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Rashid Giniatullin - One of the best experts on this subject based on the ideXlab platform.
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cholinergic nociceptive mechanisms in rat Meninges and trigeminal ganglia potential implications for migraine pain
Frontiers in Neurology, 2017Co-Authors: Rashid Giniatullin, Irina Shelukhina, Nikita Mikhailov, Leniz Nurullin, Evgeny E. Nikolsky, P A AbushikAbstract:Background: Parasympathetic innervation of Meninges and ability of carbachol, acetylcholine receptor (AChR) agonist, to induce headaches suggests contribution of cholinergic mechanisms to primary headaches. However, neurochemical mechanisms of cholinergic regulation of peripheral nociception in Meninges, origin place for headache, are almost unknown. Methods: Using electrophysiology, calcium imaging, immunohistochemistry and staining of meningeal mast cells, we studied effects of cholinergic agents on peripheral nociception in rat hemiskulls and isolated trigeminal neurons. Results: Both acetylcholine and carbachol significantly increased nociceptive firing in peripheral terminals of meningeal trigeminal nerves recorded by local suction electrode. Strong nociceptive firing was also induced by nicotine implying essential role of nicotinic AChRs in control of excitability of trigeminal nerve endings. Nociceptive firing induced by carbachol was reduced by muscarinic antagonist atropine whereas the action of nicotine was prevented by the nicotinic blocker d-tubocurarine, but was insensitive to the TRPA1 antagonist HC-300033. Carbachol but not nicotine induced massive degranulation of meningeal mast cells known to release multiple pro-nociceptive mediators. Enzymes terminating acetylcholine action, acetylcholinesterase and butyrylcholinesterase, were revealed in perivascular meningeal nerves. The inhibitor of AChE neostigmine did not change the firing per se, but induced nociceptive activity, sensitive to d-tubocurarine, after pretreatment of Meninges with the migraine mediator CGRP. This observation suggested the pro-nociceptive action of endogenous acetylcholine in Meninges. Both nicotine and carbachol induced intracellular Ca2+ transients in trigeminal neurons partially overlapping with expression of capsaicin-sensitive TRPV1 receptors. Conclusion: Trigeminal nerve terminals in Meninges, as well as dural mast cells and trigeminal ganglion neurons express a repertoire of pro-nociceptive nicotinic and muscarinic AChRs which could be activated by the acetylcholine released from parasympathetic nerves. These receptors represent a potential target for novel therapeutic interventions in trigeminal pain and probably in migraine.
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Cholinergic Nociceptive Mechanisms in Rat Meninges and Trigeminal Ganglia: Potential Implications for Migraine Pain
Frontiers Media S.A., 2017Co-Authors: Polina Abushik, Rashid Giniatullin, Irina Shelukhina, Nikita Mikhailov, Leniz Nurullin, Evgeny E. NikolskyAbstract:BackgroundParasympathetic innervation of Meninges and ability of carbachol, acetylcholine (ACh) receptor (AChR) agonist, to induce headaches suggests contribution of cholinergic mechanisms to primary headaches. However, neurochemical mechanisms of cholinergic regulation of peripheral nociception in Meninges, origin place for headache, are almost unknown.MethodsUsing electrophysiology, calcium imaging, immunohistochemistry, and staining of meningeal mast cells, we studied effects of cholinergic agents on peripheral nociception in rat hemiskulls and isolated trigeminal neurons.ResultsBoth ACh and carbachol significantly increased nociceptive firing in peripheral terminals of meningeal trigeminal nerves recorded by local suction electrode. Strong nociceptive firing was also induced by nicotine, implying essential role of nicotinic AChRs in control of excitability of trigeminal nerve endings. Nociceptive firing induced by carbachol was reduced by muscarinic antagonist atropine, whereas the action of nicotine was prevented by the nicotinic blocker d-tubocurarine but was insensitive to the TRPA1 antagonist HC-300033. Carbachol but not nicotine induced massive degranulation of meningeal mast cells known to release multiple pro-nociceptive mediators. Enzymes terminating ACh action, acetylcholinesterase (AChE) and butyrylcholinesterase, were revealed in perivascular meningeal nerves. The inhibitor of AChE neostigmine did not change the firing per se but induced nociceptive activity, sensitive to d-tubocurarine, after pretreatment of Meninges with the migraine mediator CGRP. This observation suggested the pro-nociceptive action of endogenous ACh in Meninges. Both nicotine and carbachol induced intracellular Ca2+ transients in trigeminal neurons partially overlapping with expression of capsaicin-sensitive TRPV1 receptors.ConclusionTrigeminal nerve terminals in Meninges, as well as dural mast cells and trigeminal ganglion neurons express a repertoire of pro-nociceptive nicotinic and muscarinic AChRs, which could be activated by the ACh released from parasympathetic nerves. These receptors represent a potential target for novel therapeutic interventions in trigeminal pain and probably in migraine
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Nucleotide homeostasis and purinergic nociceptive signaling in rat Meninges in migraine-like conditions
Purinergic Signalling, 2016Co-Authors: Gennady G. Yegutkin, Cindy Guerrero-toro, Erkan Kilinc, Kseniya Koroleva, Yevheniia Ishchenko, Polina Abushik, Raisa Giniatullina, Dmitriy Fayuk, Rashid GiniatullinAbstract:Extracellular ATP is suspected to contribute to migraine pain but regulatory mechanisms controlling pro-nociceptive purinergic mechanisms in the Meninges remain unknown. We studied the peculiarities of metabolic and signaling pathways of ATP and its downstream metabolites in rat Meninges and in cultured trigeminal cells exposed to the migraine mediator calcitonin gene-related peptide (CGRP). Under resting conditions, meningeal ATP and ADP remained at low nanomolar levels, whereas extracellular AMP and adenosine concentrations were one-two orders higher. CGRP increased ATP and ADP levels in Meninges and trigeminal cultures and reduced adenosine concentration in trigeminal cells. Degradation rates for exogenous nucleotides remained similar in control and CGRP-treated Meninges, indicating that CGRP triggers nucleotide release without affecting nucleotide-inactivating pathways. Lead nitrate-based enzyme histochemistry of whole mount Meninges revealed the presence of high ATPase, ADPase, and AMPase activities, primarily localized in the medial meningeal artery. ATP and ADP induced large intracellular Ca^2+ transients both in neurons and in glial cells whereas AMP and adenosine were ineffective. In trigeminal glia, ATP partially operated via P2X7 receptors. ATP, but not other nucleotides, activated nociceptive spikes in meningeal trigeminal nerve fibers providing a rationale for high degradation rate of pro-nociceptive ATP. Pro-nociceptive effect of ATP in meningeal nerves was reproduced by α,β-meATP operating via P2X3 receptors. Collectively, extracellular ATP, which level is controlled by CGRP, can persistently activate trigeminal nerves in Meninges which considered as the origin site of migraine headache. These data are consistent with the purinergic hypothesis of migraine pain and suggest new targets against trigeminal pain.
Irina Shelukhina - One of the best experts on this subject based on the ideXlab platform.
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cholinergic nociceptive mechanisms in rat Meninges and trigeminal ganglia potential implications for migraine pain
Frontiers in Neurology, 2017Co-Authors: Rashid Giniatullin, Irina Shelukhina, Nikita Mikhailov, Leniz Nurullin, Evgeny E. Nikolsky, P A AbushikAbstract:Background: Parasympathetic innervation of Meninges and ability of carbachol, acetylcholine receptor (AChR) agonist, to induce headaches suggests contribution of cholinergic mechanisms to primary headaches. However, neurochemical mechanisms of cholinergic regulation of peripheral nociception in Meninges, origin place for headache, are almost unknown. Methods: Using electrophysiology, calcium imaging, immunohistochemistry and staining of meningeal mast cells, we studied effects of cholinergic agents on peripheral nociception in rat hemiskulls and isolated trigeminal neurons. Results: Both acetylcholine and carbachol significantly increased nociceptive firing in peripheral terminals of meningeal trigeminal nerves recorded by local suction electrode. Strong nociceptive firing was also induced by nicotine implying essential role of nicotinic AChRs in control of excitability of trigeminal nerve endings. Nociceptive firing induced by carbachol was reduced by muscarinic antagonist atropine whereas the action of nicotine was prevented by the nicotinic blocker d-tubocurarine, but was insensitive to the TRPA1 antagonist HC-300033. Carbachol but not nicotine induced massive degranulation of meningeal mast cells known to release multiple pro-nociceptive mediators. Enzymes terminating acetylcholine action, acetylcholinesterase and butyrylcholinesterase, were revealed in perivascular meningeal nerves. The inhibitor of AChE neostigmine did not change the firing per se, but induced nociceptive activity, sensitive to d-tubocurarine, after pretreatment of Meninges with the migraine mediator CGRP. This observation suggested the pro-nociceptive action of endogenous acetylcholine in Meninges. Both nicotine and carbachol induced intracellular Ca2+ transients in trigeminal neurons partially overlapping with expression of capsaicin-sensitive TRPV1 receptors. Conclusion: Trigeminal nerve terminals in Meninges, as well as dural mast cells and trigeminal ganglion neurons express a repertoire of pro-nociceptive nicotinic and muscarinic AChRs which could be activated by the acetylcholine released from parasympathetic nerves. These receptors represent a potential target for novel therapeutic interventions in trigeminal pain and probably in migraine.
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Cholinergic Nociceptive Mechanisms in Rat Meninges and Trigeminal Ganglia: Potential Implications for Migraine Pain
Frontiers Media S.A., 2017Co-Authors: Polina Abushik, Rashid Giniatullin, Irina Shelukhina, Nikita Mikhailov, Leniz Nurullin, Evgeny E. NikolskyAbstract:BackgroundParasympathetic innervation of Meninges and ability of carbachol, acetylcholine (ACh) receptor (AChR) agonist, to induce headaches suggests contribution of cholinergic mechanisms to primary headaches. However, neurochemical mechanisms of cholinergic regulation of peripheral nociception in Meninges, origin place for headache, are almost unknown.MethodsUsing electrophysiology, calcium imaging, immunohistochemistry, and staining of meningeal mast cells, we studied effects of cholinergic agents on peripheral nociception in rat hemiskulls and isolated trigeminal neurons.ResultsBoth ACh and carbachol significantly increased nociceptive firing in peripheral terminals of meningeal trigeminal nerves recorded by local suction electrode. Strong nociceptive firing was also induced by nicotine, implying essential role of nicotinic AChRs in control of excitability of trigeminal nerve endings. Nociceptive firing induced by carbachol was reduced by muscarinic antagonist atropine, whereas the action of nicotine was prevented by the nicotinic blocker d-tubocurarine but was insensitive to the TRPA1 antagonist HC-300033. Carbachol but not nicotine induced massive degranulation of meningeal mast cells known to release multiple pro-nociceptive mediators. Enzymes terminating ACh action, acetylcholinesterase (AChE) and butyrylcholinesterase, were revealed in perivascular meningeal nerves. The inhibitor of AChE neostigmine did not change the firing per se but induced nociceptive activity, sensitive to d-tubocurarine, after pretreatment of Meninges with the migraine mediator CGRP. This observation suggested the pro-nociceptive action of endogenous ACh in Meninges. Both nicotine and carbachol induced intracellular Ca2+ transients in trigeminal neurons partially overlapping with expression of capsaicin-sensitive TRPV1 receptors.ConclusionTrigeminal nerve terminals in Meninges, as well as dural mast cells and trigeminal ganglion neurons express a repertoire of pro-nociceptive nicotinic and muscarinic AChRs, which could be activated by the ACh released from parasympathetic nerves. These receptors represent a potential target for novel therapeutic interventions in trigeminal pain and probably in migraine
Julie A Siegenthaler - One of the best experts on this subject based on the ideXlab platform.
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Single-Cell Transcriptomic Analyses of the Developing Meninges Reveal Meningeal Fibroblast Diversity and Function.
Developmental cell, 2020Co-Authors: John Desisto, Rebecca O’rourke, Hannah E. Jones, Bradley Pawlikowski, Alexandra D. Malek, Stephanie Bonney, Fabien Guimiot, Kenneth L. Jones, Julie A SiegenthalerAbstract:The Meninges are a multilayered structure composed of fibroblasts, blood and lymphatic vessels, and immune cells. Meningeal fibroblasts secrete a variety of factors that control CNS development, yet strikingly little is known about their heterogeneity or development. Using single-cell sequencing, we report distinct transcriptional signatures for fibroblasts in the embryonic dura, arachnoid, and pia. We define new markers for meningeal layers and show conservation in human Meninges. We find that embryonic meningeal fibroblasts are transcriptionally distinct between brain regions and identify a regionally localized pial subpopulation marked by the expression of μ-crystallin. Developmental analysis reveals a progressive, ventral-to-dorsal maturation of telencephalic Meninges. Our studies have generated an unparalleled view of meningeal fibroblasts, providing molecular profiles of embryonic meningeal fibroblasts by layer and yielding insights into the mechanisms of Meninges development and function.
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A cellular atlas of the developing Meninges reveals meningeal fibroblast diversity and function
2019Co-Authors: John Desisto, Rebecca O’rourke, Hannah E. Jones, Stephanie Bonney, Fabien Guimiot, Kenneth L. Jones, Julie A SiegenthalerAbstract:The Meninges, a multilayered structure that encases the CNS, is composed mostly of fibroblasts, along with vascular and immune cells. Meningeal fibroblasts are a vital source of signals that control neuronal migration and neurogenesis yet strikingly little is known about their development. We used single cell RNA sequencing to generate a cellular atlas of embryonic meningeal fibroblasts in control and Foxc1-KO mice in which severe CNS defects arise from failed meningeal fibroblast development. We report unique transcriptional signatures for dura, arachnoid and pial fibroblasts and identify S100a6 as the first unique marker of the pial layer. We describe a new meningeal fibroblast subtype marked by μ-Crystallin expression and show these cell types and markers are conserved in human fetal Meninges. Our analysis demonstrates layer specific production of extracellular matrix components, transporter expression, and synthesis of secreted factors. Lastly, the cellular atlas of Foxc1-KO Meninges provides insight into their severe phenotype, confirming a massive loss in arachnoid and dura fibroblasts and Foxc1-KO pial fibroblasts are so altered that they cluster as a different cell type based on gene expression. These studies provide an unprecedented view of meningeal fibroblast development, highlighting unexpected fibroblast diversity and function, while providing mechanistic insights into the Meninges role in CNS development.
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cerebrovascular defects in foxc1 mutants correlate with aberrant wnt and vegf a pathways downstream of retinoic acid from the Meninges
Developmental Biology, 2016Co-Authors: Swati Mishra, Samuel J. Pleasure, Youngshik Choe, Julie A SiegenthalerAbstract:Growth and maturation of the cerebrovasculature is a vital event in neocortical development however mechanisms that control cerebrovascular development remain poorly understood. Mutations in or deletions that include the FOXC1 gene are associated with congenital cerebrovascular anomalies and increased stroke risk in patients. Foxc1 mutant mice display severe cerebrovascular hemorrhage at late gestational ages. While these data demonstrate Foxc1 is required for cerebrovascular development, its broad expression in the brain vasculature combined with Foxc1 mutant's complex developmental defects have made it difficult to pinpoint its function(s). Using global and conditional Foxc1 mutants, we find 1) significant cerebrovascular growth defects precede cerebral hemorrhage and 2) expression of Foxc1 in neural crest-derived Meninges and brain pericytes, though not endothelial cells, is required for normal cerebrovascular development. We provide evidence that reduced levels of Meninges-derived retinoic acid (RA), caused by defects in Meninges formation in Foxc1 mutants, is a major contributing factor to the cerebrovascular growth defects in Foxc1 mutants. We provide data that suggests that Meninges-derived RA ensures adequate growth of the neocortical vasculature via regulating expression of WNT pathway proteins and neural progenitor derived-VEGF-A. Our findings offer the first evidence for a role of the Meninges in brain vascular development and provide new insight into potential causes of cerebrovascular defects in patients with FOXC1 mutations.
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A cascade of morphogenic signaling initiated by the Meninges controls corpus callosum formation
Neuron, 2012Co-Authors: Youngshik Choe, Julie A Siegenthaler, Samuel J. PleasureAbstract:Summary The corpus callosum is the most prominent commissural connection between the cortical hemispheres, and numerous neurodevelopmental disorders are associated with callosal agenesis. By using mice either with meningeal overgrowth or selective loss of Meninges, we have identified a cascade of morphogenic signals initiated by the Meninges that regulates corpus callosum development. The Meninges produce BMP7, an inhibitor of callosal axon outgrowth. This activity is overcome by the induction of expression of Wnt3 by the callosal pathfinding neurons, which antagonize the inhibitory effects of BMP7. Wnt3 expression in the cingulate callosal pathfinding axons is developmentally regulated by another BMP family member, GDF5, which is produced by the adjacent Cajal-Retzius neurons and turns on before outgrowth of the callosal axons. The effects of GDF5 are in turn under the control of a soluble GDF5 inhibitor, Dan, made by the Meninges. Thus, the Meninges and medial neocortex use a cascade of signals to regulate corpus callosum development.
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We have got you 'covered': how the Meninges control brain development.
Current opinion in genetics & development, 2011Co-Authors: Julie A Siegenthaler, Samuel J. PleasureAbstract:The Meninges have traditionally been viewed as specialized membranes surrounding and protecting the adult brain from injury. However, there is increasing evidence that the fetal Meninges play important roles during brain development. Through the release of diffusible factors, the Meninges influence the proliferative and migratory behaviors of neural progenitors and neurons in the forebrain and hindbrain. Meningeal cells also secrete and organize the pial basement membrane (BM), a critical anchor point for the radially oriented fibers of neuroepithelial stem cells. With its emerging role in brain development, the potential that defects in meningeal development may underlie certain congenital brain abnormalities in humans should be considered. In this review, we will discuss what is known about assembly of the fetal Meninges and review the role of meningeal-derived proteins in mouse and human brain development.
Evgeny E. Nikolsky - One of the best experts on this subject based on the ideXlab platform.
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cholinergic nociceptive mechanisms in rat Meninges and trigeminal ganglia potential implications for migraine pain
Frontiers in Neurology, 2017Co-Authors: Rashid Giniatullin, Irina Shelukhina, Nikita Mikhailov, Leniz Nurullin, Evgeny E. Nikolsky, P A AbushikAbstract:Background: Parasympathetic innervation of Meninges and ability of carbachol, acetylcholine receptor (AChR) agonist, to induce headaches suggests contribution of cholinergic mechanisms to primary headaches. However, neurochemical mechanisms of cholinergic regulation of peripheral nociception in Meninges, origin place for headache, are almost unknown. Methods: Using electrophysiology, calcium imaging, immunohistochemistry and staining of meningeal mast cells, we studied effects of cholinergic agents on peripheral nociception in rat hemiskulls and isolated trigeminal neurons. Results: Both acetylcholine and carbachol significantly increased nociceptive firing in peripheral terminals of meningeal trigeminal nerves recorded by local suction electrode. Strong nociceptive firing was also induced by nicotine implying essential role of nicotinic AChRs in control of excitability of trigeminal nerve endings. Nociceptive firing induced by carbachol was reduced by muscarinic antagonist atropine whereas the action of nicotine was prevented by the nicotinic blocker d-tubocurarine, but was insensitive to the TRPA1 antagonist HC-300033. Carbachol but not nicotine induced massive degranulation of meningeal mast cells known to release multiple pro-nociceptive mediators. Enzymes terminating acetylcholine action, acetylcholinesterase and butyrylcholinesterase, were revealed in perivascular meningeal nerves. The inhibitor of AChE neostigmine did not change the firing per se, but induced nociceptive activity, sensitive to d-tubocurarine, after pretreatment of Meninges with the migraine mediator CGRP. This observation suggested the pro-nociceptive action of endogenous acetylcholine in Meninges. Both nicotine and carbachol induced intracellular Ca2+ transients in trigeminal neurons partially overlapping with expression of capsaicin-sensitive TRPV1 receptors. Conclusion: Trigeminal nerve terminals in Meninges, as well as dural mast cells and trigeminal ganglion neurons express a repertoire of pro-nociceptive nicotinic and muscarinic AChRs which could be activated by the acetylcholine released from parasympathetic nerves. These receptors represent a potential target for novel therapeutic interventions in trigeminal pain and probably in migraine.
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Cholinergic Nociceptive Mechanisms in Rat Meninges and Trigeminal Ganglia: Potential Implications for Migraine Pain
Frontiers Media S.A., 2017Co-Authors: Polina Abushik, Rashid Giniatullin, Irina Shelukhina, Nikita Mikhailov, Leniz Nurullin, Evgeny E. NikolskyAbstract:BackgroundParasympathetic innervation of Meninges and ability of carbachol, acetylcholine (ACh) receptor (AChR) agonist, to induce headaches suggests contribution of cholinergic mechanisms to primary headaches. However, neurochemical mechanisms of cholinergic regulation of peripheral nociception in Meninges, origin place for headache, are almost unknown.MethodsUsing electrophysiology, calcium imaging, immunohistochemistry, and staining of meningeal mast cells, we studied effects of cholinergic agents on peripheral nociception in rat hemiskulls and isolated trigeminal neurons.ResultsBoth ACh and carbachol significantly increased nociceptive firing in peripheral terminals of meningeal trigeminal nerves recorded by local suction electrode. Strong nociceptive firing was also induced by nicotine, implying essential role of nicotinic AChRs in control of excitability of trigeminal nerve endings. Nociceptive firing induced by carbachol was reduced by muscarinic antagonist atropine, whereas the action of nicotine was prevented by the nicotinic blocker d-tubocurarine but was insensitive to the TRPA1 antagonist HC-300033. Carbachol but not nicotine induced massive degranulation of meningeal mast cells known to release multiple pro-nociceptive mediators. Enzymes terminating ACh action, acetylcholinesterase (AChE) and butyrylcholinesterase, were revealed in perivascular meningeal nerves. The inhibitor of AChE neostigmine did not change the firing per se but induced nociceptive activity, sensitive to d-tubocurarine, after pretreatment of Meninges with the migraine mediator CGRP. This observation suggested the pro-nociceptive action of endogenous ACh in Meninges. Both nicotine and carbachol induced intracellular Ca2+ transients in trigeminal neurons partially overlapping with expression of capsaicin-sensitive TRPV1 receptors.ConclusionTrigeminal nerve terminals in Meninges, as well as dural mast cells and trigeminal ganglion neurons express a repertoire of pro-nociceptive nicotinic and muscarinic AChRs, which could be activated by the ACh released from parasympathetic nerves. These receptors represent a potential target for novel therapeutic interventions in trigeminal pain and probably in migraine
Christopher M. Bernards - One of the best experts on this subject based on the ideXlab platform.
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Acetylcholinesterase and butyrylcholinesterase are expressed in the spinal Meninges of monkeys and pigs.
Anesthesiology, 1998Co-Authors: Wolfgang C. Ummenhofer, Sean M. Brown, Christopher M. BernardsAbstract:BACKGROUND Acetylcholinesterase inhibition at the spinal level has been shown to produce a potent antinociceptive effect. However, the site of cholinesterase inhibition is unknown. To determine whether the spinal Meninges participate in acetylcholine metabolism, the spinal Meninges of monkeys and pigs were assayed for cholinesterase activity. METHODS Spinal cord, dura mater, and arachnoid mater specimens from anesthetized pigs and monkeys were mechanically homogenized and cholinesterase activity was determined quantitatively using a commercially available colorimetric assay. The ability of neostigmine to inhibit cholinesterase activity in vitro was also measured. Finally, the reverse transcriptase polymerase chain reaction (RT-PCR) was used to identify the cholinesterase metabolizing enzymes expressed by the spinal Meninges. RESULTS All spinal cord and meningeal specimens showed cholinesterase activity. In pigs, the dura mater showed less enzyme activity (36 +/- 17.7 U/mg protein) than the arachnoid mater (73.4 +/- 30.3 U/mg protein; P < 0.05), and the arachnoid mater showed less activity than the spinal cord (131.3 +/- 55.2 U/mg protein; P < 0.05). In monkeys, the dura mater again showed less cholinesterase activity (45.8 +/- 20.1 U/mg protein; P < 0.05), whereas cholinesterase activity in the arachnoid mater (90.3 +/- 45.9 U/mg protein) and spinal cord specimens (101.9 +/- 37.5 U/mg protein) were not significantly different. There were no significant species-related differences in cholinesterase activity. Neostigmine inhibited cholinesterase activity in a log-dose-dependent manner. The RT-PCR identified mRNA for acetylcholinesterase and butyrylcholinesterase in monkey pia-arachnoid mater. CONCLUSIONS These data show that the spinal Meninges express acetylcholinesterase and butyrylcholinesterase; for monkeys, although not pigs, the level of cholinesterase activity is comparable with that found in the spinal cord. This finding suggests that the Meninges may be an important site for acetylcholine metabolism and may play a role in the analgesic effect produced by intrathecally administered cholinesterase inhibitors.
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Effect of (Hydroxypropyl)‐β‐cyclodextrin on Flux of Morphine, Fentanyl, Sufentanil, and Alfentanil through the Spinal Meninges of Monkey
Journal of pharmaceutical sciences, 1994Co-Authors: Christopher M. BernardsAbstract:Abstract Previous studies have demonstrated that (hydroxypropyl)‐β‐cyclodextrin behaves as a slow‐release reservoir when used as a vehicle for intrathecal administration of opioids. The goal of the current investigation was to determine if (hydroxypropyl)‐β‐cyclodextrin might serve as a slow‐release vehicle for epidural opioid administration as well. An in vitro diffusion cell model was used to determine the flux of morphine, fentanyl, alfentanil, and sufentanil through the spinal Meninges of Macaque nemestrina monkeys in the absence or presence of varying concentrations of (hydroxypropyl)‐β‐cyclodextrin. No concentration of cyclodextrin slowed the flux of any of the opioids through the Meninges, indicating that (hydroxypropyl)‐β‐cyclodextrin will not behave as a slow‐release reservoir for these opioids in the epidural space. This finding suggests that the rate‐limiting step in opioid transfer was diffusion through the Meninges not dissociation of the opioid cyclodextrin complex. However, (hydroxypropyl)‐β‐cyclodextrin significantly increased the flux of sufentanil through the Meninges. Since sufentanil's hydrophobicity has previously been shown to impede its meningeal flux, this finding suggests that cyclodextrin effectively decreases sufentanil's hydrophobicity by formation of inclusion complexes in the aqueous environments of the spinal Meninges.
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physical and chemical properties of drug molecules governing their diffusion through the spinal Meninges
Anesthesiology, 1992Co-Authors: Christopher M. Bernards, Harlan F HillAbstract:Drugs administered into the epidural space for selective spinal analgesia must diffuse through the spinal Meninges to gain access to their sites of action in the spinal cord. Therefore, knowledge of the physical and chemical properties of drug molecules that govern their diffusion through the Meninges is important for understanding the pharmacokinetics of epidural analgesia. To determine the physicochemical properties of drug molecules that govern the rate at which drugs diffuse through the spinal Meninges, the authors measured the permeability coefficient of eight different drug molecules through the spinal Meninges of the monkey using a previously established in vitro model. We previously reported permeability measurements for four of the molecules used in this study; the other four molecules' permeability measurements are new. The measured permeability coefficient was then correlated with the drugs' molecular weight, molecular surface area, molecular volume, length of the major molecular axis, and octanol:buffer distribution coefficient. We found no relationship between the drugs' permeability coefficients and any measure of drug mass, molecular shape, or molecular size. There was, however, a biphasic relationship between the octanol: buffer distribution coefficient and the drugs' measured permeability coefficients. Drugs that were either very hydrophilic or very hydrophobic had permeability coefficients that were significantly less than drugs of intermediate hydrophobicity. These data suggest that it should be possible to design novel analgesics for which meningeal permeability is maximal.