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Mary M Heinricher - One of the best experts on this subject based on the ideXlab platform.
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Purinergic receptor immunoreactivity in the Rostral Ventromedial Medulla.
Neuroscience, 2008Co-Authors: Liesl N. Close, Mary M Heinricher, Justin S. Cetas, Nathan R. SeldenAbstract:Abstract The Rostral Ventromedial Medulla (RVM) has long been recognized to play a pivotal role in nociceptive modulation. Pro-nociception within the RVM is associated with a distinct functional class of neurons, ON-cells that begin to discharge immediately before nocifensive reflexes. Anti-nociceptive function within the RVM, including the analgesic response to opiates, is associated with another distinct class, OFF-cells, which pause immediately prior to nocifensive reflexes. A third class of RVM neurons, NEUTRAL-cells, does not alter firing in association with nocifensive reflexes. ON-, OFF- and NEUTRAL-cells show differential responsiveness to various behaviorally relevant neuromodulators, including purinergic ligands. Iontophoresis of semi-selective P2X ligands, which are associated with nociceptive transmission in the spinal cord and dorsal root ganglia, preferentially activate ON-cells. By contrast, P2Y ligands activate OFF-cells and P1 ligands suppress the firing of NEUTRAL cells. The current study investigates the distribution of P2X, P2Y and P1 receptor immunoreactivity in RVM neurons of Sprague-Dawley rats. Co-localization with tryptophan hydroxylase (TPH), a well-established marker for serotonergic neurons was also studied. Immunoreactivity for the four purinergic receptor subtypes examined was abundant in all anatomical subdivisions of the RVM. By contrast, TPH-immunoreactivity was restricted to a relatively small subset of RVM neurons concentrated in the nucleus raphe magnus and pallidus, as expected. There was a significant degree of co-localization of each purinergic receptor subtype with TPH-immunoreactivity. This co-localization was most pronounced for P2Y1 receptor immunoreactivity, although this was the least abundant among the different purinergic receptor subtypes examined. Immunoreactivity for multiple purinergic receptor subtypes was often co-localized in single neurons. These results confirm the physiological finding that purinergic receptors are widely expressed in the RVM. Purinergic neurotransmission in this region may play an important role in nociception and/or nociceptive modulation, as at other levels of the neuraxis.
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sensitization of pain modulating neurons in the Rostral Ventromedial Medulla after peripheral nerve injury
The Journal of Neuroscience, 2007Co-Authors: Jonathan D Carlson, Jennifer Maire, Melissa E Martenson, Mary M HeinricherAbstract:Nerve injury can lead to mechanical hypersensitivity in both humans and animal models, such that innocuous touch produces pain. Recent functional studies have demonstrated a critical role for descending pain-facilitating influences from the Rostral Ventromedial Medulla (RVM) in neuropathic pain, but the underlying mechanisms and properties of the relevant neurons within the RVM are essentially unknown. We therefore characterized mechanical responsiveness of physiologically characterized neurons in the RVM after spinal nerve ligation, a model of neuropathic pain that produces robust mechanical hyperalgesia and allodynia. RVM neurons were studied 7–14 d after spinal nerve ligation, and classified as “on-cells,” “off-cells,” or “neutral cells” using standard criteria of changes in firing associated with heat-evoked reflexes. On-cells are known to promote nociception, and off-cells to suppress nociception, whereas the role of neutral cells in pain modulation remains an open question. Neuronal and behavioral responses to innocuous and noxious mechanical stimulation were tested using calibrated von Frey filaments (4–100 g) applied to the hindpaws ipsilateral and contralateral to the injury, and in sham-operated and unoperated control animals. On- and off-cells recorded in nerve-injured animals exhibited novel responses to innocuous mechanical stimulation, and enhanced responses to noxious mechanical stimulation. Neuronal hypersensitivity in the RVM was correlated with behavioral hypersensitivity. Neutral cells remained unresponsive to cutaneous stimulation after nerve injury. These data demonstrate that both on- and off-cells in the RVM are sensitized to innocuous and noxious mechanical stimuli after nerve injury. This sensitization likely contributes to allodynia and hyperalgesia of neuropathic pain states.
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Are opioid-sensitive neurons in the Rostral Ventromedial Medulla inhibitory interneurons?
Neuroscience, 2007Co-Authors: Daniel R. Cleary, Miranda J. Neubert, Mary M HeinricherAbstract:Abstract μ-Opioid agonists frequently activate output neurons in the brain via disinhibition, that is, by inhibiting “secondary cells,” which results in disinhibition of “primary cells,” considered to be output neurons. Secondary cells are generally presumed to be inhibitory interneurons that serve only to regulate the activity of the output neurons. However, studies of the opioid-sensitive neurons in the Rostral Ventromedial Medulla, a region with a well-documented role in nociceptive modulation, indicate that the opioid-inhibited neurons in this region (termed “on-cells” when recorded in vivo) have a distinct functional role that parallels and opposes the output of the subset of RVM neurons that are activated following opioid administration, the “off-cells.” The aim of the present study was to analyze the relative timing of on- and off-cell reflex-related firing in the Rostral Ventromedial Medulla to help determine whether on-cells are likely to function as inhibitory interneurons in this region. On- and off-cells display complementary firing patterns during noxious-evoked withdrawal: off-cells stop firing and on-cells show a burst of activity. If on-cells are inhibitory interneurons mediating the off-cell pause, the on-cells would be expected to begin their reflex-related discharge before the off-cells cease firing. To examine this we recorded activity of on- and off-cell pairs during heat-evoked paw or tail withdrawal in lightly anesthetized rats. For each cell pair, we measured the onsets of the off-cell pause and the on-cell burst. Contrary to what would be expected if on-cells were inhibitory interneurons, off-cells typically ceased firing before on-cells began reflex-related firing, with a mean 481 (±69) ms lag between the final off-cell spike and the first on-cell spike. This suggests that on-cells do not mediate the off-cell pause, and points instead to presynaptic mechanisms in opioid-mediated disinhibition of Medullary output neurons. These data also support an independent role for on-cells in pain modulation.
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Purinergic actions on neurons that modulate nociception in the Rostral Ventromedial Medulla.
Neuroscience, 2007Co-Authors: Nathan R. Selden, Justin S. Cetas, Liesl N. Close, Jonathan D Carlson, Mary M HeinricherAbstract:Abstract The Rostral Ventromedial Medulla (RVM) serves as a critical link in bulbo-spinal nociceptive modulation. Within the RVM, ‘off-cells’ pause and ‘on-cells’ discharge immediately prior to a nocifensive reflex. These neurons are also activated and inactivated, respectively, by local or systemic application of opioids. Off-cell activation leads to behavioral anti-nociception and on-cell activation to hyperalgesia. Thus, on- and off-cell populations allow bi-directional modulation of nociception by the RVM. A third neuronal population, neutral cells, shows no reflex-related change in discharge. The role of neutral cells in nociception, if any, is unknown. We investigated the responses of on-, off- and neutral cells to the iontophoretic application of purinergic ligands in lightly anesthetized rats. On-cell firing increased rapidly in response to application of ATP and to the P2X-receptor agonist, α,β-methylene ATP. Off-cell firing increased gradually in response to ATP and to the P2Y-receptor agonist, 2-methylthio-ATP. All of these responses were attenuated or reversed by the non-specific P2-receptor antagonists, suramin and pyridoxal-phosphate-6-azophenyl-2′,4′-disulfonic acid (PPADS). Activation of off-cells was preferentially antagonized by the relatively selective P2Y antagonist, MRS2179. By contrast with activation of on- and off-cells by ATP, neutral cell firing was depressed by ATP, adenosine and the P1-receptor agonist, 5′-( N -ethylcarboxamido) adenosine (NECA). Neutral cell responses to these agonists were at least partially reversed by the adenosine-receptor antagonist, 8-phenyltheophylline (8PT). These data imply that on-cells preferentially express P2X-receptors, off-cells P2Y-receptors and neutral cells P1-receptors. Immunohistochemical localization of purinergic receptors confirms the presence of some subtypes of P2X, P2Y and A1 receptors on neuronal cell bodies and fibers within the RVM. The differential responses of on-, off- and neutral-cells to purinergic ligands highlight the value of pharmacological signatures in further delineation of the anatomy, connectivity and function of this therapeutically important system.
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neural basis for the hyperalgesic action of cholecystokinin in the Rostral Ventromedial Medulla
Journal of Neurophysiology, 2004Co-Authors: Mary M Heinricher, Miranda J. NeubertAbstract:The analgesic actions of opioids can be modified by endogenous “anti-opioid” peptides, among them cholecystokinin (CCK). CCK is now thought to have a broader, pronociceptive role, and contributes to hyperalgesia in inflammatory and neuropathic pain states. The aim of this study was to determine whether anti-opioid and pronociceptive actions of CCK have a common underlying mechanism. We showed previously that a low dose of CCK microinjected into the Rostral Ventromedial Medulla (RVM) blocked the analgesic effect of systemically administered morphine by preventing activation of off-cells, which are the antinociceptive output of this well characterized pain-modulating region. At this anti-opioid dose, CCK had no effect on the spontaneous activity of these neurons or on the activity of on-cells (hypothesized to facilitate nociception) or “neutral cells” (which have no known role in pain modulation). In this study, we used microinjection of a higher dose of CCK into the RVM to test whether activation of on-cells could explain the pronociceptive action of this peptide. Paw withdrawal latencies to noxious heat and the activity of a characterized RVM neuron were recorded in rats lightly anesthetized with methohexital. CCK (30 ng/200 nl) activated on-cells selectively and produced behavioral hyperalgesia. Firing of off-cells and neutral cells was unaffected. These data show that direct, selective activation of RVM on-cells by CCK is sufficient to produce thermal hyperalgesia and indicate that the anti-opioid and pronociceptive effects of this peptide are mediated by actions on different RVM cell classes.
Howard L Fields - One of the best experts on this subject based on the ideXlab platform.
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alterations in the Rostral Ventromedial Medulla after the selective ablation of μ opioid receptor expressing neurons
Pain, 2016Co-Authors: Ichiro Harasawa, Frank Porreca, Howard L Fields, Joshua P Johansen, Ian D MengAbstract:AbstractThe Rostral Ventromedial Medulla (RVM) exerts both inhibitory and excitatory controls over nociceptive neurons in the spinal cord and Medullary dorsal horn. Selective ablation of mu-opioid receptor (MOR)-expressing neurons in the RVM using saporin conjugated to the MOR agonist dermorphin–sap
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engagement of descending inhibition from the Rostral Ventromedial Medulla protects against chronic neuropathic pain
Pain, 2011Co-Authors: Milena De Felice, Louis P Veraportocarrero, Michael H Ossipov, Tamara King, Ruizhong Wang, Todd W Vanderah, Raul Sanoja, Janice Oyarzo, Gregory Dussor, Howard L FieldsAbstract:Abstract A puzzling observation is why peripheral nerve injury results in chronic pain in some, but not all, patients. We explored potential mechanisms that may prevent the expression of chronic pain. Sprague Dawley (SD) or Holtzman (HZ) rats showed no differences in baseline sensory thresholds or responses to inflammatory stimuli. However, spinal nerve ligation (SNL)-induced tactile allodynia occurred in approximately 85% of SD and 50% of HZ rats, respectively. No apparent differences were observed in a survey of dorsal root ganglion or spinal neuropathic markers after SNL regardless of allodynic phenotype. SNL-induced allodynia was reversed by administration of lidocaine within the Rostral Ventromedial Medulla (RVM), a site that integrates descending pain modulation via pain inhibitory (ie, OFF) and excitatory (ie, ON) cells. However, in SD or HZ rats with SNL but without allodynia, RVM lidocaine precipitated allodynia. Additionally, RVM lidocaine produced conditioned place preference in allodynic SD or HZ rats but conditioned place aversion in nonallodynic HZ rats. Similarly, RVM U69,593 (kappa opioid agonist) or blockade of spinal α 2 adrenergic receptors precipitated allodynia in previously nonallodynic HZ rats with SNL. All rats showed an equivalent first-phase formalin responses. However, HZ rats had reduced second-phase formalin behaviors along with fewer RVM OFF cell pauses and RVM ON cell bursts. Thus, expression of nerve injury-induced pain may ultimately depend on descending modulation. Engagement of descending inhibition protects in the transition from acute to chronic pain. These unexpected findings might provide a mechanistic explanation for medications that engage descending inhibition or mimic its consequences.
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delta opioid receptor mediated actions in the Rostral Ventromedial Medulla on tail flick latency and nociceptive modulatory neurons
Pain, 2000Co-Authors: Ichiro Harasawa, Howard L Fields, Ian D MengAbstract:Abstract The Rostral Ventromedial Medulla (RVM) is critical for the modulation of dorsal horn nociceptive transmission. Three classes of RVM neurons (ON, OFF, and NEUTRAL) have been described that have distinct responses to noxious stimuli and mu opioid receptor (MOR) agonists. The present study in barbiturate anesthetized rats investigated the effects of the delta 2 opioid receptor (DOR2) agonist, [D-Ala2]deltorphin II (DELT), microinfused into the RVM on the tail flick reflex and activity of RVM neurons. Tail flick latencies increased dose-dependently after administration of DELT (0.6 nmol and 1.2 nmol). Furthermore, DELT inhibited the tail flick related increase in ON cell activity and shortened the tail flick related pause in OFF cell activity. The activity of NEUTRAL cells was not affected. The antinociceptive effects and corresponding changes in ON and OFF cell activity produced by DELT were antagonized by the DOR2 antagonist, naltriben methanesulfonate, administered at the same site. These DOR2 mediated effects on noxious stimulation-evoked changes in RVM neuronal activity are similar to those reported for MOR agonists and suggest that both DOR2 and MOR produce analgesia through activation of OFF cells.
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mu and kappa opioid receptors in periaqueductal gray and Rostral Ventromedial Medulla
Neuroreport, 1998Co-Authors: Howard B Gutstein, Alfred Mansour, Stanley J Watson, Huda Akil, Howard L FieldsAbstract:: The periaqueductal gray (PAG) and Rostral Ventromedial Medulla (RVM) are important brain stem pain modulating regions. Recent evidence suggests that kappa opioids antagonize the effects of mu opioids in the RVM. However, the anatomical relationship between mu and kappa opioid receptors in PAG and RVM is not well characterized. This study examined relationships between mu and kappa opioid receptor immunoreactivity (IR) and mRNA in PAG and RVM. Brain slices were processed for either immunocytochemistry or in situ hybridization. We found considerable anatomical overlap of mu and kappa opioid IR and mRNA in the RVM and PAG. These results provide an anatomical basis for recent behavioral and electrophysiological findings in RVM, and suggest modulatory interactions between mu and kappa opioids in PAG.
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endogenous opioid mediated inhibition of putative pain modulating neurons in rat Rostral Ventromedial Medulla
Neuroscience, 1996Co-Authors: Howard L FieldsAbstract:Abstract The Rostral Ventromedial Medulla is a critical relay for midbrain regions, including the periaqueductal gray and nucleus cuneiformis, that control nociception at the spinal cord. Opioid-containing neurons and terminals are concentrated in both the periaqueductal gray and the Rostral Ventromedial Medulla in the rat. However, the function of endogenous opioid peptides within the Medulla in pain modulation is unclear. In this study, bicuculline (30–50 ng) or morphine (5 μg) microinjected into the periaqueductal gray inhibited the tail-flick reflex and the firing of on-cells (cells that increase firing just before tail flick) in the Medulla. Iontophoretically applied naloxone (20 or 30 nA), which blocked the inhibition of on-cell firing induced by iontophoresis of morphine (20 or 30 nA), consistently reduced the on-cell inhibition produced by bicuculline or morphine microinjected into the periaqueductal gray. Naloxone did not reduce the inhibition of on-cell firing induced by iontophoretically applied clonidine (10 or 20 nA), an α 2 adrenoceptor agonist. The firing of off-cells (cells that pause in firing just prior to tail-flick) in the Medulla was increased by bicuculline applied in the periaqueductal gray and was not affected by naloxone. The present results suggest that when activation of neurons in the periaqueductal gray produces antinociception, endogenous opioid peptides are released in the Rostral Ventromedial Medulla and selectively inhibit on-cells, which presumably have a facilitating action on spinal nociceptive transmission. This action is proposed to be critical for the behavioral antinociception induced by bicuculline or morphine in the periaqueductal gray.
G F Gebhart - One of the best experts on this subject based on the ideXlab platform.
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neurotensin produced antinociception in the Rostral Ventromedial Medulla is partially mediated by spinal cord norepinephrine
Pain, 2008Co-Authors: Amber V Buhler, H K Proudfit, G F GebhartAbstract:Abstract Microinjection of neurotensin (NT) into the Rostral Ventromedial Medulla (RVM) produces dose-dependent antinociception. Here we show that antinociception produced by intra-RVM microinjection of neurotensin (NT) or the selective NT receptor subtype 1 (NTR1) agonist PD149163 can be partially blocked by intrathecal (i.t.) yohimbine, an α2-adrenoceptor antagonist and by methysergide, a serotonin receptor antagonist. Antinociception produced by the NTR2 agonist beta-lactotensin (β-LT) is blocked by intrathecal (i.t.) yohimbine, but not by methysergide i.t. It is not known which noradrenergic cell group is involved in this newly identified noradrenergic component of NTR-mediated antinociception. These experiments provide the first evidence that selective activation of NTR2 in the RVM produces antinociception. These results also provide evidence that activation of NTR1 in the RVM produces antinociception through spinal release of norepinephrine (NE) and serotonin, and that activation of NTR2 in the RVM produces antinociception mediated by spinal release of NE.
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Neurotensin activation of the NTR1 on spinally-projecting serotonergic neurons in the Rostral Ventromedial Medulla is antinociceptive
Pain, 2005Co-Authors: Amber V Buhler, H K Proudfit, J. Choi, G F GebhartAbstract:Microinjection of neurotensin (NT) in the Rostral Ventromedial Medulla (RVM) produces dose-dependent antinociception. The NTR1 (Neurotensin Receptor Subtype 1) may mediate part of this response, however definitive evidence is lacking, and the spinal mediators of NTR1-induced antinociception are unknown. In the present study, we used immunohistochemical techniques to show that the NTR1, but not the NTR2 is expressed by spinally projecting serotonergic neurons of the RVM. We also show that microinjection of NT or the NTR1-selective agonist PD149163 in the RVM both produce dose-dependent antinociception in the tail-flick test that is blocked by the NTR1-selective antagonist SR48692. The antinociception produced by NT or PD149163 is also blocked by intrathecal administration of the non-selective serotonergic receptor antagonist methysergide. The results of these experiments provide anatomical and behavioral evidence that activation of NTR1-expressing spinally projecting neurons in the RVM produces antinociception through release of serotonin in the spinal dorsal horn. These results support the conclusion that the NTR1 plays an important role in the central modulation of nociception.
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biphasic modulation of visceral nociception by neurotensin in rat Rostral Ventromedial Medulla
Journal of Pharmacology and Experimental Therapeutics, 1999Co-Authors: M O Urban, S V Coutinho, G F GebhartAbstract:A potential role for neurotensin in the Rostral Ventromedial Medulla (RVM) in modulation of visceral nociceptive transmission was examined in this study. Microinjection of neurotensin (3–3000 pmol) into the RVM of awake rats produced a dose-dependent inhibition of the visceromotor response (VMR) to noxious colorectal distension (CRD) that lasted 30 to 120 min. Additionally, intra-RVM injection of neurotensin (300 pmol) significantly reduced the slope of the stimulus-response function to graded CRD (20–80 mm Hg), whereas the greatest dose of neurotensin (3000 pmol) completely inhibited the VMR at all intensities of CRD. General motor function was unaffected after intra-RVM injection of neurotensin (3000 pmol). Intra-RVM injection of lesser doses of neurotensin (0.03–0.30 pmol) resulted an enhancement of the VMR to noxious CRD that had a short duration (18–30 min), and produced a leftward shift of the stimulus-response function to graded CRD without a change in the slope of the function. Additionally, intra-RVM injection of the neurotensin-receptor antagonist SR48692 (0.3–300 fmol) in naive animals produced dose-dependent inhibition of VMR to noxious CRD, whereas a lesser dose (0.03 fmol) enhanced the VMR. These data support a role for neurotensin in the RVM in biphasic modulation of visceral nociception. The results obtained with SR48692 suggest that endogenous neurotensin in the RVM modulates VMR to noxious CRD via a prominent interaction with neurotensin receptors that mediate facilitatory influences and a lesser interaction with neurotensin receptors that mediate masked inhibitory influences.
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role of glutamate receptors and nitric oxide in the Rostral Ventromedial Medulla in visceral hyperalgesia
Pain, 1998Co-Authors: S V Coutinho, M O Urban, G F GebhartAbstract:Abstract The present study was undertaken to examine the involvement of descending pain modulatory systems from the brainstem Rostral Ventromedial Medulla (RVM) in modulating visceral hyperalgesia produced by intracolonic instillation of zymosan. Three hours after intracolonic zymosan, the visceromotor response (VMR) to noxious colorectal distension (CRD, 80 mmHg, 20s) was increased significantly. This hyperalgesia was attenuated in a dose-dependent manner by the selective NMDA receptor antagonist APV (10–30 fmol, 1 μl) microinjected into the RVM. The hyperalgesia was also attenuated by intra-RVM administration of the nitric oxide synthase (NOS) inhibitor L-NAME. In support, there was a significant increase in the number of cells in the RVM labeled for NADPH diaphorase (NADPH-d) or neuronal NOS (nNOS) in zymosan-treated rats. In contrast to the effects of APV and l -NAME, administration of the non-NMDA receptor antagonist DNQX into the RVM further enhanced the already facilitated VMR to CRD in zymosan-treated rats. Taken together, these data suggest that zymosan-produced visceral hyperalgesia is influenced by two descending pain modulatory systems: a facilitatory system mediated by activation of NMDA receptors in the RVM and production of nitric oxide, and an inhibitory system mediated by activity at non-NMDA receptors in the RVM. The unmasking of one system by selective blockade of the other suggests simultaneous activation of both by colonic inflammation.
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characterization of biphasic modulation of spinal nociceptive transmission by neurotensin in the rat Rostral Ventromedial Medulla
Journal of Neurophysiology, 1997Co-Authors: M O Urban, G F GebhartAbstract:Urban, M. O. and G. F. Gebhart. Characterization of biphasic modulation of spinal nociceptive transmission by neurotensin in the rat Rostral Ventromedial Medulla. J. Neurophysiol. 78: 1550–1562, 1997. Modulation of spinal nociceptive transmission by neurotensin microinjected in the Rostral Ventromedial Medulla (RVM) was examined in anesthetized, paralyzed rats. Forty-three spinal dorsal horn neurons in the L3–L5 spinal segments responding to mechanical and noxious thermal stimulation (50°C) of the plantar surface of the ipsilateral hind foot were studied. Spinal units were classified as either wide dynamic range or nociceptive specific and were located in spinal laminae I–V. Microinjection of neurotensin (0.03 pmol/0.2 μl) into the RVM produced a significant facilitation (135% of control) of spinal unit responses to noxious thermal stimulation (50°C) that lasted ∼12 min. In contrast, injection of greater doses of neurotensin (300 or 3,000 pmol) produced an inhibition of spinal unit responses to noxious he...
Hiroki Imbe - One of the best experts on this subject based on the ideXlab platform.
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Increase of histone acetylation in the GABAergic neurons in the Rostral Ventromedial Medulla associated with mechanical hypersensitivity after repeated restraint stress.
Brain Research Bulletin, 2018Co-Authors: Hiroki Imbe, Akihisa KimuraAbstract:Abstract Psychophysical stresses frequently increase sensitivity and response to pain, which is termed stress-induced hyperalgesia (SIH). However, the mechanism remains unknown. The Rostral Ventromedial Medulla (RVM) and locus coeruleus (LC) are core elements of the descending pain modulatory system, which modulate nociceptive transmission in the spinal dorsal horn. In the present study we examined the acetylation of histone H3 in the RVM and LC after repeated restraint stress for 3 weeks to clarify changes in the descending pain modulatory system in the rat with SIH. The repeated restraint stress induced mechanical hypersensitivity in the hindpaw and an increase in acetylation of histone H3 in the RVM but not the LC. The number of acetylated histone H3-IR cells in the RVM was significantly higher in the repeated restraint group (282.9 ± 43.1) than that in the control group (134.7 ± 15.6, p
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effects of restraint stress on glial activity in the Rostral Ventromedial Medulla
Neuroscience, 2013Co-Authors: Hiroki Imbe, Akihisa Kimura, Tomohiro Donishi, Yoshiki KaneokeAbstract:Abstract Stress affects brain activity and promotes long-term changes in multiple neural systems. Exposure to stressors causes substantial effects on the perception and response to pain. In several animal models, chronic stress produces lasting hyperalgesia. Postmortem studies of patients with stress-related psychiatric disorders have demonstrated a decrease in the number of astrocytes and the level of glial fibrillary acidic protein (GFAP), a marker for astrocyte, in the cerebral cortex. Since astrocytes play vital roles in maintaining neuroplasticity via synapse maintenance and secretion of neurotrophins, damage of astrocytes is thought to be involved in the neuropathology. In the present study we examined GFAP, S100β and CD11b protein levels in the Rostral Ventromedial Medulla (RVM) after the subacute and chronic restraint stresses to clarify changes in descending pain modulatory system in the rat with stress-induced hyperalgesia. Chronic restraint stress (6 h/day for 3 weeks), but not subacute restraint stress (6 h/day for 3 days), caused a marked mechanical hypersensitivity. Subacute and chronic restraint stresses induced a significant decrease of GFAP protein level in the RVM (21.9 ± 3.6%, p
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involvement of descending facilitation from the Rostral Ventromedial Medulla in the enhancement of formalin evoked nocifensive behavior following repeated forced swim stress
Brain Research, 2010Co-Authors: Hiroki Imbe, Tomohiro Donishi, Keiichiro Okamoto, Emiko Senba, Akihisa KimuraAbstract:Abstract In the present study we examined whether the descending facilitation from the Rostral Ventromedial Medulla (RVM) is required for the enhancement of formalin-evoked nocifensive behavior following repeated forced swim stress. Rats were subjected to forced or sham swim stress for 3 days. Withdrawal latency to noxious thermal stimuli and mechanical withdrawal threshold to von Frey filaments did not change significantly in both groups at 24 h after the last stress session. The forced swim stress showed significantly enhanced nocifensive behavior to the subcutaneous administration of formalin at 2 days after the last stress session (1330.1 ± 62.8 s), compared to the sham swim (1076 ± 102.4 s, p p
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activation of erk in the Rostral Ventromedial Medulla is involved in hyperalgesia during peripheral inflammation
Brain Research, 2008Co-Authors: Hiroki Imbe, Akihisa Kimura, Tomohiro Donishi, Keiichiro Okamoto, Fumiko Aikawa, Emiko Senba, Y TamaiAbstract:Abstract We have previously shown that the extracellular signal-regulated kinase (ERK) is activated in the Rostral Ventromedial Medulla (RVM) during peripheral inflammation. In the present study, the relationship between ERK signaling in the RVM and pain hypersensitivity was investigated in the rat. Microinjection of U0126, a mitogen-activated protein kinase kinase inhibitor, into the RVM decreased phosphorylated ERK at 7 h after complete Freund's adjuvant (CFA) injection into the hindpaw. The U0126 microinjection also attenuated thermal hyperalgesia in the ipsilateral hindpaw at 24 h after CFA injection. The ipsilateral paw withdrawal latency in the U0126 group (67.9% ± 5.3% vs. baseline, n = 7) was significantly longer than that in the control group (52.0% ± 3.6% vs. baseline, n = 8). These findings suggest that activation of ERK in the RVM contributes to thermal hyperalgesia during peripheral inflammation.
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effects of peripheral inflammation on activation of p38 mitogen activated protein kinase in the Rostral Ventromedial Medulla
Brain Research, 2007Co-Authors: Hiroki Imbe, Akihisa Kimura, Tomohiro Donishi, Keiichiro Okamoto, Fumiko Aikawa, Y Tamai, Yasutomo Iwailiao, Emiko SenbaAbstract:Abstract In the present study, the activation of p38 mitogen-activated protein kinase (p38 MAPK) in the Rostral Ventromedial Medulla (RVM) following the injection of complete Freund's adjuvant (CFA) into the rat hindpaw was examined in order to clarify the mechanisms underlying the dynamic changes in the descending pain modulatory system after peripheral inflammation. Phospho-p38 MAPK-immunoreactive (p-p38 MAPK-IR) neurons were observed in the nucleus raphe magnus (NRM) and nucleus reticularis gigantocellularis pars alpha (GiA). Inflammation induced the activation of p38 MAPK in the RVM, with a peak at 30 min after the injection of CFA into the hindpaw, which lasted for 1 h. In the RVM, the number of p-p38 MAPK-IR neurons per section in rats killed at 30 min after CFA injection (19.4 ± 2.0) was significantly higher than that in the naive group (8.4 ± 2.4) [p
Allan I Basbaum - One of the best experts on this subject based on the ideXlab platform.
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neurochemical characterization of extracellular serotonin in the Rostral Ventromedial Medulla and its modulation by noxious stimuli
Journal of Neurochemistry, 2002Co-Authors: Bradley K Taylor, Allan I BasbaumAbstract:: Using in vivo microdialysis, we have characterized serotonin release from the Rostral Ventromedial Medulla of the freely moving rat. Addition of tetrodotoxin or removal of calcium from the dialysis solution diminished the dialysate serotonin content, suggesting that spontaneous, calcium channel- and sodium channel-dependent neuronal release mechanisms contribute to the extracellular serotonin collected from the Rostral Ventromedial Medulla. Extracellular serotonin concentration was increased by depolarization (with 100 mM potassium) and by the local administration of either a reuptake blocker (citalopram), a monoamine oxidase inhibitor (pargyline), or amphetamine. Serotonin release was reduced significantly by 8-hydroxy-2-(di-n-propylamino)tetralin, suggesting that serotonin1A receptors may regulate release from Rostral Ventromedial Medulla neurons. Because the basal serotonin concentration in the Rostral Ventromedial Medulla was approximately twofold higher than that collected from the Rostral ventrolateral Medulla, a region that contains serotonin terminals but many fewer cell bodies, the possibility of release of serotonin from Rostral Ventromedial Medulla neurons is discussed. Finally, intraplantar formalin injection significantly increased serotonin release, suggesting that this neurotransmitter contributes to nociceptive modulation by regulating the outflow of the Rostral Ventromedial Medulla neurons.
