Dopamine-neurotransmission and nociception in zebrafish: An anti-nociceptive role of dopamine receptor drd2a

Dopamine (DA) is an important modulator in nociception and analgesia. Spinal DA receptors are involved in descending modulation of the nociceptive transmission. Genetic variations within DA neurotransmission have been associated with altered pain sensitivity and development of chronic pain syndromes. The variant rs6277 in dopamine receptor 2 a (drd2a) has been associated with a decreased D2 receptor availability and increased nociception. The aim of this study is to further characterize the role of DA neurotransmission in nociception and the anti-nociceptive function of drd2a. The phenotype caused by rs6277 was modelled in zebrafish larvae using morpholino's and the effect on nociception was tested using a validated behavioural assay. The anti-nociceptive role of drd2a was tested using pharmacological intervention of D2 agonist Quinpirole. The experiments demonstrate that a decrease in drd2a expression results in a pro-nociceptive behavioural phenotype (P = 0.016) after a heat stimulus. Furthermore, agonism of drd2a with agonist Quinpirole (0.2 mu M) results in dose-dependent anti-nociception (P = 0.035) after a heat stimulus. From these results it is concluded that the dopamine receptor drd2a is involved in anti-nociceptive behaviour in zebrafish. The model allows further screening and testing of genetic variation and treatment involved in nociception

Streptococcus pneumoniae exposure is associated with human metapneumovirus seroconversion and increased susceptibility to in vitro HMPV infection

AbstractIt remains largely unknown which factors determine the clinical outcome of human metapneumovirus (HMPV) infections. The aim of the present study was to analyse whether exposure to bacterial pathogens can influence HMPV infections. From 57 children, serum samples and colonization data for Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus and Streptococcus pneumoniae were collected at 1.5, 6, 14 and 24 months of age. Seroconversion rates to HMPV were determined and related to bacterial carriage. Frequent nasopharyngeal carriage (≥2 times in the first 2 years of life) of S. pneumoniae, but not of the other three pathogens, was associated with increased seroconversion rates of infants to HMPV at the age of 2 years (frequently vs. less exposed, 93% vs. 59%; p <0.05). Subsequently, the susceptibility of well-differentiated normal human bronchial epithelial cells (wd-NHBE) pre-incubated with bacterial pathogens to in vitro HMPV infection was evaluated. Pre-incubation of wd-NHBE with S. pneumoniae resulted in increased susceptibility to infection with HMPV-enhanced green fluorescent protein (EGFP), as determined by enumeration of EGFP-positive cells. This was not the case for cells pre-incubated with H. influenzae, M. catarrhalis on S. aureus. We conclude that exposure to S. pneumoniae can modulate HMPV infection

Renormalization Group Approach to Generalized Cosmological models

We revisit here the problem of generalized cosmology using renormalization group approach. A complete analysis of these cosmologies, where specific models appear as asymptotic fixed-points, is given here along with their linearized stability analysis.Comment: 10 pages, to appear in the International Journal of Theoretical Physic

Cosmological evolution of general scalar fields in a brane-world cosmology

We study the cosmology of a general scalar field and barotropic fluid during the early stage of a brane-world where the Friedmann constraint is dominated by the square of the energy density. Assuming both the scalar field and fluid are confined to the brane, we find a range of behaviour depending on the form of the potential. Generalising an approach developed for a standard Friedmann cosmology, in \cite{delaMacorra:1999ff}, we show that the potential dependence $V(\phi)$ can be described through a parameter $\lambda \equiv -\sqrt{2} m_5^{3/2} V'/(\sqrt{H}V)$, where $m_5$ is the 5-dimensional Planck mass, $H$ is the Hubble parameter and $V' \equiv \frac{dV}{d\phi}$. For the case where $\lambda$ asymptotes to zero, we show that the solution exhibits stable inflationary behaviour. On the other hand if it approaches a finite constant, then $V(\phi) \propto \frac{1}{\phi^2}$. For $\lambda \to \infty$ asymptotically, we find examples where it does so both with and without oscillating. In the latter case, the barotropic fluid dominates the scalar filed asymptotically. Finally we point out an interesting duality which leads to identical evolution equations in the high energy $\rho^2$ dominated regime and the low energy $\rho$ dominated regime.Comment: 10 pages, 3 figure

Neonatal procedural pain affects state, but not trait anxiety behavior in adult rats

The influence of neonatal experiences upon later-life affective behavior is increasingly recognized, but the reported effects on anxiety are often contradictory. The observed effect may depend upon the type of anxiety (state or trait) affected. The current study aims to investigate whether neonatal repetitive needle pricking alters anxiety behavior in adulthood, by assessing both state and trait anxiety in rats. Sprague-Dawley rat pups received four unilateral needle pricks per day, while controls received four tactile stimuli or were left completely undisturbed during the first postnatal week. Mechanical sensitivity was assessed in the neonatal phase and throughout the development. State anxiety was assessed in the open field test and trait anxiety in the elevated zero maze. The results show that repetitive needle pricking leads to acute mechanical hypersensitivity, but does not affect baseline mechanical sensitivity throughout development. In adulthood, animals previously exposed to neonatal procedural pain (including repetitive handling and removal from litter) showed lower state anxiety but did not differ in trait anxiety, as compared with the undisturbed controls. These findings indicate that early-life procedural pain decreases state but not trait anxiety behavior in later life in a rodent model of repetitive needle pricking

The development of descending serotonergic modulation of the spinal nociceptive network: a life span perspective

The nociceptive network, responsible for transmission of nociceptive signals that generate the pain experience, is not fully developed at birth. Descending serotonergic modulation of spinal nociception, an important part of the pain network, undergoes substantial postnatal maturation and is suggested to be involved in the altered pain response observed in human newborns. This review summarizes preclinical data of the development of descending serotonergic modulation of the spinal nociceptive network across the life span, providing a comprehensive background to understand human newborn pain experience and treatment. Sprouting of descending serotonergic axons, originating from the rostroventral medulla, as well as changes in receptor function and expression take place in the first postnatal weeks of rodents, corresponding to human neonates in early infancy. Descending serotonergic modulation switches from facilitation in early life to bimodal control in adulthood, masking an already functional 5-HT inhibitory system at early ages. Specifically the 5-HT3 and 5-HT7 receptors seem distinctly important for pain facilitation at neonatal and early infancy, while the 5-HT1a, 5-HT1b, and 5-HT2 receptors mediate inhibitory effects at all ages. Analgesic therapy that considers the neurodevelopmental phase is likely to result in a more targeted treatment of neonatal pain and may improve both short- and long-term effects. Impact The descending serotonergic system undergoes anatomical changes from birth to early infancy, as its sprouts and descending projections increase and the dorsal horn innervation pattern changes. Descending serotonergic modulation from the rostral ventral medulla switches from facilitation in early life via the 5-HT3 and 5-HT7 receptors to bimodal control in adulthood. A functional inhibitory serotonergic system mainly via 5-HT1a, 5-HT1b, and 5-HT2a receptors at the spinal level exists already at the neonatal phase but is masked by descending facilitation

Methadone effectively attenuates acute and long-term consequences of neonatal repetitive procedural pain in a rat model

Background Painful procedures in early life cause acute pain and can alter pain processing at a spinal level lasting into adulthood. Current methods of analgesia seem unable to prevent both acute and long-term hypersensitivity associated with neonatal pain. The current study aims to prevent acute and long-term hypersensitivity associated with neonatal procedural pain using methadone analgesia in rat pups. Methods Sprague-Dawley rat pups received either methadone (1 mg/kg) or saline prior to repetitive needle pricks into the left hind paw from the day of birth (postnatal day (P)0) to P7. Control littermates received a tactile stimulus. Mechanical sensitivity was assessed during the neonatal period (P0-P7), from weaning to adulthood (3-7 weeks) and following surgical re-injury of the same dermatome in adulthood. Results Methadone administration completely reversed acute hypersensitivity from P0 to P7. In addition, neonatal methadone analgesia prevented prolonged hypersensitivity after re-injury in adulthood, without affecting sensitivity from weaning to adulthood. Conclusions The current study shows that neonatal methadone analgesia can attenuate acute as well as long-term hypersensitivity associated with neonatal procedural pain in a rat model. ImpactMethadone treatment attenuates acute and long-term hypersensitivity associated with neonatal pain in a rat model. Clinical effectiveness studies are urgently warranted to assess acute and long-term analgesic effectivity of methadone

Neonatal procedural pain affects state, but not trait anxiety behavior in adult rats

The influence of neonatal experiences upon later‐life affective behavior is increasingly recognized, but the reported effects on anxiety are often contradictory. The observed effect may depend upon the type of anxiety (state or trait) affected. The current study aims to investigate whether neonatal repetitive needle pricking alters anxiety behavior in adulthood, by assessing both state and trait anxiety in rats. Sprague–Dawley rat pups received four unilateral needle pricks per day, while controls received four tactile stimuli or were left completely undisturbed during the first postnatal week. Mechanical sensitivity was assessed in the neonatal phase and throughout the development. State anxiety was assessed in the open field test and trait anxiety in the elevated zero maze. The results show that repetitive needle pricking leads to acute mechanical hypersensitivity, but does not affect baseline mechanical sensitivity throughout development. In adulthood, animals previously exposed to neonatal procedural pain (including repetitive handling and removal from litter) showed lower state anxiety but did not differ in trait anxiety, as compared with the undisturbed controls. These findings indicate that early‐life procedural pain decreases state but not trait anxiety behavior in later life in a rodent model of repetitive needle pricking

Dopamine-neurotransmission and nociception in zebrafish: An anti-nociceptive role of dopamine receptor drd2a

Dopamine (DA) is an important modulator in nociception and analgesia. Spinal DA receptors are involved in descending modulation of the nociceptive transmission. Genetic variations within DA neurotransmission have been associated with altered pain sensitivity and development of chronic pain syndromes. The variant rs6277 in dopamine receptor 2 a (drd2a) has been associated with a decreased D2 receptor availability and increased nociception. The aim of this study is to further characterize the role of DA neurotransmission in nociception and the anti-nociceptive function of drd2a. The phenotype caused by rs6277 was modelled in zebrafish larvae using morpholino's and the effect on nociception was tested using a validated behavioural assay. The anti-nociceptive role of drd2a was tested using pharmacological intervention of D2 agonist Quinpirole. The experiments demonstrate that a decrease in drd2a expression results in a pro-nociceptive behavioural phenotype (P = 0.016) after a heat stimulus. Furthermore, agonism of drd2a with agonist Quinpirole (0.2 mu M) results in dose-dependent anti-nociception (P = 0.035) after a heat stimulus. From these results it is concluded that the dopamine receptor drd2a is involved in anti-nociceptive behaviour in zebrafish. The model allows further screening and testing of genetic variation and treatment involved in nociception