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1
Omura, Yukiko, Jasmine P. Kipke, Siamak Salavatian, Andrew Shea Afyouni, Christian Wooten, Robert F. Herkenham, Uri Maoz, et al. "Spinal Anesthesia Reduces Myocardial Ischemia–triggered Ventricular Arrhythmias by Suppressing Spinal Cord Neuronal Network Interactions in Pigs." Anesthesiology 134, no. 3 (January 7, 2021): 405–20. http://dx.doi.org/10.1097/aln.0000000000003662.
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Background Cardiac sympathoexcitation leads to ventricular arrhythmias. Spinal anesthesia modulates sympathetic output and can be cardioprotective. However, its effect on the cardio-spinal reflexes and network interactions in the dorsal horn cardiac afferent neurons and the intermediolateral nucleus sympathetic neurons that regulate sympathetic output is not known. The authors hypothesize that spinal bupivacaine reduces cardiac neuronal firing and network interactions in the dorsal horn–dorsal horn and dorsal horn–intermediolateral nucleus that produce sympathoexcitation during myocardial ischemia, attenuating ventricular arrhythmogenesis. Methods Extracellular neuronal signals from the dorsal horn and intermediolateral nucleus neurons were simultaneously recorded in Yorkshire pigs (n = 9) using a 64-channel high-density penetrating microarray electrode inserted at the T2 spinal cord. Dorsal horn and intermediolateral nucleus neural interactions and known markers of cardiac arrhythmogenesis were evaluated during myocardial ischemia and cardiac load–dependent perturbations with intrathecal bupivacaine. Results Cardiac spinal neurons were identified based on their response to myocardial ischemia and cardiac load–dependent perturbations. Spinal bupivacaine did not change the basal activity of cardiac neurons in the dorsal horn or intermediolateral nucleus. After bupivacaine administration, the percentage of cardiac neurons that increased their activity in response to myocardial ischemia was decreased. Myocardial ischemia and cardiac load–dependent stress increased the short-term interactions between the dorsal horn and dorsal horn (324 to 931 correlated pairs out of 1,189 pairs, P < 0.0001), and dorsal horn and intermediolateral nucleus neurons (11 to 69 correlated pairs out of 1,135 pairs, P < 0.0001). Bupivacaine reduced this network response and augmentation in the interactions between dorsal horn–dorsal horn (931 to 38 correlated pairs out of 1,189 pairs, P < 0.0001) and intermediolateral nucleus–dorsal horn neurons (69 to 1 correlated pairs out of 1,135 pairs, P < 0.0001). Spinal bupivacaine reduced shortening of ventricular activation recovery interval and dispersion of repolarization, with decreased ventricular arrhythmogenesis during acute ischemia. Conclusions Spinal anesthesia reduces network interactions between dorsal horn–dorsal horn and dorsal horn–intermediolateral nucleus cardiac neurons in the spinal cord during myocardial ischemia. Blocking short-term coordination between local afferent–efferent cardiac neurons in the spinal cord contributes to a decrease in cardiac sympathoexcitation and reduction of ventricular arrhythmogenesis. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New
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Sharma, K., and E. Frank. "Sensory axons are guided by local cues in the developing dorsal spinal cord." Development 125, no. 4 (February 15, 1998): 635–43. http://dx.doi.org/10.1242/dev.125.4.635.
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During development, different classes of sensory neurons establish distinctive central projections within the spinal cord. Muscle spindle afferents (Ia fibers) grow ventrally through the dorsal horn to the ventral cord, whereas cutaneous sensory collaterals remain confined to the dorsal horn. We have studied the nature of the cues used by Ia fibers in establishing their characteristic projections within the dorsal horn. An organotypic culture preparation of embryonic chicken spinal cord and sensory ganglia was used to test the influence of ventral spinal cord and local cues within the dorsal spinal cord on the growing Ia afferents. When the ventral half of the spinal cord was replaced with an inverted duplicate dorsal half, Ia fibers entering through the dorsal columns still grew ventrally within the host dorsal horn. After the fibers entered the duplicate dorsal half, they continued growing in the same direction. With respect to the duplicate dorsal tissue, this was in an opposite, ventral-to-dorsal, direction. In both cases, however, Ia collaterals remained confined to the medial dorsal laminae. Restriction to these laminae was maintained even when the fibers had to change their direction of growth to stay within them. These results show that cues from the ventral cord are not required for the development of correct Ia projections within the dorsal horn. Local, rather than long-range directional, cues appear to determine the pattern of these projections. When the ventral half of the spinal cord was left intact but sensory axons were forced to enter the dorsal gray matter growing rostrally or caudally, their collateral axons grew in random directions, further showing the absence of directional cues even when the ventral cord was present. Taken together, these observations suggest that Ia fibers are guided by local positional cues that keep them confined to the medial gray matter within the dorsal horn, but their direction of growth is determined primarily by their orientation and position as they enter the dorsal gray matter.
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Harrington, Andrea M., Sonia Garcia Caraballo, Jessica E. Maddern, Luke Grundy, Joel Castro, and Stuart M. Brierley. "Colonic afferent input and dorsal horn neuron activation differs between the thoracolumbar and lumbosacral spinal cord." American Journal of Physiology-Gastrointestinal and Liver Physiology 317, no. 3 (September 1, 2019): G285—G303. http://dx.doi.org/10.1152/ajpgi.00013.2019.
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The distal colon is innervated by the splanchnic and pelvic nerves, which relay into the thoracolumbar and lumbosacral spinal cord, respectively. Although the peripheral properties of the colonic afferent nerves within these pathways are well studied, their input into the spinal cord remain ill defined. The use of dual retrograde tracing from the colon wall and lumen, in conjunction with in vivo colorectal distension and spinal neuronal activation labeling with phosphorylated MAPK ERK 1/2 (pERK), allowed us to identify thoracolumbar and lumbosacral spinal cord circuits processing colonic afferent input. In the thoracolumbar dorsal horn, central projections of colonic afferents were primarily labeled from the wall of the colon and localized in laminae I and V. In contrast, lumbosacral projections were identified from both lumen and wall tracing, present within various dorsal horn laminae, collateral tracts, and the dorsal gray commissure. Nonnoxious in vivo colorectal distension evoked significant neuronal activation (pERK-immunoreactivity) within the lumbosacral dorsal horn but not in thoracolumbar regions. However, noxious in vivo colorectal distension evoked significant neuronal activation in both the thoracolumbar and lumbosacral dorsal horn, with the distribution of activated neurons correlating to the pattern of traced projections. Dorsal horn neurons activated by colorectal distension were identified as possible populations of projection neurons or excitatory and inhibitory interneurons based on their neurochemistry. Our findings demonstrate how colonic afferents in splanchnic and pelvic pathways differentially relay mechanosensory information into the spinal cord and contribute to the recruitment of spinal cord pathways processing non-noxious and noxious stimuli. NEW & NOTEWORTHY In mice, retrograde tracing from the colon wall and lumen was used to identify unique populations of afferent neurons and central projections within the spinal cord dorsal horn. We show that there are pronounced differences between the spinal cord regions in the distribution pattern of colonic afferent central projections and the pattern of dorsal horn neuron activation evoked by colorectal distension. These findings demonstrate how colonic afferent input influences spinal processing of colonic mechanosensation.
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Sengul, Gulgun, Huazheng Liang, Teri M. Furlong, and George Paxinos. "Dorsal Horn of Mouse Lumbar Spinal Cord Imaged with CLARITY." BioMed Research International 2020 (August 14, 2020): 1–8. http://dx.doi.org/10.1155/2020/3689380.
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The organization of the mouse spinal dorsal horn has been delineated in 2D for the six Rexed laminae in our publication Atlas of the Spinal Cord: Mouse, Rat, Rhesus, Marmoset, and Human. In the present study, the tissue clearing technique CLARITY was used to observe the cyto- and chemoarchitecture of the mouse spinal cord in 3D, using a variety of immunohistochemical markers. We confirm prior observations regarding the location of glycine and serotonin immunoreactivities. Novel observations include the demonstration of numerous calcitonin gene-related peptide (CGRP) perikarya, as well as CGRP fibers and terminals in all laminae of the dorsal horn. We also observed sparse choline acetyltransferase (ChAT) immunoreactivity in small perikarya and fibers and terminals in all dorsal horn laminae, while gamma aminobutyric acid (GABA) and glutamate decarboxylase-67 (GAD67) immunoreactivities were found only in small perikarya and fibers. Finally, numerous serotonergic fibers were observed in all laminae of the dorsal horn. In conclusion, CLARITY confirmed the 2D immunohistochemical properties of the spinal cord. Furthermore, we observed novel anatomical characteristics of the spinal cord and demonstrated that CLARITY can be used on spinal cord tissue to examine many proteins of interest.
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Dodd, J., and T. M. Jessell. "Cell surface glycoconjugates and carbohydrate-binding proteins: possible recognition signals in sensory neurone development." Journal of Experimental Biology 124, no. 1 (September 1, 1986): 225–38. http://dx.doi.org/10.1242/jeb.124.1.225.
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Dorsal root ganglion (DRG) neurones transmit cutaneous sensory information from the periphery to the dorsal horn of the spinal cord. Subpopulations of DRG neurones that subserve distinct sensory modalities project to discrete regions in the dorsal horn. The formation of specific sensory connections during development may involve cell-surface interactions with spinal cord cells. Molecules that are expressed on the surface of functional subpopulations of DRG and dorsal horn neurones have therefore been identified. Distinct subsets of DRG neurones express globo- or lactoseries carbohydrate differentiation antigens. The expression of defined carbohydrate structures correlates with the embryonic lineage, peptide phenotype and the central termination site of DRG neurones. Similar or identical glycoconjugates have been implicated in cellular interactions that contribute to preimplantation embryonic development. Small-diameter DRG neurones that project to the superficial dorsal horn express N-acetyllactosamine backbone structures that are potential ligands for beta-galactoside-specific binding proteins (lectins). Two lectins have been identified that are expressed early in development in the superficial dorsal horn. These complementary molecules may contribute to the development of sensory afferent projections in the spinal cord.
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Olsen, M. L., S. L. Campbell, and H. Sontheimer. "Differential Distribution of Kir4.1 in Spinal Cord Astrocytes Suggests Regional Differences in K+ Homeostasis." Journal of Neurophysiology 98, no. 2 (August 2007): 786–93. http://dx.doi.org/10.1152/jn.00340.2007.
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Neuronal activity in the spinal cord results in extracellular potassium accumulation that is significantly higher in the dorsal horn than in the ventral horn. This is suggestive of differences in K+ clearance, widely thought to involve diffusional K+ uptake by astrocytes. We previously identified the inward rectifying K+ channel Kir4.1 as the major K+ conductance in spinal cord astrocytes in situ and hence hypothesized that different expression levels of Kir4.1 may account for the observed differences in potassium dynamics in spinal cord. Our results with immunohistochemical staining demonstrated highest Kir4.1 channel expression in the ventral horn and very low levels of Kir4.1 in the apex of the dorsal horn. Western blots from tissue of these two regions similarly confirmed much lower levels of Kir4.1 in the apex of the dorsal horn. Whole cell patch-clamp recordings from astrocytes in rat spinal cord slices also showed a difference in inwardly rectifying currents in these two regions. However, no statistical difference in either fast-inactivating (Ka) or delayed rectifying potassium currents (Kd) was observed, suggesting these differences were specific to Kir currents. Importantly, when astrocytes in each region were challenged with high [K+]o, astrocytes from the dorsal horn showed significantly smaller (60%) K+ uptake currents than astrocytes from the ventral horn. Taken together, these data support the conclusion that regional differences in astrocytic expression of Kir4.1 channels result in marked changes in potassium clearance rates in these two regions of the spinal cord.
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Chen, Shao-Rui, Kristi L. Sweigart, Joan M. Lakoski, and Hui-Lin Pan. "Functional μ Opioid Receptors Are Reduced in the Spinal Cord Dorsal Horn of Diabetic Rats." Anesthesiology 97, no. 6 (December 1, 2002): 1602–8. http://dx.doi.org/10.1097/00000542-200212000-00037.
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Background The mechanisms of decreased spinal analgesic potency of morphine in neuropathic pain are not fully known. Agonist-stimulated [35S]GTPgammaS receptor autoradiography has been used to measure receptor activation of G proteins in vitro. Using this technique, we determined changes in the functional mu opioid receptors in the spinal dorsal horn in diabetic rats. Methods Rats were rendered diabetic with an intraperitoneal injection of streptozotocin. The lumbar spinal cord was obtained from age-matched normal and diabetic rats 4 weeks after streptozotocin treatment. [D-Ala2,N-MePhe4,Gly5-ol]-enkephalin (DAMGO, 10 microm)-stimulated [35S]GTPgammaS binding was performed in both tissue sections and isolated membranes. Results The DAMGO-stimulated [35S]GTPgammaS binding in the spinal dorsal horn was significantly reduced (approximately 37%) in diabetic rats compared with normal rats. However, [35S]GTPgammaS bindings in the spinal dorsal horn stimulated by other G protein-coupled receptor agonists, including [D-Pen2,D-Pen5]-enkephalin, R(-)N6-(2-phenylisopropyl)-adenosine, and WIN-55212, were not significantly altered in diabetic rats. The basal [35S]GTPgammaS binding in the spinal dorsal horn was slightly (approximately 13%) but significantly increased in diabetic rats. Western blot analysis revealed no significant difference in the expression of the alpha subunits of G(i) and G(o) proteins in the dorsal spinal cord between normal and diabetic rats. Conclusions These data suggest that the functional mu opioid receptors in the spinal cord dorsal horn of diabetic rats are reduced. The impaired functional mu opioid receptors in the spinal cord may constitute one of the mechanisms underlying the reduced spinal analgesic effect of mu opioids in diabetic neuropathic pain.
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Li, Ping, Amelita A. Calejesan, and Min Zhuo. "ATP P2× Receptors and Sensory Synaptic Transmission Between Primary Afferent Fibers and Spinal Dorsal Horn Neurons in Rats." Journal of Neurophysiology 80, no. 6 (December 1, 1998): 3356–60. http://dx.doi.org/10.1152/jn.1998.80.6.3356.
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Li, Ping, Amelita A. Calean, and Min Zhuo. ATP P2× receptors and sensory synaptic transmission between primary afferent fibers and spinal dorsal horn neurons in rats. J. Neurophysiol. 80: 3356–3360, 1998. Glutamate is a major fast transmitter between primary afferent fibers and dorsal horn neurons in the spinal cord. Recent evidence indicates that ATP acts as another fast transmitter at the rat cervical spinal cord and is proposed to serve as a transmitter for nociception and pain. Sensory synaptic transmission between dorsal root afferent fibers and neurons in the superficial dorsal horn of the lumbar spinal cord were examined by whole cell patch-clamp recording techniques. Experiments were designed to test if ATP could serve as a transmitter at the lumbar spinal cord. Monosynaptic excitatory postsynaptic currents (EPSCs) were completely abolished after the blockade of both glutamatergic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate and N-methyl-d-aspartate receptors. No residual current was detected, indicating that glutamate but not ATP is a fast transmitter at the dorsal horn of the lumbar spinal cord. Pyridoxal-phosphate-6-azophenyl-2′,4′-disulfonic acid (PPADS), a selective P2× receptor antagonist, produced an inhibitory modulatory effect on fast EPSCs and altered responses to paired-pulse stimulation, suggesting the involvement of a presynaptic mechanism. Intrathecal administration of PPADS did not produce any antinociceptive effect in two different types of behavioral nociceptive tests. The present results suggest that ATP P2×2 receptors modulate excitatory synaptic transmission in the superficial dorsal horn of the lumbar spinal cord by a presynaptic mechanism, and such a mechanism does not play an important role in behavioral responses to noxious heating. The involvement of other P2× subtype receptors, which is are less sensitive to PPADS, in acute nociceptive modulation and persistent pain remains to be investigated.
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Bremner, L., M. Fitzgerald, and M. Baccei. "Functional GABAA-Receptor–Mediated Inhibition in the Neonatal Dorsal Horn." Journal of Neurophysiology 95, no. 6 (June 2006): 3893–97. http://dx.doi.org/10.1152/jn.00123.2006.
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Neonatal nociceptive circuits and dorsal horn cells are characterized by an apparent lack of inhibitory control: receptive fields are large and thresholds low in the first weeks of life. It has been suggested that this may reflect immature GABAA-receptor (GABAAR) signaling whereby an early developmental shift in transmembrane anion gradient is followed by a longer period of low Cl− extrusion capacity. To investigate whether functional GABAAR-mediated inhibition does indeed undergo postnatal regulation at the level of dorsal horn circuits, we applied the selective GABAAR antagonist gabazine to the spinal cord in anesthetized rat pups [postnatal day (P) 3 or 21] while recording spike activity in single lumbar dorsal horn cells in vivo. At both ages, blockade of GABAAR activity resulted in enlarged hind paw receptive field areas and increased activity evoked by low- and high-intensity cutaneous stimulation, revealing comparable inhibition of dorsal horn cell firing by spinal GABAARs at P3 and P21. This inhibition did not require descending pathways to the spinal cord because perforated patch-clamp recordings of deep dorsal horn neurons in P3 spinal cord slices also showed an increase in evoked spike activity after application of gabazine. We conclude that spinal GABAergic inhibitory transmission onto single dorsal horn cells “in vivo” is functional at P3 and that low Cl− extrusion capacity does not restrict GABAergic function over the normal range of evoked sensory activity. The excitability of neonatal spinal sensory circuits could reflect immaturity in other intrinsic or descending inhibitory networks rather than weak spinal GABAergic inhibition.
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Sharma, K., Z. Korade, and E. Frank. "Development of specific muscle and cutaneous sensory projections in cultured segments of spinal cord." Development 120, no. 5 (May 1, 1994): 1315–23. http://dx.doi.org/10.1242/dev.120.5.1315.
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Development of sensory projections was studied in cultured spinal segments with attached dorsal root ganglia. In spinal segments from stage 30 (E6.5) and older chicken embryos, prelabeled muscle and cutaneous afferents established appropriate projections. Cutaneous afferents terminated solely within the dorsolateral laminae, whereas some muscle afferents (presumably Ia afferents) projected ventrally towards motoneurons. Development of appropriate projections suggests that sufficient cues are preserved in spinal segments to support the formation of modality-specific sensory projections. Further, because these projections developed in the absence of muscle or skin, these results show that the continued presence of peripheral targets is not required for the formation of specific central projections after stage 29 (E6.0). Development of the dorsal horn in cultured spinal segments was assessed using the dorsal midline as a marker. In ovo, this midline structure appears at stage 29. Lack of midline formation in stage 28 and 29 cultured spinal segments suggests that the development of the dorsal horn is arrested in this preparation. This is consistent with earlier reports suggesting that dorsal horn development may be dependent on factors outside the spinal cord. Because dorsal horn development is blocked in cultured spinal segments, this preparation makes it possible to study the consequences of premature ingrowth of sensory axons into the spinal cord. In chicken embryos sensory afferents reach the spinal cord at stage 25 (E4.5) but do not arborize within the gray matter until stage 30. During this period dorsal horn cells are still being generated. In spinal segments, only those segments that have developed a midline at the time of culture support the formation of midline at the time of culture support the formation of specific sensory projections.(ABSTRACT TRUNCATED AT 250 WORDS)
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Dykes, Robert W., and A. D. Craig. "Control of Size and Excitability of Mechanosensory Receptive Fields in Dorsal Column Nuclei by Homolateral Dorsal Horn Neurons." Journal of Neurophysiology 80, no. 1 (July 1, 1998): 120–29. http://dx.doi.org/10.1152/jn.1998.80.1.120.
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Dykes, Robert W. and A. D. Craig. Control of size and excitability of mechanosensory receptive fields in dorsal column nuclei by homolateral dorsal horn neurons. J. Neurophysiol. 80: 120–129 1998. Both accidental and experimental lesions of the spinal cord suggest that neuronal processes occurring in the spinal cord modify the relay of information through the dorsal column-lemniscal pathway. How such interactions might occur has not been adequately explained. To address this issue, the receptive fields of mechanosensory neurons of the dorsal column nuclei were studied before and after manipulation of the spinal dorsal horn. After either a cervical or lumbar laminectomy and exposure of the dorsal column nuclei in anesthetized cats, the representation of the hindlimb or of the forelimb was defined by multiunit recordings in both the dorsal column nuclei and in the ipsilateral spinal cord. Next, a single cell was isolated in the dorsal column nuclei, and its receptive field carefully defined. Each cell could be activated by light mechanical stimuli from a well-defined cutaneous receptive field. Generally the adequate stimulus was movement of a few hairs or rapid skin indentation. Subsequently a pipette containing either lidocaine or cobalt chloride was lowered into the ipsilateral dorsal horn at the site in the somatosensory representation in the spinal cord corresponding to the receptive field of the neuron isolated in the dorsal column nuclei. Injection of several hundred nanoliters of either lidocaine or cobalt chloride into the dorsal horn produced an enlargement of the receptive field of the neuron being studied in the dorsal column nuclei. The experiment was repeated 16 times, and receptive field enlargements of 147–563% were observed in 15 cases. These data suggest that the dorsal horn exerts a tonic inhibitory control on the mechanosensory signals relayed through the dorsal column-lemniscal pathway. Because published data from other laboratories have shown that receptive field size is controlled by signals arising from the skin, we infer that the control of neuronal excitability, receptive field size and location for lemniscal neurons is determined by tonic afferent activity that is relayed through a synapse in the dorsal horn. This influence of dorsal horn neurons on the relay of mechanosensory information through the lemniscal pathways must modify our traditional views concerning the relative independence of these two systems.
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Kang, Byeol-Rim, Chang-Beohm Ahn, and Byung-Tae Choi. "N-Methyl-D-Aspartate Antagonist Inhibits NR-1 Subunit Phosphorylation of the Spinal N-Methyl-D-Aspartate Receptor Induced by Low Frequency Electroacupuncture." American Journal of Chinese Medicine 35, no. 06 (January 2007): 987–93. http://dx.doi.org/10.1142/s0192415x07005454.
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We investigated whether the 2 Hz electroacupuncture (EA) analgesia is associated with phosphorylation of N-methyl-D-aspartate receptor (NMDAR) NR-1 subunits and NMDAR antagonism in the lumbar spinal cord of rats. EA stimulation produced an increase of serine phosphorylation of NMDAR NR-1 subunits in the spinal cord as compared with normal conditions. However, the intrathecal injection of NMDAR antagonist D-2-amino-5-phosphonopentanoic acid significantly prevented serine phosphorylation of NMDAR NR-1 subunits induced by EA stimulation in the dorsal horn of spinal cord. These results indicate that EA analgesia by stimulation of peripheral nerves may be involved in an increase of NR-1 serine phosphorylation in the dorsal horn of the spinal cord.
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Jessell, T. M., K. Yoshioka, and C. E. Jahr. "Amino acid receptor-mediated transmission at primary afferent synapses in rat spinal cord." Journal of Experimental Biology 124, no. 1 (September 1, 1986): 239–58. http://dx.doi.org/10.1242/jeb.124.1.239.
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Intracellular recording techniques have been used to provide information on the identity of excitatory transmitters released at synapses formed between dorsal root ganglion (DRG) and spinal cord neurones in two in vitro preparations. Explants of embryonic rat DRG were added to dissociated cultures of embryonic dorsal horn neurones and synaptic potentials recorded intracellularly from dorsal horn neurones after DRG explant stimulation. More than 80% of dorsal horn neurones received at least one fast, DRG-evoked, monosynaptic input. In the presence of high divalent cation concentrations (5 mmol l-1 Ca2+, 3 mmol l-1 Mg2+) the acidic amino acid receptor agonists, L-glutamate, kainate (KA) and quisqualate (QUIS) excited all dorsal horn neurones which received a monosynaptic DRG neurone input, whereas L-aspartate and N-methyl-D-aspartate (NMDA) had little or no action. 2-Amino-5-phosphonovalerate (APV), a selective NMDA receptor antagonist, was relatively ineffective at antagonizing DRG-evoked synaptic potentials and L-glutamate-evoked responses. In contrast, kynurenate was found to be a potent antagonist of amino acid-evoked responses and of synaptic transmission at all DRG-dorsal horn synapses examined. The blockade of synaptic transmission by kynurenate appeared to result from a postsynaptic action on dorsal horn neurones. Intracellular recordings from motoneurones in new-born rat spinal cord were used to study the sensitivity of the Ia excitatory postsynaptic potential (EPSP) to antagonists of excitatory amino acids. Superfusion of the spinal cord with APV did not inhibit the Ia EPSP but did suppress later, polysynaptic components of the afferent-evoked response. Kynurenate was a potent and selective inhibitor of the Ia EPSP, acting via a postsynaptic mechanism. These findings indicate that L-glutamate, or a glutamate-like compound, but not L-aspartate, is likely to be the predominant excitatory transmitter that mediates fast excitatory postsynaptic potentials at primary afferent synapses with both dorsal horn neurones and motoneurones.
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Li, Jianhua, Jian Lu, Zhaohui Gao, Satoshi Koba, Jihong Xing, Nicholas King, and Lawrence Sinoway. "Spinal P2X receptor modulates muscle pressor reflex via glutamate." Journal of Applied Physiology 106, no. 3 (March 2009): 865–70. http://dx.doi.org/10.1152/japplphysiol.90879.2008.
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Static contraction of skeletal muscle evokes reflex increases in blood pressure and heart rate. Previous studies showed that P2X receptors located at the dorsal horn of the spinal cord play a role in modulating the muscle pressor reflex. P2X stimulation can alter release of the excitatory amino acid, glutamate (Glu). In this report, we tested the hypothesis that stimulation of P2X receptors enhances the concentrations of Glu ([Glu]) in the dorsal horn, and that blocking P2X receptors attenuates contraction-induced Glu increases and the resultant reflex pressor response. Contraction was elicited by electrical stimulation of the L7 and S1 ventral roots of 14 cats. Glu samples were collected from microdialysis probes inserted in the L7 level of the dorsal horn of the spinal cord, and dialysate [Glu] was determined using the HPLC method. First, microdialyzing α,β-methylene ATP (0.4 mM) into the dorsal horn significantly increased [Glu]. In addition, contraction elevated [Glu] from baseline of 536 ± 53 to 1,179 ± 192 nM ( P < 0.05 vs. baseline), and mean arterial pressure by 39 ± 8 mmHg in the control experiment. Microdialyzing the P2X receptor antagonist pyridoxal phosphate-6-azophenyl-2′,4′-disulfonic acid (10 mM) into the dorsal horn attenuated the contraction induced-Glu increase (610 ± 128 to 759 ± 147 nM; P > 0.05) and pressor response (16 ± 3 mmHg, P < 0.05 vs. control). Our findings demonstrate that P2X modulates the cardiovascular responses to static muscle contraction by affecting the release of Glu in the dorsal horn of the spinal cord.
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Wang, Han-Jun, Wei Wang, Kaushik P. Patel, George J. Rozanski, and Irving H. Zucker. "Spinal cord GABA receptors modulate the exercise pressor reflex in decerebrate rats." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 305, no. 1 (July 1, 2013): R42—R49. http://dx.doi.org/10.1152/ajpregu.00140.2013.
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Neurotransmitters and neuromodulators released by contraction-activated skeletal muscle afferents into the dorsal horn of the spinal cord initiate the central component of the exercise pressor reflex (EPR). Whether γ-aminobutyric acid (GABA), a major inhibitory neurotransmitter within the mammalian central nervous system, is involved in the modulation of the EPR at the level of dorsal horn remains to be determined. We performed local microinjection of either the GABA(A) antagonist bicuculline or the GABA(B) antagonist CGP 52432 into the ipisilateral L4/L5 dorsal horns to investigate the effect of GABA receptor blockade on the pressor response to either static contraction induced by stimulation of the peripheral end of L4/L5 ventral roots, passive stretch, or hindlimb arterial injection of capsaicin (0.1 μg/0.2 ml) in decerebrate rats. Microinjection of either bicuculline (1 mM, 100 nl) or CGP 52432 (10 mM, 100 nl) into the L4/5 dorsal horns significantly increased the pressor and cardioaccelerator responses to all stimuli. Microinjection of either bicuculline or CGP 52432 into the L5 dorsal horn significantly increased the pressor and cardioaccelerator responses to direct microinjection of l-glutatmate (10 mM, 100 nl) into this spinal segment. The disinhibitory effect of both GABA receptor antagonists on the EPR was abolished by microinjection of the broad-spectrum glutamate receptor antagonist kynurenate (10 mM/100 nl). These data suggest that 1) GABA exerts a tonic inhibition of the EPR at the level of dorsal horn; and 2) that an interaction between glutamatergic and GABAergic inputs exist at the level of dorsal horn, contributing to spinal control of the EPR.
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Wang, Dong, Kwan Yeop Lee, Zachary B. Kagan, Kerry Bradley, and Dongchul Lee. "Frequency-Dependent Neural Modulation of Dorsal Horn Neurons by Kilohertz Spinal Cord Stimulation in Rats." Biomedicines 12, no. 6 (June 18, 2024): 1346. http://dx.doi.org/10.3390/biomedicines12061346.
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Kilohertz high-frequency spinal cord stimulation (kHF-SCS) is a rapidly advancing neuromodulatory technique in the clinical management of chronic pain. However, the precise cellular mechanisms underlying kHF-SCS-induced paresthesia-free pain relief, as well as the neural responses within spinal pain circuits, remain largely unexplored. In this study, using a novel preparation, we investigated the impact of varying kilohertz frequency SCS on dorsal horn neuron activation. Employing calcium imaging on isolated spinal cord slices, we found that extracellular electric fields at kilohertz frequencies (1, 3, 5, 8, and 10 kHz) induce distinct patterns of activation in dorsal horn neurons. Notably, as the frequency of extracellular electric fields increased, there was a clear and significant monotonic escalation in neuronal activity. This phenomenon was observed not only in superficial dorsal horn neurons, but also in those located deeper within the dorsal horn. Our study demonstrates the unique patterns of dorsal horn neuron activation in response to varying kilohertz frequencies of extracellular electric fields, and we contribute to a deeper understanding of how kHF-SCS induces paresthesia-free pain relief. Furthermore, our study highlights the potential for kHF-SCS to modulate sensory information processing within spinal pain circuits. These insights pave the way for future research aimed at optimizing kHF-SCS parameters and refining its therapeutic applications in the clinical management of chronic pain.
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Xiao, Zhenping, Mengjun Liao, Yunwu He, Yonglin Li, Wuzhou Yang, Liping Jiang, and Cong Zou. "Pregabalin alleviates postherpetic neuralgia by downregulating spinal TRPV1 channel protein." Tropical Journal of Pharmaceutical Research 20, no. 11 (December 11, 2021): 2287–92. http://dx.doi.org/10.4314/tjpr.v20i11.8.
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Purpose: To determine the mechanism involved in pregabalin-induced alleviation of postherpetic neuralgia in a rat model.Methods: Ninety-sixty healthy Sprague-Dawley (SD) rats were assigned to sham, model andpregabalin groups (32 rats per group). A model of postherpetic neuralgia (PN) was established. The expressions of IL-1β and TNF-α in spinal cord tissue were determined 7 days after administration of treatments. The proportions of fluorescence areas in astrocytes in the dorsal horn, prefrontal lobe and hippocampus, and level of spinal cord TRPV1 channel protein in each group were evaluated.Results: Relative to model rats, IL-1β and TNF-α in spinal cord of pregabalin rats were significantly reduced (p < 0.05). The areas of fluorescence in astrocytes in dorsal horn of spinal cord, prefrontal lobe and hippocampus of model group were significantly increased, relative to sham, but were decreased in rats in pregabalin group (p < 0.05).Conclusion: Pregabalin significantly alleviates postherpetic neuralgia via mechanisms which may be related to the inflammatory response of spinal dorsal horn and downregulation of TRPV1 channel protein expression. This finding may be useful in developing new drugs for alleviating postherpetic neuralgia.
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Carlsen, Eva Meier, and Rune Rasmussen. "Bursting deep dorsal horn neurons: the pharmacological target for the antispastic effects of zolmitriptan?" Journal of Neurophysiology 117, no. 5 (May 1, 2017): 1841–43. http://dx.doi.org/10.1152/jn.00880.2016.
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In a recent publication, Thaweerattanasinp et al. ( J Neurophysiol 116: 1644–1653, 2016) investigated spinal cord injury and firing properties of deep dorsal horn neurons during NMDA or zolmitriptan application by employing electrophysiology in an in vitro spinal cord preparation. Deep dorsal horn neurons were classified into bursting, simple, or tonic firing groups,with bursting neurons showing NMDA and zolmitriptan sensitivity. We discuss the findings in a methodological framework and propose future experiments of importance for translating the results into physiological settings.
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Degtyarenko, A. M., and M. P. Kaufman. "Fictive locomotion and scratching inhibit dorsal horn neurons receiving thin fiber afferent input." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 279, no. 2 (August 1, 2000): R394—R403. http://dx.doi.org/10.1152/ajpregu.2000.279.2.r394.
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In decerebrate paralyzed cats, we examined the effects of two central motor commands (fictive locomotion and scratching) on the discharge of dorsal horn neurons receiving input from group III and IV tibial nerve afferents. We recorded the impulse activity of 74 dorsal horn neurons, each of which received group III input from the tibial nerve. Electrical stimulation of the mesencephalic locomotor region (MLR), which evoked fictive static contraction or fictive locomotion, inhibited the discharge of 44 of the 64 dorsal horn neurons tested. The mean depth from the dorsal surface of the spinal cord of the 44 neurons whose discharge was inhibited by MLR stimulation was 1.77 ± 0.04 mm. Fictive scratching, evoked by topical application of bicuculline to the cervical spinal cord and irritation of the ear, inhibited the discharge of 22 of the 29 dorsal horn neurons tested. Fourteen of the twenty-two neurons whose discharge was inhibited by fictive scratching were found to be inhibited by MLR stimulation as well. The mean depth from the dorsal surface of the cord of the 22 neurons whose discharge was inhibited by fictive scratching was 1.77 ± 0.06 mm. Stimulation of the MLR or the elicitation of fictive scratching had no effect on the activity of 22 dorsal horn neurons receiving input from group III and IV tibial nerve afferents. The mean depth from the dorsal surface of the cord was 1.17 ± 0.07 mm, a value that was significantly ( P < 0.05) less than that for the neurons whose discharge was inhibited by either MLR stimulation or fictive scratching. We conclude that centrally evoked motor commands can inhibit the discharge of dorsal horn neurons receiving thin fiber input from the periphery.
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Hao, Jing-Xia, Ron C. Kupers, and Xiao-Jun Xu. "Response Characteristics of Spinal Cord Dorsal Horn Neurons in Chronic Allodynic Rats After Spinal Cord Injury." Journal of Neurophysiology 92, no. 3 (September 2004): 1391–99. http://dx.doi.org/10.1152/jn.00121.2004.
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The physiological mechanisms of chronic pain in patients with spinal cord injury (SCI) are poorly understood. In the present study, we explored response characteristics of dorsal horn neurons of spinally injured rats exhibiting chronic pain (pain-like response to innocuous mechanical and cold stimulation). Several abnormalities were found in the distribution and response characteristics of dorsal horn neurons in chronic allodynic rats. First, 17% of the recorded neurons (vs. 0% in control animals) had no receptive field. Most of these units were located at or close to the lesioned spinal segment, and they discharged spontaneously at high frequencies. Allodynic rats also showed a significant decrease in the proportion of low-threshold (LT) neurons and an increase in the proportion of wide dynamic range (WDR) neurons. The rate of spontaneous activity of high-threshold (HT) neurons was significantly higher in allodynic compared with control rats. Moreover, HT neurons in allodynic animals showed increased neuronal responses to mechanical stimulation. WDR neurons responded with higher discharge rates to innocuous von Frey hair stimulation in allodynic compared with control rats. The percentage of WDR and HT neurons showing afterdischarges to noxious pinch was also significantly increased in the allodynic rats. The proportion of WDR and HT neurons responding to innocuous cold stimulation respectively increased from 53 and 25% in control rats to 91 and 75% in allodynic animals. These results suggest that the chronic pain-like behaviors in spinally injured rats may be generated and maintained by abnormalities in dorsal horn neurons.
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Bardoni, Rita. "Serotonergic Modulation of Nociceptive Circuits in Spinal Cord Dorsal Horn." Current Neuropharmacology 17, no. 12 (November 12, 2019): 1133–45. http://dx.doi.org/10.2174/1570159x17666191001123900.
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Background: Despite the extensive number of studies performed in the last 50 years, aimed at describing the role of serotonin and its receptors in pain modulation at the spinal cord level, several aspects are still not entirely understood. The interpretation of these results is often complicated by the use of different pain models and animal species, together with the lack of highly selective agonists and antagonists binding to serotonin receptors. Method: In this review, a search has been conducted on studies investigating the modulatory action exerted by serotonin on specific neurons and circuits in the spinal cord dorsal horn. Particular attention has been paid to studies employing electrophysiological techniques, both in vivo and in vitro. Conclusion: The effects of serotonin on pain transmission in dorsal horn depend on several factors, including the type of receptors activated and the populations of neurons involved. Recently, studies performed by activating and/or recording from identified neurons have importantly contributed to the understanding of serotonergic modulation on dorsal horn circuits.
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Ritz, L. A., J. L. Culberson, and P. B. Brown. "Somatotopic organization in cat spinal cord segments with fused dorsal horns: caudal and thoracic levels." Journal of Neurophysiology 54, no. 5 (November 1, 1985): 1167–77. http://dx.doi.org/10.1152/jn.1985.54.5.1167.
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We have explored the somatotopic organization of the two cat spinal cord regions where the dorsal horns are fused (i.e., continuous across the midline): the caudal and thoracic segments. We have mapped the low-threshold component of dorsal horn cell receptive fields (RFs) in these segments and have charted the locations of dorsal root low-threshold mechanoreceptive dermatomes. We also have determined the projections of caudal and thoracic dorsal roots to laminae III and IV by using degeneration techniques. The dorsal skin of the tail or thorax is represented laterally, and ventral skin is represented at the midline, in the fused dorsal horns. Many caudal and thoracic dorsal horn units had RFs that crossed the dorsal or ventral midline of the skin; these units were encountered near the edges or the midline, respectively, of the fused dorsal horns. The tail is fully represented within dorsal root dermatomes S3 to Ca5. Roots more caudal than Ca5 represent progressively smaller skin areas of the distal tail. Adjacent dermatomes overlapped 15-65%. Thoracic dermatomes had a nearly vertical orientation; adjacent dermatomes overlapped by 30-75%. Dorsal roots in caudal and thoracic regions have crossed projections to the medial and lateral (but not middle) portions of the contralateral dorsal horn. These crossed projections are a possible anatomical substrate for RFs that cross the ventral or dorsal midline. The dorsal root projection patterns are consistent with those that would be predicted from the dorsal root dermatomes and dorsal horn cell somatotopy, assuming that the presynaptic terminals' somatotopy is in register with that of dorsal horn cells (the presynaptic somatotopy hypothesis; see Ref. 12).
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Nakatsuka, Terumasa, Meng Chen, Daisuke Takeda, Christopher King, Jennifer Ling, g. Xing, Toyofumi Ataka, Charles Vierck, Robert Yezierski, and Jianguo G. Gu. "Substance P-Driven Feed-Forward Inhibitory Activity in the Mammalian Spinal Cord." Molecular Pain 1 (January 1, 2005): 1744–8069. http://dx.doi.org/10.1186/1744-8069-1-20.
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In mammals, somatosensory input activates feedback and feed-forward inhibitory circuits within the spinal cord dorsal horn to modulate sensory processing and thereby affecting sensory perception by the brain. Conventionally, feedback and feed-forward inhibitory activity evoked by somatosensory input to the dorsal horn is believed to be driven by glutamate, the principle excitatory neurotransmitter in primary afferent fibers. Substance P (SP), the prototypic neuropeptide released from primary afferent fibers to the dorsal horn, is regarded as a pain substance in the mammalian somatosensory system due to its action on nociceptive projection neurons. Here we report that endogenous SP drives a novel form of feed-forward inhibitory activity in the dorsal horn. The SP-driven feed-forward inhibitory activity is long-lasting and has a temporal phase distinct from glutamate-driven feed-forward inhibitory activity. Compromising SP-driven feed-forward inhibitory activity results in behavioral sensitization. Our findings reveal a fundamental role of SP in recruiting inhibitory activity for sensory processing, which may have important therapeutic implications in treating pathological pain conditions using SP receptors as targets.
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Yoshizumi, Masaru, Renee A. Parker, James C. Eisenach, and Ken-ichiro Hayashida. "Gabapentin Inhibits γ-Amino Butyric Acid Release in the Locus Coeruleus but Not in the Spinal Dorsal Horn after Peripheral Nerve Injury in Rats." Anesthesiology 116, no. 6 (June 1, 2012): 1347–53. http://dx.doi.org/10.1097/aln.0b013e318254e6fd.
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Background Gabapentin reduces acute postoperative and chronic neuropathic pain, but its sites and mechanisms of action are unclear. Based on previous electrophysiologic studies, the authors tested whether gabapentin reduced γ-amino butyric acid (GABA) release in the locus coeruleus (LC), a major site of descending inhibition, rather than in the spinal cord. Methods Male Sprague-Dawley rats with or without L5-L6 spinal nerve ligation (SNL) were used. Immunostaining for glutamic acid decarboxylase and GABA release in synaptosomes and microdialysates were examined in the LC and spinal dorsal horn. Results Basal GABA release and expression of glutamic acid decarboxylase increased in the LC but decreased in the spinal dorsal horn after SNL. In microdialysates from the LC, intravenously administered gabapentin decreased extracellular GABA concentration in normal and SNL rats. In synaptosomes prepared from the LC, gabapentin and other α2δ ligands inhibited KCl-evoked GABA release in normal and SNL rats. In microdialysates from the spinal dorsal horn, intravenous gabapentin did not alter GABA concentrations in normal rats but slightly increased them in SNL rats. In synaptosomes from the spinal dorsal horn, neither gabapentin nor other α2δ ligands affected KCl-evoked GABA release in normal and SNL rats. Discussion These results suggest that peripheral nerve injury induces plasticity of GABAergic neurons differently in the LC and spinal dorsal horn and that gabapentin reduces presynaptic GABA release in the LC but not in the spinal dorsal horn. The current study supports the idea that gabapentin activates descending noradrenergic inhibition via disinhibition of LC neurons.
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Dallo, João Gabriel Martins, Bernardo Vergara Reichert, José Benedito Ramos Valladão Júnior, Camila Silva, Bianca Aparecida de Luca, Beatriz de Freitas Azevedo Levy, and Gerson Chadi. "Differential astroglial responses in the spinal cord of rats submitted to a sciatic nerve double crush treated with local injection of cultured Schwann cell suspension or lesioned spinal cord extract: implications on cell therapy for nerve repair." Acta Cirurgica Brasileira 22, no. 6 (December 2007): 485–94. http://dx.doi.org/10.1590/s0102-86502007000600013.
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PURPOSE: Reactive astrocytes are implicated in several mechanisms after central or peripheral nervous system lesion, including neuroprotection, neuronal sprouting, neurotransmission and neuropathic pain. Schwann cells (SC), a peripheral glia, also react after nerve lesion favoring wound/repair, fiber outgrowth and neuronal regeneration. We investigated herein whether cell therapy for repair of lesioned sciatic nerve may change the pattern of astroglial activation in the spinal cord ventral or dorsal horn of the rat. METHODS: Injections of a cultured SC suspension or a lesioned spinal cord homogenized extract were made in a reservoir promoted by a contiguous double crush of the rat sciatic nerve. Local injection of phosphate buffered saline (PBS) served as control. One week later, rats were euthanized and spinal cord astrocytes were labeled by immunohistochemistry and quantified by means of quantitative image analysis. RESULTS: In the ipsilateral ventral horn, slight astroglial activations were seen after PBS or SC injections, however, a substantial activation was achieved after cord extract injection in the sciatic nerve reservoir. Moreover, SC suspension and cord extract injections were able to promote astroglial reaction in the spinal cord dorsal horn bilaterally. Conclusion: Spinal cord astrocytes react according to repair processes of axotomized nerve, which may influence the functional outcome. The event should be considered during the neurosurgery strategies.
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Waataja, Jonathan J., Cristina D. Peterson, Harsha Verma, Cory J. Goracke-Postle, Philippe Séguéla, Eric Delpire, George L. Wilcox, and Carolyn A. Fairbanks. "Agmatine preferentially antagonizes GluN2B-containing N-methyl-d-aspartate receptors in spinal cord." Journal of Neurophysiology 121, no. 2 (February 1, 2019): 662–71. http://dx.doi.org/10.1152/jn.00172.2018.
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The role of the N-methyl-d-aspartate receptor (NMDAr) as a contributor to maladaptive neuroplasticity underlying the maintenance of chronic pain is well established. Agmatine, an NMDAr antagonist, has been shown to reverse tactile hypersensitivity in rodent models of neuropathic pain while lacking the side effects characteristic of global NMDAr antagonism, including sedation and motor impairment, indicating a likely subunit specificity of agmatine’s NMDAr inhibition. The present study assessed whether agmatine inhibits subunit-specific NMDAr-mediated current in the dorsal horn of mouse spinal cord slices. We isolated NMDAr-mediated excitatory postsynaptic currents (EPSCs) in small lamina II dorsal horn neurons evoked by optogenetic stimulation of Nav1.8-containing nociceptive afferents. We determined that agmatine abbreviated the amplitude, duration, and decay constant of NMDAr-mediated EPSCs similarly to the application of the GluN2B antagonist ifenprodil. In addition, we developed a site-specific knockdown of the GluN2B subunit of the NMDAr. We assessed whether agmatine and ifenprodil were able to inhibit NMDAr-mediated current in the spinal cord dorsal horn of mice lacking the GluN2B subunit of the NMDAr by analysis of electrically evoked EPSCs. In control mouse spinal cord, agmatine and ifenprodil both inhibited amplitude and accelerated the decay kinetics. However, agmatine and ifenprodil failed to attenuate the decay kinetics of NMDAr-mediated EPSCs in the GluN2B-knockdown mouse spinal cord. The present study indicates that agmatine preferentially antagonizes GluN2B-containing NMDArs in mouse dorsal horn neurons. NEW & NOTEWORTHY Our study is the first to report that agmatine preferentially antagonizes the GluN2B receptor subunit of the N-methyl-d-aspartate (NMDA) receptor in spinal cord. The preferential targeting of GluN2B receptor is consistent with the pharmacological profile of agmatine in that it reduces chronic pain without the motor side effects commonly seen with non-subunit-selective NMDA receptor antagonists.
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Ongjoco, Rita R. S., Charlene D. Richardson, Xiaowen L. Rudner, Mark Stafford-Smith, and Debra A. Schwinn. "α2-Adrenergic Receptors in Human Dorsal Root Ganglia." Anesthesiology 92, no. 4 (April 1, 2000): 968–76. http://dx.doi.org/10.1097/00000542-200004000-00013.
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Background Nonselective alpha2-adrenergic receptor (alpha2AR) agonists (e.g., clonidine) mediate antinociception in part through alpha2ARs in spinal cord dorsal horn; however, use of these agents for analgesia in humans is limited by unwanted sedation and hypotension. The authors previously demonstrated alpha2a approximately alpha2b > > > alpha2c mRNA in human spinal cord dorsal horn cell bodies. However, because 20% of dorsal horn alpha2ARs derive from cell bodies that reside in the associated dorsal root ganglion (DRG), it is important to evaluate alpha2AR expression in this tissue as well. Therefore, the authors evaluated the hypothesis that alpha2b mRNA, alpha2c mRNA, or both are present in human DRG. Methods Molecular approaches were used to determine alpha2AR expression in 28 human DRGs because of low overall receptor mRNA expression and small sample size. After creation of synthetic competitor cDNA and establishment of amplification conditions with parallel efficiencies, competitive reverse transcription polymerase chain reaction was performed using RNA isolated from human DRG. Results Overall expression of alpha2AR mRNA in DRG is low but reproducible at all spinal levels. alpha2b and alpha2cAR subtype mRNAs predominate (alpha2b approximately alpha2c), accounting for more than 95% of the total alpha2AR mRNA in DRG at all human spinal nerve root levels. Conclusions Predominance of alpha2b and alpha2cAR mRNA in human DRG is distinct from alpha2AR mRNA expression in cell bodies originating in human spinal cord dorsal horn, where alpha2a and alpha2b predominate with little or absent alpha2c expression. These findings also highlight species heterogeneity in alpha2AR expression in DRG. If confirmed at a protein level, these findings provide an additional step in unraveling mechanisms involved in complex neural pathways such as those for pain.
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Hayano, Yasufumi, Keiko Takasu, Yoshihisa Koyama, Moe Yamada, Koichi Ogawa, Kazuhisa Minami, Toshiyuki Asaki, Kazuhiro Kitada, Satoshi Kuwabara, and Toshihide Yamashita. "Dorsal horn interneuron-derived Netrin-4 contributes to spinal sensitization in chronic pain via Unc5B." Journal of Experimental Medicine 213, no. 13 (November 17, 2016): 2949–66. http://dx.doi.org/10.1084/jem.20160877.
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Because of the incomplete understanding of the molecular mechanisms that underlie chronic pain, the currently available treatments for this type of pain remain inefficient. In this study, we show that Netrin-4, a member of the axon guidance molecule family, was expressed in dorsal horn inner lamina II excitatory interneurons in the rat spinal cord. A similar expression pattern for Netrin-4 was also observed in human spinal cord. Behavioral analysis revealed that tactile and heat hyperalgesia after peripheral nerve injury or inflammation were abolished in Netrin-4–mutant rats. Transient suppression of Netrin-4 or its receptor Unc5B after injury could also prevent allodynia. Conversely, intrathecal administration of Netrin-4 protein to naive rats enhanced excitatory synaptic transmission in the dorsal horn and induced allodynia, suggesting that Netrin-4 is involved in spinal sensitization. Furthermore, the Unc5B receptor and subsequent activation of the tyrosine phosphatase SHP2 mediated Netrin-4–induced pain signaling in the spinal cord. These results identify Netrin-4 as a novel protein regulating spinal sensitization leading to chronic pain. Our findings provide evidence for the function of Netrin in the adult nervous system, as well as a previously unknown function in inducing pain signals from dorsal horn interneurons.
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Chen, Li Min, Arabinda Mishra, Pai-Feng Yang, Feng Wang, and John C. Gore. "Injury alters intrinsic functional connectivity within the primate spinal cord." Proceedings of the National Academy of Sciences 112, no. 19 (April 22, 2015): 5991–96. http://dx.doi.org/10.1073/pnas.1424106112.
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Recent demonstrations of correlated low-frequency MRI signal variations between subregions of the spinal cord at rest in humans, similar to those found in the brain, suggest that such resting-state functional connectivity constitutes a common feature of the intrinsic organization of the entire central nervous system. We report our detection of functional connectivity within the spinal cords of anesthetized squirrel monkeys at rest and show that the strength of connectivity within these networks is altered by the effects of injuries. By quantifying the low-frequency MRI signal correlations between different horns within spinal cord gray matter, we found distinct functional connectivity relationships between the different sensory and motor horns, a pattern that was similar to activation patterns evoked by nociceptive heat or tactile stimulation of digits. All horns within a single spinal segment were functionally connected, with the strongest connectivity occurring between ipsilateral dorsal and ventral horns. Each horn was strongly connected to the same horn on neighboring segments, but this connectivity reduced drastically along the spinal cord. Unilateral injury to the spinal cord significantly weakened the strength of the intrasegment horn-to-horn connectivity only on the injury side and in slices below the lesion. These findings suggest resting-state functional connectivity may be a useful biomarker of functional integrity in injured and recovering spinal cords.
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Chen, Shao-Rui, and Hui-Lin Pan. "Antinociceptive Effect of Morphine, but not μ Opioid Receptor Number, Is Attenuated in the Spinal Cord of Diabetic Rats." Anesthesiology 99, no. 6 (December 1, 2003): 1409–14. http://dx.doi.org/10.1097/00000542-200312000-00026.
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Background The mechanisms of decreased analgesic potency of mu opioids in diabetic neuropathic pain are not fully known. The authors recently found that G protein activation stimulated by the mu opioid agonist is significantly reduced in the spinal cord dorsal horn in diabetes. In the current study, they determined potential changes in the number and binding affinity of mu opioid receptors in the spinal cord in diabetic rats. Methods Rats were rendered diabetic with an intraperitoneal injection of streptozotocin. The nociceptive withdrawal threshold was measured before and after intrathecal injection of morphine by applying a noxious pressure stimulus to the hind paw. The mu opioid receptor was determined with immunocytochemistry labeling and a specific mu opioid receptor radioligand, [3H]-(D-Ala2,N-Me-Phe4,Gly-ol5)-enkephalin ([3H]-DAMGO), in the dorsal spinal cord obtained from age-matched normal and diabetic rats 4 weeks after streptozotocin treatment. Results The antinociceptive effect of intrathecal morphine (2-10 microg) was significantly reduced in diabetic rats, with an ED50 about twofold higher than that in normal rats. However, both the dissociation constant (3.99 +/- 0.22 vs. 4.01 +/- 0.23 nm) and the maximal specific binding (352.78 +/- 37.26 vs. 346.88 +/- 35.23 fmol/mg protein) of [3H]-DAMGO spinal membrane bindings were not significantly different between normal and diabetic rats. The mu opioid receptor immunoreactivity in the spinal cord dorsal horn also was similar in normal and diabetic rats. Conclusions The reduced analgesic effect of intrathecal morphine in diabetes is probably due to impairment of mu opioid receptor-G protein coupling rather than reduction in mu opioid receptor number in the spinal cord dorsal horn.
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Milhorat, Thomas H., Harrison T. M. Mu, Carole C. LaMotte, and Ade T. Milhorat. "Distribution of substance P in the spinal cord of patients with syringomyelia." Journal of Neurosurgery 84, no. 6 (June 1996): 992–98. http://dx.doi.org/10.3171/jns.1996.84.6.0992.
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✓ The distribution of substance P, a putative neurotransmitter and pain-related peptide, was studied using the peroxidase—antiperoxidase immunohistochemical method in the spinal cords obtained from autopsy of 10 patients with syringomyelia and 10 age- and sex-matched, neurologically normal individuals. Substance P immunoreactivity was present in axons and in terminal-like processes in close apposition to neurons in the first, second, and third laminae of the dorsal horn. Smaller amounts of peroxidase-positive staining were found in the fifth lamina of the dorsal horn, the intermediolateral nucleus, the intermediomedial nucleus, and the ventral horn. In nine of 10 patients with syringomyelia, there was a substantial increase in substance P immunoreactivity in the first, second, third, and fifth laminae below the level of the lesion. A marked reduction or absence of staining was present in segments of the spinal cord occupied by the syrinx. Central cavities produced bilateral abnormalities, whereas eccentric cavities produced changes that were ipsilateral to the lesion. No alterations in staining were found in the spinal cord of an asymptomatic patient with a small central syrinx. The authors conclude that syringomyelia can be associated with abnormalities in spinal cord levels of substance P, which may affect the modulation and perception of pain.
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Hagains, Christopher E., Arun K. Senapati, Paula J. Huntington, Ji-Wei He, and Yuan B. Peng. "Inhibition of spinal cord dorsal horn neuronal activity by electrical stimulation of the cerebellar cortex." Journal of Neurophysiology 106, no. 5 (November 2011): 2515–22. http://dx.doi.org/10.1152/jn.00719.2010.
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The cerebellum plays a major role in not only modulating motor activity, but also contributing to other functions, including nociception. The intermediate hemisphere of the cerebellum receives sensory input from the limbs. With the extensive connection between the cerebellum to brain-stem structures and cerebral cortex, it is possible that the cerebellum may facilitate the descending system to modulate spinal dorsal horn activity. This study provided the first evidence to support this hypothesis. Thirty-one wide-dynamic-range neurons from the left lumbar and 27 from the right lumbar spinal dorsal horn were recorded in response to graded mechanical stimulation (brush, pressure, and pinch) at the hind paws. Electrical stimulation of the cerebellar cortex of the left intermediate hemisphere significantly reduced spinal cord dorsal horn neuron-evoked responses bilaterally in response to peripheral high-intensity mechanical stimuli. It is concluded that the cerebellum may play a potential antinociceptive role, probably through activating descending inhibitory pathways indirectly.
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Chung, J. M., K. H. Lee, J. Kim, and R. E. Coggeshall. "Activation of dorsal horn cells by ventral root stimulation in the cat." Journal of Neurophysiology 54, no. 2 (August 1, 1985): 261–72. http://dx.doi.org/10.1152/jn.1985.54.2.261.
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Responses of dorsal horn cells to ventral root stimulation were determined for the L7 and S1 levels of the spinal cord of 14 anesthetized cats. Forty-six dorsal horn cells were found that were excited by stimulation of the distal stump of the cut ventral root. For maximum excitation it was necessary to use a train of stimuli. For the 34 dorsal horn cells whose peripheral receptive-field properties could be characterized, 14 were wide dynamic range cells and 19 were high-threshold cells. The other cell responded exclusively to stimulation of deep tissue. None of the cells responded exclusively to innocuous stimuli, and all responded more vigorously to noxious than to innocuous stimuli. Some cells also responded to noxious heat applied to the skin of the receptive field. Locations of 10 of the activated dorsal horn cells were identified. They were distributed throughout the dorsal horn, but most were found in laminae V and VI. In four animals, both the proximal and distal stumps of the cut S1 ventral root were stimulated while searching for dorsal horn cells. Ten dorsal horn cells were found that were excited by stimulation of the distal stump of the ventral root. No cells were found that responded to proximal stump stimulation. To prevent current spread by stimulation of the ventral root, an extra ground electrode was placed distal to the stimulating electrodes. When the ground electrode was removed, distinctive signs of current spread appeared in that a cord dorsum potential could be recorded and the dorsal horn neuronal responses changed. Dorsal horn neurons could also be excited by nonelectrical stimuli such as crushing the ventral root. If the ventral root was crushed distal to the stimulating electrodes, however, the initially excited cell could no longer be activated by ventral root stimulation. Activation of dorsal horn cells by stimulation of the distal stump of a cut ventral root was abolished when the dorsal root of the same segment was sectioned. Conduction velocities of the fibers in the ventral root that excited dorsal horn cells ranged between 0.25 and 1.78 m/s with a mean of 0.91 +/- 0.47 (SD) m/s. These results show that there are unmyelinated afferent fibers in the ventral root that enter the spinal cord through the dorsal root and excite dorsal horn cells.(ABSTRACT TRUNCATED AT 400 WORDS)
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Olschewski, Andrea, Michael E. Bräu, Gunter Hempelmann, Werner Vogel, and Boris V. Safronov. "Differential Block of Fast and Slow Inactivating Tetrodotoxin-sensitive Sodium Channels by Droperidol in Spinal Dorsal Horn Neurons." Anesthesiology 92, no. 6 (June 1, 2000): 1667–76. http://dx.doi.org/10.1097/00000542-200006000-00026.
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Background Dorsal horn neurons of the spinal cord participate in neuronal pain transmission. During spinal and epidural anesthesia, dorsal horn neurons are exposed to local anesthetics and opioids. Droperidol is usually given with opioids to avoid nausea and vomiting. A recently developed method of "entire soma isolation" has made it possible to study directly the action of droperidol on different components of Na+ current in dorsal horn neurons. Methods Using a combination of the whole-cell patch-clamp recording from spinal cord slices and the entire soma isolation method, we studied the direct action of droperidol on two types of Na+ currents in dorsal horn neurons of young rats. Results The tetrodotoxin-sensitive Na+ current in isolated somata consisted of a fast inactivating (tauF, 0.5-2 ms; 80-90% of the total amplitude) and a slow inactivating (tauS, 6-20 ms; 10-20% of the total amplitude) component. Droperidol, at concentrations relevant for spinal and epidural anesthesia, selectively and reversibly suppressed the fast component with a half-maximum inhibiting concentration (IC50) of 8.3 microm. The slow inactivating component was much less sensitive to droperidol; the estimated IC50 value was 809 microm. Conclusions Droperidol selectively blocks fast Na+ channels, the fast and slow components of the Na+ current in dorsal horn neurons are carried through pharmacologically distinct types of Na+ channels, and the effects of droperidol differ from those of local anesthetics and tetrodotoxin, which equipotently suppress both components. Droperidol may be suggested as a pharmacologic tool for separation of different types of inactivating tetrodotoxin-sensitive Na+ channel.
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Jeanmonod, Daniel, and Marc Sindou. "Somatosensory function following dorsal root entry zone lesions in patients with neurogenic pain or spasticity." Journal of Neurosurgery 74, no. 6 (June 1991): 916–32. http://dx.doi.org/10.3171/jns.1991.74.6.0916.
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✓ The goal of this study was to assess the effects of the dorsal root entry zone (DREZ) lesioning procedure, microsurgical DREZ-otomy (MDT), on spinal cord somatosensory function based on peri- and intraoperative clinical and electrophysiological data. The study was performed prospectively on a series of 20 patients suffering from either chronic neurogenic pain or spasticity. Physiological observations were made of the intraoperative evoked electrospinographic recordings as collected from the surface of the spinal cord. The MDT procedure produced analgesia or severe hypalgesia, moderate hypesthesia, and only slight deficits in proprioception and cutaneous spatial discrimination on the body segments operated on. These clinical data correlated well with evoked electrospinographic recordings, which showed a moderate effect of MDT on presynaptic compound action potentials recorded from the spinal cord (N11 and N21), a partial or even reversible effect on the cortical postcentral N20 wave, a more marked effect on the postsynaptic dorsal horn waves N13 and N24 related to large primary afferent fibers, and a disappearance of dorsal horn waves related to finer afferents (N2 and possibly N3). These data provide evidence for an acceptably selective action of MDT on spinal cord nociceptive mechanisms, and for a partial, often slight, involvement of the other somatosensory domains. The presence of abnormal evoked electrospinographic waves is discussed in relation to the mechanisms of neurogenic pain and spasticity. The hypothesis of a “retuning” of the dorsal horn as the mode of action of MDT is presented.
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Olschewski, Andrea, Gunter Hempelmann, Werner Vogel, and Boris V. Safronov. "Blockade of Na+and K+Currents by Local Anesthetics in the Dorsal Horn Neurons of the Spinal Cord." Anesthesiology 88, no. 1 (January 1, 1998): 172–79. http://dx.doi.org/10.1097/00000542-199801000-00025.
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Background The dorsal horn of the spinal cord is a pivotal point for transmission of neuronal pain. During spinal and epidural anesthesia, the neurons of the dorsal horn are exposed to local anesthetics. Unfortunately, little is known about the action of local anesthetics on the major ionic conductances in dorsal horn neurons. In this article, the authors describe the effects of bupivacaine, lidocaine, and mepivacaine on voltage-gated Na+ and K+ currents in the membranes of these neurons. Methods The patch-clamp technique was applied to intact dorsal horn neurons from laminae I-III identified in 200-microm slices of spinal cord from newborn rats. Under voltage-clamp conditions, the whole-cell Na+ and K+ currents activated by depolarization were recorded in the presence of different concentrations of local anesthetics. Results Externally applied bupivacaine, lidocaine, and mepivacaine produced tonic block of Na+ currents with different potencies. Half-maximum inhibiting concentrations (IC50) were 26, 112, and 324 microM, respectively. All local anesthetics investigated also showed a phasic, that is, a use-dependent, block of Na+ channels. Rapidly inactivating K+ currents (KA currents) also were sensitive to the blockers with IC50 values for tonic blocks of 109, 163, and 236 microM, respectively. The block of KA currents was not use dependent. In contrast to Na+ and KA currents, delayed-rectifier K+ currents were almost insensitive to the local anesthetics applied. Conclusions In clinically relevant concentrations, local anesthetics block Na+ and KA currents but not delayed-rectifier K+ currents in spinal dorsal horn neurons. The molecular mechanisms of Na+ and K+ channel block by local anesthetics seem to be different. Characterization of these mechanisms could be an important step in understanding the complexity of local anesthetic action during spinal and epidural anesthesia.
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Laird, J. M., and F. Cervero. "Tonic descending influences on receptive-field properties of nociceptive dorsal horn neurons in sacral spinal cord of rat." Journal of Neurophysiology 63, no. 5 (May 1, 1990): 1022–32. http://dx.doi.org/10.1152/jn.1990.63.5.1022.
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1. Single-unit electrical activity has been recorded from 34 dorsal horn neurons in the sacral segments (S1-2) of the spinal cord in halothane-anesthetized rats. All of the neurons had cutaneous receptive fields (RFs) on the rat's tail. The neurons were classified according to their responses to both innocuous and noxious mechanical stimulation of their RFs. Twenty-five cells were driven by both innocuous and noxious skin stimulation (multireceptive or class 2), and 9 neurons were driven only by noxious skin stimulation (nocireceptive or class 3). 2. The RF size, mechanical threshold, and afferent input properties of these neurons were determined in the intact anesthetized and spinalized states. Reversible spinalization was achieved by cooling the cervical spinal cord to 4 degrees C. 3. The class 2 neurons had a mean RF size of 919.8 +/- 112.0 (SE) mm2 in the intact animal. Fourteen of the 25 class 2 cells had larger RFs in the spinal state (mean increase = 330.0 mm2, SE = 79.2) and so were under tonic descending inhibition. Five neurons, all with C-fiber input, had smaller RFs (mean decrease = 247.6 mm2, SE = 136.6) and higher mechanical thresholds in the spinal state and so were under tonic descending excitation. Six neurons were unaffected by spinalization. 4. Five class 3 neurons recorded in the superficial dorsal horn had small RFs in the intact animal (mean = 201.0 mm2, SE = 48.8) and showed little or no change in RF size on spinalization (mean increase = 33.4 mm2, SE = 16.7), but their mechanical thresholds did decrease, indicating weak tonic descending inhibition. In contrast, four class 3 neurons recorded in the deep dorsal horn had larger RFs in the intact animal (mean = 566.8 mm2, SE = 156.8), and were under strong tonic descending inhibition, because they had much larger RFs (mean increase = 461.0 mm2, SE = 68.3), lower mechanical thresholds, and stronger C-fiber afferent input in the spinal state. 5. We conclude that the majority of nociceptive dorsal horn neurons are subject to a net tonic descending control of their RF properties. The class 2 neurons in the deep dorsal horn appear to be a heterogeneous population, some cells being under tonic descending excitation and others under tonic descending inhibition. Class 3 cells can be separated into those located in the superficial dorsal horn, whose RF properties show very little change on spinalization, and those in the deep dorsal horn, whose RF properties change markedly on spinalization.(ABSTRACT TRUNCATED AT 400 WORDS)
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Meneses, Constanza Stefania, Heine Yacob Müller, Daniel Eduardo Herzberg, Benjamín Uberti, Hedie Almagro Bustamante, and Marianne Patricia Werner. "Immunofluorescence characterization of spinal cord dorsal horn microglia and astrocytes in horses." PeerJ 5 (October 27, 2017): e3965. http://dx.doi.org/10.7717/peerj.3965.
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The role of glial cells in pain modulation has recently gathered attention. The objective of this study was to determine healthy spinal microglia and astrocyte morphology and disposition in equine spinal cord dorsal horns using Iba-1 and GFAP/Cx-43 immunofluorescence labeling, respectively. Five adult horses without visible wounds or gait alterations were selected. Spinal cord segments were obtained post-mortem for immunohistochemical and immunocolocalization assays. Immunodetection of spinal cord dorsal horn astrocytes was done using a polyclonal goat antibody raised against Glial Fibrillary Acidic Protein (GFAP) and a polyclonal rabbit antibody against Connexin 43 (Cx-43). For immunodetection of spinal cord dorsal horn microglia, a polyclonal rabbit antibody against a synthetic peptide corresponding to the C-terminus of ionized calcium-binding adaptor molecule 1 (Iba-1) was used. Epifluorescence and confocal images were obtained for the morphological and organizational analysis. Evaluation of shape, area, cell diameter, cell process length and thickness was performed on dorsal horn microglia and astrocyte. Morphologically, an amoeboid spherical shape with a mean cell area of 92.4 + 34 µm2 (in lamina I, II and III) was found in horse microglial cells, located primarily in laminae I, II and III. Astrocyte primary stem branches (and cellular bodies to a much lesser extent) are mainly detected using GFAP. Thus, double GFAP/Cx-43 immunolabeling was needed in order to accurately characterize the morphology, dimension and cell density of astrocytes in horses. Horse and rodent astrocytes seem to have similar dimensions and localization. Horse astrocyte cells have an average diameter of 56 + 14 µm, with a main process length of 28 + 8 µm, and thickness of 1.4 + 0.3 µm, mainly situated in laminae I, II and III. Additionally, a close association between end-point astrocyte processes and microglial cell bodies was found. These results are the first characterization of cell morphology and organizational aspects of horse spinal glia. Iba-1 and GFAP/Cx-43 can successfully immune-label microglia and astrocytes respectively in horse spinal cords, and thus reveal cell morphology and corresponding distribution within the dorsal horn laminae of healthy horses. The conventional hyper-ramified shape that is normally visible in resting microglial cells was not found in horses. Instead, horse microglial cells had an amoeboid spherical shape. Horse protoplasmic astroglia is significantly smaller and structurally less complex than human astrocytes, with fewer main GFAP processes. Instead, horse astrocytes tend to be similar to those found in rodent’s model, with small somas and large cell processes. Microglia and astrocytes were found in the more superficial regions of the dorsal horn, similarly to that previously observed in humans and rodents. Further studies are needed to demonstrate the molecular mechanisms involved in the neuron-glia interaction in horses.
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Rosas-Arellano, M. Patricia, L. Pastor Solano-Flores, and John Ciriello. "c-Fos induction in spinal cord neurons after renal arterial or venous occlusion." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 276, no. 1 (January 1, 1999): R120—R127. http://dx.doi.org/10.1152/ajpregu.1999.276.1.r120.
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Experiments were done in the anesthetized rat to identify the dorsal root ganglia (DRG) and the spinal cord segments that contain neurons activated by either renal venous occlusion (RVO) or by renal arterial occlusion (RAO). Fos induction, detected immunohistochemically in DRG and the spinal cord neurons, was used as a marker for neuronal activation. RVO induced Fos immunoreactivity in neurons in the DRG of spinal segments T8-L2on the side ipsilateral to that of occlusion. The largest number of Fos-labeled neurons was found in the T11 DRG. In the spinal cord the largest number of Fos-labeled neurons was found in the ipsilateral dorsal horn of spinal segments T11-T12, predominantly in a cluster near the dorsomedial edge of laminae I-II. A few additional Fos-labeled neurons were observed in laminae IV and V. After RAO Fos-labeled neurons were found in the ipsilateral DRG of spinal segments similar to those observed to contain neurons after RVO. However, most of the Fos-labeled neurons were observed within the T12-L1DRG. In the spinal cord Fos-labeled neurons were scattered throughout lamina I-II of the ipsilateral dorsal horn of spinal segments T8-L2, although the largest number was observed at the T13 level. Additionally, a distinct cluster of Fos-labeled neurons was observed predominantly in the region of the ipsilateral intermediolateral cell column, although a few neurons were found scattered throughout the nucleus intercalatus, central autonomic areas, and laminae IV and V of the cord bilaterally. No Fos labeling was observed in the complementary contralateral DRG or dorsal horns after either RVO or RAO. In addition, renal nerve transection prevented Fos labeling in the ipsilateral DRG and dorsal horns after RVO or RAO. Taken together, these data suggest that functionally different renal afferent fibers activate DRG neurons that may have distinct projections in the spinal cord.
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Yu, Huasheng, Suna L. Cranfill, and Wenqin Luo. "ErbB4+ spinal cord dorsal horn neurons process heat pain." Neuron 110, no. 14 (July 2022): 2206–8. http://dx.doi.org/10.1016/j.neuron.2022.06.014.
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Hagains, Christopher E., Ji-Wei He, Jung-Chih Chiao, and Yuan Bo Peng. "Septal stimulation inhibits spinal cord dorsal horn neuronal activity." Brain Research 1382 (March 2011): 189–97. http://dx.doi.org/10.1016/j.brainres.2011.01.074.
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Zhang, Chousheng, Frances M. Davies, Tian-Zhi Guo, and Mervyn Maze. "The Analgesic Action of Nitrous Oxide Is Dependent on the Release of Norepinephrine in the Dorsal Horn of the Spinal Cord." Anesthesiology 91, no. 5 (November 1, 1999): 1401. http://dx.doi.org/10.1097/00000542-199911000-00033.
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Background The authors and others have demonstrated that supraspinal opiate receptors and spinal alpha2 adrenoceptors are involved in the analgesic mechanism for nitrous oxide (N2O). The authors hypothesize that activation of opiate receptors in the periaqueductal gray results in the activation of a descending noradrenergic pathway that releases norepinephrine onto alpha2 adrenoceptors in the dorsal horn of the spinal cord. Methods The spinal cord was transected at the level of T3-T4 in rats and the analgesic response to 70% N2O in oxygen was determined by the tail flick latency test. In a separate experiment in rats a dialysis fiber was positioned transversely in the dorsal horn of the spinal cord at the T12 level. The following day, the dialysis fiber was infused with artificial cerebrospinal fluid at a rate of 1.3 microl/min, and the effluent was sampled at 30-min intervals. After a 60-min equilibration period, the animals were exposed to 70% N2O in oxygen. The dialysis experiment was repeated in animals that were pretreated with naltrexone (10 mg/kg, intraperitoneally) before N2O. In a third series, spinal norepinephrine was depleted with n-(2-chloroethyl)-n-ethyl-2-bromobenzylamine (DSP-4), and the analgesic response to 70% N2O in oxygen was determined. Results The analgesic effect of N2O was prevented by spinal cord transection. After exposure to N2O, there was a fourfold increase in norepinephrine released in the first 30-min period, and norepinephrine was still significantly elevated after 1 h of exposure. The increased norepinephrine release was prevented by previous administration of naltrexone. Depletion of norepinephrine in the spinal cord blocked the analgesic response to N2O. Conclusions A descending noradrenergic pathway in the spinal cord links N2O-induced activation of opiate receptors in the periaqueductal gray, with activation of alpha2 adrenoceptors in the spinal cord. N2O-induced release of norepinephrine in the dorsal horn of the spinal cord is blocked by naltrexone, as is the analgesic response. Spinal norepinephrine is necessary for the analgesic response to the N2O.
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Antognini, Joseph F., and Earl Carstens. "Increasing Isoflurane from 0.9 to 1.1 Minimum Alveolar Concentration Minimally Affects Dorsal Horn Cell Responses to Noxious Stimulation." Anesthesiology 90, no. 1 (January 1, 1999): 208–14. http://dx.doi.org/10.1097/00000542-199901000-00027.
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Background The spinal cord appears to be the site at which isoflurane suppresses movement that occurs in response to a noxious stimulus. In an attempt to localize its site of suppressant action, the authors determined the effect of isoflurane on dorsal horn neuronal responses to supramaximal noxious stimulation at end-tidal concentrations that just permitted and just prevented movement. Methods Rats (n = 14) were anesthetized with isoflurane, and after lumbar laminectomy, the minimum alveolar concentration (MAC) for each rat was determined using a supramaximal mechanical stimulus. In these same rats, after extracellular microelectrode placement in the lumbar spinal cord, dorsal horn neuronal responses to the supramaximal stimulus were determined at the concentrations of isoflurane that bracketed each rat's MAC (0.1% higher and lower than MAC). The MAC of isoflurane was then re-determined. Results Dorsal horn neuronal response was 1,757+/-892 impulses/min at 0.9 MAC and 1,508+/-988 impulses/min at 1.1 MAC, a 14% decrease (P < 0.05). Cell responses varied, with some cells increasing their response at the higher concentration of isoflurane. The MAC of isoflurane was 1.38+/-0.2% before and 1.34+/-0.2% after determination of dorsal horn neuronal responses. Conclusions Isoflurane, at concentrations that bracket MAC, has a variable and minimal depressant effect on dorsal horn cell responses to noxious mechanical stimulation. These data suggest that the major action of isoflurane to suppress movement evoked by a noxious stimulus might occur primarily at a site other than the dorsal horn.
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Zhang, Huanzhen, Bingqian Wang, Shuijin Chen, Lechun Chen, Jingjing Jiang, Yu Jiang, Jincheng Chen, et al. "基于NR2B/PSD-95通路探讨推拿对腰椎间盘突出症大鼠脊髓背角树突结构的影响." Journal of Acupuncture and Tuina Science 21, no. 2 (April 2023): 129–36. http://dx.doi.org/10.1007/s11726-023-1368-2.
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Abstract Objective To investigate the analgesic mechanism of Tuina (Chinese therapeutic massage) by observing the effect of the N-methyl-D-aspartate receptor subunit 2B (NR2B)/postsynaptic density-95 (PSD-95) pathway on the dendritic structure of spinal cord dorsal horn in rats with lumbar disc herniation. Methods Fifty Sprague-Dawley rats were randomly divided into a blank group, a model group, a Tuina group, a blocker agent group, and a blocker agent + Tuina group. The sciatic nerve chronic constriction injury (CCI) model was prepared by the sciatic nerve ligation method. From the 4th day after modeling, rats in the Tuina group and the blocker agent + Tuina group were subject to daily Tuina intervention, and those in the blocker agent group and the blocker agent + Tuina group were daily intrathecally injected with NR2B blocker agent (MK-801). The spontaneous pain score was used to observe the pain behavior of all rats. The expression levels of NR2B and downstream PSD-95 were measured by immunohistochemistry, and the dendritic structure changes were observed by Golgi staining for rat spinal cord dorsal horn after 14 d of continuous intervention. Results Compared with the blank group, the degree of rat spontaneous pain after CCI was elevated in both the model and the Tuina groups (P<0.01) and was reduced in the Tuina group after the Tuina intervention compared with the model group (P<0.05). Compared with the model group, the rat spontaneous pain level after blocking NR2B was reduced in both the blocker agent group and the blocker agent + Tuina group (P<0.05). The NR2B and PSD-95 protein levels were significantly higher in the model group compared with the blank group (P<0.01); the total number of dendritic branches was increased (P<0.01), and the total dendritic length became longer (P<0.01) in the spinal cord dorsal horn. The rat NR2B and PSD-95 protein levels were significantly decreased in the Tuina group compared with the model group (P<0.01); the total dendritic branch number was reduced (P<0.01) and the total length was shortened (P<0.01) in the spinal cord dorsal horn. After blocking NR2B, the expression levels of NR2B and downstream PSD-95 protein were significantly lower in both the blocker agent group and the blocker agent + Tuina group compared to the model group (P<0.01). The total branch number was significantly reduced (P<0.01), and the total length was significantly shortened (P<0.01) of the dendrites in the spinal cord dorsal horn. Conclusion Tuina may exert an analgesic effect by remodeling the dendritic structure in the spinal cord dorsal horn in rats with lumbar disc herniation, and its mechanism may be related to the inhibition of NR2B/PSD-95 signaling pathway.
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Sun, Rui-Qing, Nada B. Lawand, Qing Lin, and William D. Willis. "Role of Calcitonin Gene-Related Peptide in the Sensitization of Dorsal Horn Neurons to Mechanical Stimulation After Intradermal Injection of Capsaicin." Journal of Neurophysiology 92, no. 1 (July 2004): 320–26. http://dx.doi.org/10.1152/jn.00086.2004.
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This study was designed to assess the role of calcitonin gene-related peptide (CGRP) and its receptor in the sensitization of dorsal horn neurons induced by intradermal injection of capsaicin in rats. Extracellular recordings were made from wide dynamic range (WDR) dorsal horn neurons with receptive fields on the hindpaw in the lumbar enlargement of anesthetized rats. The background activity and responses to brushing, pressing, and pinching the skin were assessed. A postsuperfusion or a presuperfusion of CGRP8-37 paradigm was followed. When tested 30 min after capsaicin injection, there was an increase in background activity and responses to brush, press, and pinch applied to the receptive field. Superfusion of CGRP8-37 into the spinal cord at 45 min after capsaicin injection significantly reversed the increased background activity and responses to brush, press, and pinch applied to the receptive field. On the other hand, spinal superfusion of CGRP8-37 prior to capsaicin injection prevented the increased background activity and responses to brush, press, and pinch of WDR neurons that occurred following capsaicin injection in control experiments. A sensitization of spinal dorsal horn neurons could also be induced by superfusion of the spinal cord with CGRP. The effect could be blocked by CGRP8-37 dose-dependently. Collectively, these results suggest that CGRP and its receptors are involved in the spinal cord central sensitization induced by intradermal injection of capsaicin.
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Bouaziz, Herve, Chuanyao Tong, Young Yoon, David D. Hood, and James C. Eisenach. "Intravenous Opioids Stimulate Norepinephrine and Acetylcholine Release in Spinal Cord Dorsal Horn." Anesthesiology 84, no. 1 (January 1, 1996): 143–54. http://dx.doi.org/10.1097/00000542-199601000-00017.
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Background Opioids produce analgesia by direct effects as well as by activating neural pathways that release nonopioid transmitters. This study tested whether systematically administered opioids activate descending spinal noradrenergic and cholinergic pathways. Methods The effect of intravenous morphine on cerebrospinal fluid and dorsal horn microdialysate concentrations of norepinephrine and acetylcholine was examined in 20 sheep. Animals received either intravenous morphine or fentanyl alone, or morphine plus intravenous naloxone or intrathecal idazoxan. Results Intravenous morphine (0, 0.5, 1 mg/kg, intravenous) produced dose-dependent increases in cerebrospinal fluid norepinephrine and acetylcholine, but not epinephrine or dopamine. Morphine's effect was blocked by intravenous naloxone and by intrathecal idazoxan. In microdialysis experiments, intravenous morphine increased the concentration of norepinephrine and acetylcholine, but not epinephrine or dopamine, in the dorsal horn. In contrast, intravenous morphine exerted no effect on any of these monoamines in the ventral horn. Intravenous naloxone and cervical cord transection each blocked morphine's effect on dorsal horn norepinephrine. Conclusions These results support functional studies that indicate that systematically administered opioids cause spinal norepinephrine and acetylcholine release by a naloxone-sensitive mechanism. Idazoxan blockade of morphine's effects on cerebrospinal fluid norepinephrine was unexpected, and suggests that both norepinephrine and acetylcholine release in the spinal cord may be regulated by alpha 2-adrenoceptors. Microdialysis experiments suggest increased norepinephrine and acetylcholine levels in cerebrospinal fluid resulted from intravenous morphine-induced activation of bulbospinal pathways.
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Ohashi, Nobuko, Daisuke Uta, Mika Sasaki, Masayuki Ohashi, Yoshinori Kamiya, and Tatsuro Kohno. "Acetaminophen Metabolite N-Acylphenolamine Induces Analgesia via Transient Receptor Potential Vanilloid 1 Receptors Expressed on the Primary Afferent Terminals of C-fibers in the Spinal Dorsal Horn." Anesthesiology 127, no. 2 (August 1, 2017): 355–71. http://dx.doi.org/10.1097/aln.0000000000001700.
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Abstract Background The widely used analgesic acetaminophen is metabolized to N-acylphenolamine, which induces analgesia by acting directly on transient receptor potential vanilloid 1 or cannabinoid 1 receptors in the brain. Although these receptors are also abundant in the spinal cord, no previous studies have reported analgesic effects of acetaminophen or N-acylphenolamine mediated by the spinal cord dorsal horn. We hypothesized that clinical doses of acetaminophen induce analgesia via these spinal mechanisms. Methods We assessed our hypothesis in a rat model using behavioral measures. We also used in vivo and in vitro whole cell patch-clamp recordings of dorsal horn neurons to assess excitatory synaptic transmission. Results Intravenous acetaminophen decreased peripheral pinch-induced excitatory responses in the dorsal horn (53.1 ± 20.7% of control; n = 10; P < 0.01), while direct application of acetaminophen to the dorsal horn did not reduce these responses. Direct application of N-acylphenolamine decreased the amplitudes of monosynaptic excitatory postsynaptic currents evoked by C-fiber stimulation (control, 462.5 ± 197.5 pA; N-acylphenolamine, 272.5 ± 134.5 pA; n = 10; P = 0.022) but not those evoked by stimulation of Aδ-fibers. These phenomena were mediated by transient receptor potential vanilloid 1 receptors, but not cannabinoid 1 receptors. The analgesic effects of acetaminophen and N-acylphenolamine were stronger in rats experiencing an inflammatory pain model compared to naïve rats. Conclusions Our results suggest that the acetaminophen metabolite N-acylphenolamine induces analgesia directly via transient receptor potential vanilloid 1 receptors expressed on central terminals of C-fibers in the spinal dorsal horn and leads to conduction block, shunt currents, and desensitization of these fibers.
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Fitzgerald, M., G. C. Kwiat, J. Middleton, and A. Pini. "Ventral spinal cord inhibition of neurite outgrowth from embryonic rat dorsal root ganglia." Development 117, no. 4 (April 1, 1993): 1377–84. http://dx.doi.org/10.1242/dev.117.4.1377.
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Organotypic culture of embryonic rat lumbar spinal cord and dorsal root ganglia has been used to demonstrate an inhibitory effect of ventral spinal cord on neurite growth from dorsal root ganglion explants. When dorsal root ganglion explants from 14–15 day old embryos were cultured alone or in close proximity to a dorsal cord explant, the pattern of dorsal root ganglion neurite outgrowth was typically radial. However, when E14-15 dorsal root ganglion explants were cocultured for 22–24 hours in proximity to a ventral spinal cord explant from the same embryo, few, if any, dorsal root ganglion neurites grew in the direction of the ventral cord explant. This inhibitory effect appeared to be developmentally regulated; it was diminished or absent in cocultures prepared from 18 day old embryos. In contrast, in cocultures of dorsal cord and ventral cord explants from E14-15 embryos, dorsal cord neurites grew abundantly toward the ventral cord explant suggesting that the inhibition is not likely to be due to a nonspecific neurotoxic effect and that the activity responsible selectively inhibits dorsal root ganglion neurite outgrowth. We conclude that a diffusible, primary afferent inhibitory factor(s) produced by embryonic ventral horn may be responsible for the inhibition. Our results are discussed with respect to the possible involvement of inhibition in the normal development of primary afferent innervation of the spinal cord.
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Spaic, M., Dusan Mikicic, S. Ilic, I. Milosavljevic, S. Ivanovic, Eugen Slavik, and Branislav Antic. "Biomehanicke karakteristike tkiva kicmene mozdine - osnov za razvoj modifikovane tehnike DREZ operacije." Acta chirurgica Iugoslavica 51, no. 4 (2004): 59–64. http://dx.doi.org/10.2298/aci0404059s.
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Mechanical properties of the spinal cord tissue - biological basis for the development of the modality of the DREZ surgery lesioning technique Successful treatment of the chronic neurogenic pain of spinal cord and cauda equina injury origin remains a significant management problem. The mechanism of this pa-in phenomenon has been shown to be related to neurochemical changes that lead to the state of hypereactivity of the second order dorsal horn neurons. The DREZ surgery (Dorsal Root Entry Zone lesion), designed to destroy anatomy structures involved in pain generating thus interrupting the neurogenic pain mechanism, as a causative procedure in treating this chronic pain, has been performed by using different technical modalities: Radiofrequency (RF) coagulation technique, Laser, Ultrasound and Microsurgical DREZotomy technic. The purpose of the study was to assess the possibility for the establishment of the lesioning technique based on the natural difference in the mechanical properties between the white and gray cord substance. We experimentally determinate mechanical properties of the human cadaveric cord white versus gray tissue for the purpose of testing possibility of selective suction of the dorsal horn gray substance as a DREZ lesioning procedure. Based on the fact of the difference in tissue elasticity between white and gray cord substance we established a new and simple DREZ surgical lesioning technique that was tested on cadaver cord. For the purpose of testing and comparing the size and shape of the DREZ lesion achieved the DREZ surgery has been performed on cadaver cord by employing selective dorsal horn suction as a lesioning method. After the procedure cadaver cord underwent histological fixation and analysis of the DREZ lesions achieved. Our result revealed that the white cord substance with longitudinal fiber structure had four time higher dynamical viscosity than gray substance of local neuronal network structure (150 PaS versus 37,5 PaS) that provided possibility for the safe and selective suction of the gray substance of the dorsal horn. Technique includes incision of the dorsolateral sulcus according to Sindous Microsurgical DREZotomy technique than suction under visual control of the dorsal horn gray matter using sucker adopted from the lumbar puncture nidle. Operative experimental testing and hystological analysis confirmed expected size and shape of the DREZ lesion performed by dorsal horn suction as DREZ lesioning technique. The utility, selectivity and safety of this technique has been provided by the natural mechanical properties of the cord tissue itself. Application of the Dorsal horn suction as a DREZ lesioning in humans confirmed this technique as a safe and reliable DREZ lesioning method.
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Xu, Zemin, Ping Li, Chuanyao Tong, Jorge Figueroa, Joseph R. Tobin, and James C. Eisenach. "Location and Characteristics of Nitric Oxide Synthase in Sheep Spinal Cord and Its Interaction with α2-Adrenergic and Cholinergic Antinociception." Anesthesiology 84, no. 4 (April 1, 1996): 890–99. http://dx.doi.org/10.1097/00000542-199604000-00017.
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Background Nitric oxide synthase is located in the spinal cord dorsal horn and intermediolateral cell column, where it may modulate sensory and sympathetic neuronal activity. However, the biochemical characteristics of this enzyme have not been examined in these different areas in the spinal cord. Although alpha(2)-adrenergic agonists, muscarinic agonists, and nitric oxide may interact in the spinal cord to produce antinociception, these interactions have not been characterized. Methods Sheep spinal cord tissue was homogenized ad centrifuged at high sped to separate soluble and membrane-bound fractions. Nitric oxide synthase activity was determined by conversion of [(14)C]-L-arginine to [(14)C]-L-citrulline and its kinetic characteristics, dependency on cofactors, and sensitivity to inhibitors determined. Sheep spinal cord was stained for nicotinamide adenine dinucleotide phosphate diaphorase as a marker for nitric oxide synthase. Antinociception to a mechanical stimulus from intrathecal clonidine alone and with neostigmine was determined and the effects of L-arginine and n-methyl-L-arginine were determined. Results More than 85% of nitric oxide synthase activity was present in the soluble form and its kinetic, cofactor, and antagonist properties were similar to those of the neuronal isoform of nitric oxide synthase. Biochemical and histochemical studies localized nitric oxide synthase to the superficial dorsal horn and the intermediolateral cell column. Clonidine antinociception was enhanced by L-arginine and neostigmine, but not by D-arginine. Neostigmine's enhancement of clonidine antinociception was blocked by n-methyl-L-arginine. Conclusions These results confirm those of previous studies demonstrating localization of nitric oxide synthase to superficial dorsal horn and intermediolateral cell column of mammalian spinal cord, and suggesting its identity as the neuronal isoform. Spinal alpha(2)-adrenergic agonist antinociception may be partly dependent on cholinergic and nitric oxide mechanisms.