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Central sensitization
20
Abstracts
(642) Effects of a specific protein phosphatase on long lasting central sensitization following injection of capsaicin
(644) Differential alteration of glutamate uptake in the spinal dorsal and ventral horn after spinal nerve ligation
X. Zhang, J. Wu, L. Fang, W. Willis; University of Texas Medical Branch, Galveston, TX Kinases and phosphatases catalyze opposing reactions of phosphorylation and dephosphorylation, which may modulate the function of crucial proteins in the nervous system. This is an important mechanism in the regulation of cellular signal transduction and metabolism in nociceptive neurons. Fostriecin, a specific inhibitor of serine/threonine protein phosphatase type 2A (PP2A), may contribute to the process of long lasting central sensitization of nociceptive neurons in the spinal cord by causing protein hyperphosphorylation. This study was designed to assess the role of PP2A in the spinal cord in the electrophysiological manifestations induced by intradermal injection of capsaicin in rats. A microdialysis fiber was implanted in the spinal cord dorsal horn for ACSF and fostriecin pre- or postreatment. Central sensitization was initiated by injection of capsaicin into the plantar surface of the left paw. In ACSF pretreated animals, the responses to innocuous and noxious stimuli following capsaicin injection increased 15 min after injection and mostly recovered by 60 min later. Compared to the control animals, pre- or postreatment with the phosphatase inhibitor, fostriecin, into the spinal cord dorsal horn enhanced the increased responses by making the responses last more than 3 hours. These results demonstrate that fostriecin potentiates central sensitization of nociceptive transmission in the spinal cord following capsaicin injection and indicate that PP2A may be involved in determining the duration of capsaicin-induced central sensitization. Supported by NIH grants NS09743 & NS11255.
B. Binns, V. Goettl, K. Hackshaw, R. Stephens Jr.; The Ohio State University, Columbus, OH Alteration of glutamatergic (GLU) neurotransmission within the spinal cord contributes to hyperalgesic responses associated with neuropathic pain and chronic opiate therapy. In particular, changes in expression and efficacy of glutamate transporters have recently been described. These experiments were designed to utilize the superior spatial and temporal resolution of in vivo voltammetry to examine changes in glutamate uptake occurring in the spinal cord in situ after experimentally induced neuropathic pain. Sprague-Dawley rats (200-250g), were treated by either sham surgery or tight ligation of L5,L6 spinal nerves (SNL). One or five weeks later, the spinal cord of chloral hydrate-anesthetized animals was exposed, and ceramic-based platinum voltammetry electrodes equipped with glass micropipettes 50mm from the recording surfaces were placed stereotaxically at sites within the spinal cord. Pressure injection of GLU (200mM, 39-65nl) into the ipsilateral L5-6 spinal cord was performed and the appearance and dissipation of extracellular GLU within the spinal cord was assessed by an enzyme-based electrochemical reaction. SNL rats showed a 72% reduction of GLU uptake compared to sham controls in the ipsilateral L5-6 spinal cord within deep laminae. More dramatic reductions in GLU uptake in the ventral horn of the ipsilateral L5-6 spinal cord (93%) was noted. The contralateral dorsal horn and the ipsilateral L4 spinal cord in the same animals showed no changes. In contrast, glutamate uptake was enhanced at 1 week following SNL. The data represent an initial finding that spinal nerve ligation produced changes in glutamate uptake in ipsilateral deep laminae of the dorsal horn and within the ventral horn of the spinal cord. Supported by USPHS grant AR046056.
(643) A pronociceptive effect of intrathecal TIP39, a PTH2-R Agonist, in Nanve Rat
B06 - Clinical Neurophysiology: Research
C. Cao, M. Perkins, J. Laird; AstraZeneca R&D Montreal, St-Laurent, QC PTH2-R is a subtype of the parathyroid-hormone-receptor family, consisting of three members. Unlike PTH1-R and PTH3-R, the PTH2-R is present in areas containing central terminals of nociceptive primary afferents, like the superficial dorsal horn of the spinal cord and caudal part of the spinal trigeminal nucleus. The distribution of PTH2-R in the spinal cord and dorsal root ganglion suggests a role in spinal nociception. The aim of the present study was to explore the roles of PTH2-R in spinal nociception using an electrophysiological approach. Extracellular recordings of flexor ␣-motoneuron activity were made from the nerve to the semitendinosus muscles in decerebrate-spinal rats. The excitability of the flexor reflex was determined by measuring efferent activity evoked by touch, pinch and heat (water 52 °C) stimuli applied to the hind paw. The test protocol was applied at 5-min intervals during the entire course of the experiment. Intrathecal (i.t.) administration of tuberoinfundibular peptide of 39 residues (TIP39), a specific agonist at PTH2-R, dose-dependently (10, 100 and 500 pmol) increased the excitability of the nociceptive flexor reflex in naı¨ve rats. The potentiation lasted for about 40 min and peaked at 20-25 min. At 100 pmol/10mL/rat, touch, pinch and heat responses were increased by 415 ⫾ 89% (p⬍0.01, n⫽6), 185 ⫾ 23% (p⬍0.01, n⫽6) and 651 ⫾ 135% (p⬍0.005, n⫽6) respectively. TIP 39 is pronociceptive in this model, indicating a possible role of PTH2-R in mediating spinal nociception and nociceptive transmission.
(645) Neonatal procedural pain exposure predicts preterm infant cortisol response to novelty at 8 months R. Grunau, J. Weinberg, M. Whitfield; University of British Columbia, Vancouver, BC Prolonged neonatal pain exposure may alter stress systems in the long term, and changes may be prevented by early administration of morphine. Stress responses (cortisol) to visual novelty in preterm infants born at extremely low gestational age (ELGA ⱕ 28 weeks), very low gestational age (VLGA 29-32 weeks), and term born infants were compared at 8 months of age (“corrected” for prematurity; CCA). In addition, among the preterm infants, we evaluated whether cortisol levels at 8 months were related to neonatal exposure to procedural pain and morphine in the neonatal intensive care unit. Seventy-six infants, 54 preterm (ⱕ 32 weeks GA at birth) and 22 term born infants seen at 8 months CCA comprised the study sample, after excluding those with major sensory, motor or cognitive impairment. Salivary cortisol was measured prior to (basal), and 20 min following introduction of novel toys (post 1), and after developmental assessment (post 2). Salivary cortisol was significantly higher in ELGA infants at 8 months, compared to the VLGA and term groups prior to and following introduction of visual novelty (p⬍ .006). Term born and more maturely born preterm (VLGA) infants showed a slight decrease in cortisol when playing with novel toys, whereas the ELGA group showed higher basal and sustained levels of cortisol. After controlling for early illness severity and duration of supplemental oxygen, higher cortisol level in preterm infants at 8 months CCA was associated with higher neonatal exposure to pain. This effect was independent of the amount of morphine infants received. ELGA preterm infants show a different pattern or cortisol levels prior to and following positive stimulation of visual novelty than more maturely born VLGA preterm and term born infants. Early pain exposure may contribute to “resetting” arousal systems in preterm infants.
(646) WITHDRAWN
Abstracts
(642) Effects of a specific protein phosphatase on long lasting central sensitization following injection of capsaicin
(644) Differential alteration of glutamate uptake in the spinal dorsal and ventral horn after spinal nerve ligation
X. Zhang, J. Wu, L. Fang, W. Willis; University of Texas Medical Branch, Galveston, TX Kinases and phosphatases catalyze opposing reactions of phosphorylation and dephosphorylation, which may modulate the function of crucial proteins in the nervous system. This is an important mechanism in the regulation of cellular signal transduction and metabolism in nociceptive neurons. Fostriecin, a specific inhibitor of serine/threonine protein phosphatase type 2A (PP2A), may contribute to the process of long lasting central sensitization of nociceptive neurons in the spinal cord by causing protein hyperphosphorylation. This study was designed to assess the role of PP2A in the spinal cord in the electrophysiological manifestations induced by intradermal injection of capsaicin in rats. A microdialysis fiber was implanted in the spinal cord dorsal horn for ACSF and fostriecin pre- or postreatment. Central sensitization was initiated by injection of capsaicin into the plantar surface of the left paw. In ACSF pretreated animals, the responses to innocuous and noxious stimuli following capsaicin injection increased 15 min after injection and mostly recovered by 60 min later. Compared to the control animals, pre- or postreatment with the phosphatase inhibitor, fostriecin, into the spinal cord dorsal horn enhanced the increased responses by making the responses last more than 3 hours. These results demonstrate that fostriecin potentiates central sensitization of nociceptive transmission in the spinal cord following capsaicin injection and indicate that PP2A may be involved in determining the duration of capsaicin-induced central sensitization. Supported by NIH grants NS09743 & NS11255.
B. Binns, V. Goettl, K. Hackshaw, R. Stephens Jr.; The Ohio State University, Columbus, OH Alteration of glutamatergic (GLU) neurotransmission within the spinal cord contributes to hyperalgesic responses associated with neuropathic pain and chronic opiate therapy. In particular, changes in expression and efficacy of glutamate transporters have recently been described. These experiments were designed to utilize the superior spatial and temporal resolution of in vivo voltammetry to examine changes in glutamate uptake occurring in the spinal cord in situ after experimentally induced neuropathic pain. Sprague-Dawley rats (200-250g), were treated by either sham surgery or tight ligation of L5,L6 spinal nerves (SNL). One or five weeks later, the spinal cord of chloral hydrate-anesthetized animals was exposed, and ceramic-based platinum voltammetry electrodes equipped with glass micropipettes 50mm from the recording surfaces were placed stereotaxically at sites within the spinal cord. Pressure injection of GLU (200mM, 39-65nl) into the ipsilateral L5-6 spinal cord was performed and the appearance and dissipation of extracellular GLU within the spinal cord was assessed by an enzyme-based electrochemical reaction. SNL rats showed a 72% reduction of GLU uptake compared to sham controls in the ipsilateral L5-6 spinal cord within deep laminae. More dramatic reductions in GLU uptake in the ventral horn of the ipsilateral L5-6 spinal cord (93%) was noted. The contralateral dorsal horn and the ipsilateral L4 spinal cord in the same animals showed no changes. In contrast, glutamate uptake was enhanced at 1 week following SNL. The data represent an initial finding that spinal nerve ligation produced changes in glutamate uptake in ipsilateral deep laminae of the dorsal horn and within the ventral horn of the spinal cord. Supported by USPHS grant AR046056.
(643) A pronociceptive effect of intrathecal TIP39, a PTH2-R Agonist, in Nanve Rat
B06 - Clinical Neurophysiology: Research
C. Cao, M. Perkins, J. Laird; AstraZeneca R&D Montreal, St-Laurent, QC PTH2-R is a subtype of the parathyroid-hormone-receptor family, consisting of three members. Unlike PTH1-R and PTH3-R, the PTH2-R is present in areas containing central terminals of nociceptive primary afferents, like the superficial dorsal horn of the spinal cord and caudal part of the spinal trigeminal nucleus. The distribution of PTH2-R in the spinal cord and dorsal root ganglion suggests a role in spinal nociception. The aim of the present study was to explore the roles of PTH2-R in spinal nociception using an electrophysiological approach. Extracellular recordings of flexor ␣-motoneuron activity were made from the nerve to the semitendinosus muscles in decerebrate-spinal rats. The excitability of the flexor reflex was determined by measuring efferent activity evoked by touch, pinch and heat (water 52 °C) stimuli applied to the hind paw. The test protocol was applied at 5-min intervals during the entire course of the experiment. Intrathecal (i.t.) administration of tuberoinfundibular peptide of 39 residues (TIP39), a specific agonist at PTH2-R, dose-dependently (10, 100 and 500 pmol) increased the excitability of the nociceptive flexor reflex in naı¨ve rats. The potentiation lasted for about 40 min and peaked at 20-25 min. At 100 pmol/10mL/rat, touch, pinch and heat responses were increased by 415 ⫾ 89% (p⬍0.01, n⫽6), 185 ⫾ 23% (p⬍0.01, n⫽6) and 651 ⫾ 135% (p⬍0.005, n⫽6) respectively. TIP 39 is pronociceptive in this model, indicating a possible role of PTH2-R in mediating spinal nociception and nociceptive transmission.
(645) Neonatal procedural pain exposure predicts preterm infant cortisol response to novelty at 8 months R. Grunau, J. Weinberg, M. Whitfield; University of British Columbia, Vancouver, BC Prolonged neonatal pain exposure may alter stress systems in the long term, and changes may be prevented by early administration of morphine. Stress responses (cortisol) to visual novelty in preterm infants born at extremely low gestational age (ELGA ⱕ 28 weeks), very low gestational age (VLGA 29-32 weeks), and term born infants were compared at 8 months of age (“corrected” for prematurity; CCA). In addition, among the preterm infants, we evaluated whether cortisol levels at 8 months were related to neonatal exposure to procedural pain and morphine in the neonatal intensive care unit. Seventy-six infants, 54 preterm (ⱕ 32 weeks GA at birth) and 22 term born infants seen at 8 months CCA comprised the study sample, after excluding those with major sensory, motor or cognitive impairment. Salivary cortisol was measured prior to (basal), and 20 min following introduction of novel toys (post 1), and after developmental assessment (post 2). Salivary cortisol was significantly higher in ELGA infants at 8 months, compared to the VLGA and term groups prior to and following introduction of visual novelty (p⬍ .006). Term born and more maturely born preterm (VLGA) infants showed a slight decrease in cortisol when playing with novel toys, whereas the ELGA group showed higher basal and sustained levels of cortisol. After controlling for early illness severity and duration of supplemental oxygen, higher cortisol level in preterm infants at 8 months CCA was associated with higher neonatal exposure to pain. This effect was independent of the amount of morphine infants received. ELGA preterm infants show a different pattern or cortisol levels prior to and following positive stimulation of visual novelty than more maturely born VLGA preterm and term born infants. Early pain exposure may contribute to “resetting” arousal systems in preterm infants.
(646) WITHDRAWN