Gordon Barr - Academia.edu (original) (raw)

Papers by Gordon Barr

European Journal of Pain, Dec 3, 2012

Frontiers in Behavioral Neuroscience, Jul 21, 2021

Frontiers in Behavioral Neuroscience

Exposure to stress at an early age programs the HPA axis which can lead to cognitive deficits in ... more Exposure to stress at an early age programs the HPA axis which can lead to cognitive deficits in adults. However, it is not known whether these deficits emerge in adulthood or are expressed earlier in life. The aims of the study were to investigate (1) the immediate effects of early injury-induced stress in one-day-old (P1) and repeated stress on at P1 and P2 rat pups on plasma corticosterone levels; and (2) examine the subsequent long-term effects of this early stress on spatial learning and memory, and stress reactivity in early P26-34 and late P45-53 adolescent male and female rats. Intra-plantar injection of formalin induced prolonged and elevated levels of corticosterone in pups and impaired spatial learning and short- and long-term memory in late adolescent males and long-term memory in early adolescent females. There were sex differences in late adolescence in both learning and short-term memory. Performance on the long-term memory task was better than that on the short-term ...

Developmental Psychobiology, Nov 1, 2009

PLOS ONE

Background In the short term, parental presence while a human infant is in pain buffers the immed... more Background In the short term, parental presence while a human infant is in pain buffers the immediate pain responses, although emerging evidence suggests repeated social buffering of pain may have untoward long-term effects. Methods/finding To explore the short- and long-term impacts of social buffering of pain, we first measured the infant rat pup’s [postnatal day (PN) 8, or 12] response to mild tail shock with the mother present compared to shock alone or no shock. Shock with the mother reduced pain-related behavioral activation and USVs of pups at both ages and reduced Fos expression in the periaqueductal gray, hypothalamic paraventricular nucleus, and the amygdala at PN12 only. At PN12, shock with the mother compared to shock alone differentially regulated expression of several hundred genes related to G-protein-coupled receptors (GPCRs) and neural development, whereas PN8 pups showed a less robust and less coherent expression pattern. In a second set of experiments, pups were e...

Neuroscience, Jan 6, 2017

Premature or ill full-term infants are subject to a number of noxious procedures as part of their... more Premature or ill full-term infants are subject to a number of noxious procedures as part of their necessary medical care. Although we know that human infants show neural changes in response to such procedures, we know little of the sensory or affective brain circuitry activated by pain. In rodent models, the focus has been on spinal cord and, more recently, midbrain and medulla. The present study assesses activation of brain circuits using manganese-enhanced magnetic resonance imaging (MEMRI). Uptake of manganese, a paramagnetic contrast agent that is transported across active synapses and along axons, was measured in response to a hindpaw injection of dilute formalin in 12-day-old rat pups, the age at which rats begin to show aversion learning and which is roughly the equivalent of full-term human infants. Formalin induced the oft-reported biphasic response at this age and induced a conditioned aversion to cues associated with its injection, thus demonstrating the aversiveness of t...

The broad use and misuse of prescription opioids during pregnancy has resulted in a surge of infa... more The broad use and misuse of prescription opioids during pregnancy has resulted in a surge of infants diagnosed with Neonatal Opioid Withdrawal Syndrome (NOWS). Short-term irritability and neurological complications are hallmarks of NOWS, but the long-term consequences are unknown. Our newly-developed preclinical model of oxycodone self-administration enables adult female rats to readily drink oxycodone (0.06-0.12 mg/ml, ∼10/mg/kg/day) continuously before and during pregnancy and after delivery, to achieve similar liquid intake in oxycodone moms relative to water-only controls. Oxycodone levels were detected in the serum of mothers and pups. Growth parameters in dams and pups, and litter mass and size were similar to controls. Maternal behavior at postnatal day 1 (PN1) was unchanged by perinatal oxycodone consumption. Regarding the plantar thermal response, there were no differences in paw retraction latency between oxycodone and control pups at PN2 or PN14. Oxycodone and control pup...

The present study examined the ability of LY235959, a competitive N-methyl-D-aspartate (NMDA) rec... more The present study examined the ability of LY235959, a competitive N-methyl-D-aspartate (NMDA) receptor antagonist, to attenuate behaviors and c-fos mRNA expression associated with acute morphine withdrawal in the infant rat. Rat pups were given a single dose of morphine (10.0 mg/kg, s.c.) or saline. Two hours later, pups were removed from the dam and injected with either LY235959 (10.0 mg/kg, s.c.) or saline. Fifteen minutes later acute morphine withdrawal was precipitated with naltrexone (10.0 mg/kg, s.c.) and behaviors were recorded every 15 s for the next 60 min. Immediately after behavioral testing, brain and spinal cord were assayed for c-fos mRNA analysis by solution hybridization. The intensity of the morphine withdrawal syndrome was reduced in pups pre-treated with LY235959. Withdrawal behaviors such as head moves, moving paws, rolling, and walking were decreased, and vocalizations were completely eliminated in pups pre-treated with LY2359559. Acute morphine withdrawal incre...

bioRxiv, 2019

The increased abuse of opioids - such as oxycodone - poses major challenges for health and socioe... more The increased abuse of opioids - such as oxycodone - poses major challenges for health and socioeconomic systems. Human prescription opioid abuse is marked by continuous, voluntary, oral intake, and sex differences. Therefore the field would benefit from a preclinical in-depth characterization of sex differences in a chronic oral voluntary, free choice, and continuous access paradigm. Here we show in an oral oxycodone continuous access two-bottle choice paradigm sex-dependent voluntary drug intake, dependence, and motivation to take the drug. Adult female and male Long-Evans rats were given unlimited, continuous home cage access to two bottles containing water (Control) or one bottle of water and one bottle of oxycodone dissolved in water (Experimental). Most experimental rats voluntarily drank oxycodone (∼10 mg/kg/day) and escalated their intake over 22 weeks. Females self-administered twice as much oxycodone as males, leading to greater blood levels of oxycodone, and engaged in mo...

ABSTRACTThe increased abuse of opioids - such as oxycodone - poses major challenges for health an... more ABSTRACTThe increased abuse of opioids - such as oxycodone - poses major challenges for health and socioeconomic systems. Here we present a novel oral oxycodone self-administration paradigm in rats that recapitulates key aspects of prescription opioid abuse: voluntary drug intake, long-term opioid exposure, measurable levels of dependence, and increased motivation to take drug. Adult female and male Long-Evans rats were given unlimited, home cage access to two bottles containing water (Control rats) or one bottle of water and one bottle of Oxycodone dissolved in water (Experimental rats). 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 as males, leading to greater levels of oxycodone in blood, and engaged in more gnawing behavior. Precipitated withdrawal revealed high levels of dependence in both sexes in the total withdrawal score and in individual withdrawal beha...

Frontiers in behavioral neuroscience, 2017

Neonatal pain and stress induce long-term changes in pain sensitivity and behavior. Previously we... more 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 neo...

Frontiers in Neurology, 2016

Neuropathic pain is chronic pain that develops after nerve injury and is less frequent in infants... more 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.

NeuroReport, 2000

An important yet unanswered question is how neonates respond to painful stimuli, given the immatu... more An important yet unanswered question is how neonates respond to painful stimuli, given the immaturity of their neural pathways. We examined the development of the neurokinin system using a novel approach, examining changes of this system by observing the pain responses of mice lacking the NK1 receptor at different stages of development. We show that the NK1 receptor is not involved in nociception to heat, mechanical or chemical stimuli, at 3 days. In contrast, the NK1 receptor is involved in nociceptive responses to high intensity heat and mechanical stimuli, and mediates the second phase of the formalin response in 21-day-old mice. This indicates that nociception in neonates does not require the NK1 receptor and that the functional maturation of the NK1 receptor allows diversity in both the type of stimuli that activate the pain system and the types of responses elicited by nociceptive stimuli. NeuroReport 11:587±591 &

IDrugs : the investigational drugs journal, 2008

Institute) presented data revealing a role for NOP and its synthetic ligand Ro-64-6198 in alcohol... more Institute) presented data revealing a role for NOP and its synthetic ligand Ro-64-6198 in alcohol drinking and preference. Dr Kuzmin's research group had previously reported that administration of nociceptin, a natural NOP agonist, reduced the acquisition and expression of ethanol-conditioned place preference in rats.

Synapse, 2011

Estrogen modulates pain perception but how it does so is not fully understood. The aim of this st... more 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 hypothalamicpituitary-adrenal (HPA) axis regulation of cyclooxygenases (COX)-1/COX-2 activity. The first study examined the effects of estradiol (20%) or vehicle with concurrent injection non-steroidal anti-inflammatory 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 formalininduced 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 non-steroidal anti-inflammatory 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 or prostaglandin levels after the formalin test, dissociating the effects of estrogen 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 estradiolinduced antinociception in female rats is independent of COX activity and HPA axis activation.

Pharmacology Biochemistry and Behavior, 2001

Ketorolac is a potent nonsteroidal antiinflammatory drug (NSAID). In adult humans and animals, it... more Ketorolac is a potent nonsteroidal antiinflammatory drug (NSAID). In adult humans and animals, its analgesic efficacy can be comparable to opiates. However, it has not been studied in neonatal animals. We conducted a blinded, controlled study comparing the effects of ketorolac and morphine in neonatal rats using the formalin model. Animals were given intraperitoneal (ip) injections of ketorolac or morphine at 3 or 21 days of age. Ketorolac had an analgesic and antiinflammatory effect in 21-day-old pups, but not in the 3day-olds. Morphine had a significant analgesic, but no antiinflammatory effect at both ages. These results indicate that ketorolac is an effective analgesic agent in preweaning, but not neonatal rats. Opiates may be more appropriate analgesics in neonates.

Neurotoxicology and Teratology, 2000

To examine the effects of chronic perinatal cocaine exposure, cocaine was administered intravenou... more To examine the effects of chronic perinatal cocaine exposure, cocaine was administered intravenously throughout pregnancy and the postpartum period to the rat. Pregnant rats were divided into five groups: nontreated (naive); normal saline control (saline); cocaine first generation (cocaine); saline in the first generation and cocaine in the second generation (Sal-2G); and cocaine in both first and second generations (Coc-2G). The rats receiving cocaine in the second generation (Sal-2G and Coc-2G) were offspring of the saline and cocaine group, respectively. All cocaine-treated groups received cocaine 2 mg/kg/day intravenously (IV), and the saline group received normal saline 0.2 ml/day IV from GD 2 to the 21st day postpartum. Mean perinatal mortality was greater in all pups exposed to cocaine in utero during gestation; Cocaine (6.4%); Sal-2G (5.6%); Coc-2G (11.4%) groups than in the noncocaine groups (3.2%, 1.3%). Weight gain, physical, and neurological developments of the offspring were not affected. It was concluded that perinatal cocaine exposure had an increased perinatal mortality even at doses approximately 10 times lower than those previously reported, which were administered by extravascular routes. These findings indicate the importance of the route of drug administration in perinatal cocaine research.

Neuroscience, 2014

Anxiety-related disorders are among the most common psychiatric illnesses, thought to have both g... more Anxiety-related disorders are among the most common psychiatric illnesses, thought to have both genetic and environmental causes. Early-life trauma, such as abuse from a caregiver, can be predictable or unpredictable, each resulting in increased prevalence and severity of a unique set of disorders. In this study, we examined the influence of early unpredictable trauma on both the behavioral expression of adult anxiety and gene expression within the amygdala. Neonatal rats were exposed to unpaired odor-shock conditioning for 5 days, which produces deficits in adult behavior and amygdala dysfunction. In adulthood, we used the Light/Dark box test to measure anxiety-related behaviors, measuring the latency to enter the lit area and quantified urination and defecation. The amygdala was then dissected and a microarray analysis was performed to examine changes in gene expression. Animals that had received early unpredictable trauma displayed significantly longer latencies to enter the lit area and more defecation and urination. The microarray analysis revealed over-represented genes related to learning and memory, synaptic transmission and trans-membrane transport. Gene ontology and pathway analysis identified highly represented disease states related to anxiety phenotypes, including social anxiety, obsessivecompulsive disorders, PTSD and bipolar disorder. Addiction related genes were also overrepresented in this analysis. Unpredictable shock during early development increased anxietylike behaviors in adulthood with concomitant changes in genes related to neurotransmission, resulting in gene expression patterns similar to anxiety-related psychiatric disorders.