for the analysis of these data. In this review we discuss these analytical issues from the initial quality control to normalization, differential expression, clustering and finally functional pathway analysis. We focus on Affymetrix data but many of the issues are the same for other array platforms.
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http://dx.doi.org/10.1080/13556210412331308930DOI Listing
March 2005