This was accompanied with reduced c-Fos immunoreactivity in the spinal cord dorsal horn in EP3 knockouts. Deficiency of either EP2 or DP1 was associated with increased formalin-evoked flinching responses and c-Fos IR in dorsal horn neurons suggesting facilitated spinal cord pain reflex circuity. 
In vincristine-treated rats, the number of nociceptive dorsal root ganglion cells expressing the 5-HT2AR was increased by 38%, and 5-HT2AR immunolabelling was enhanced in layers I-IV of the dorsal horn. At the EM level, a 76.3% increase in the density of 5-HT2AR immunopositive axon terminals within superficial layers of the dorsal horn was noted after vincristine treatment. Double labelling experiments showed that Fos-positive neurons were endowed with 5-HT2AR immunolabelling in the dorsal horn of vincristine-treated rats.
The result suggests that in the LC/SC both ipsilateral and contralateral to the inflamed paw, only neurons which project to the dorsal horn ipsilateral to the inflamed paw were activated following peripheral inflammation..
Importantly, as compared to naïve mice, we observed that in mice with unilateral hindpaw inflammation, calcium signals were potentiated to 159+/-10% in the ipsilateral dorsal horn and 179+/-8% in the contralateral dorsal horn.
Exclusive unilateral, first-order labeling of the phrenic motoneuron pool with pseudorabies virus demonstrated a substantial number of second-order, bilaterally distributed cervical interneurons predominantly in the dorsal horn and around the central canal.
We demonstrate that p38 MAPK is rapidly and robustly activated in the superficial spinal dorsal horn after mild thermal injury to the hind paw.
We report here that PSD-93 deficiency significantly decreased the amount of NR2A and NR2B in the synaptosomal membrane fractions derived from spinal cord dorsal horn and forebrain cortex but did not change their levels in the total soluble fraction from either region. These findings indicate that impaired NMDAR-dependent neuronal plasticity following repeated morphine injection in PSD-93 knockout mice is attributed to PSD-93 deletion-induced alterations of synaptic NR2A and NR2B expression in dorsal horn and forebrain cortex neurons.
ABSTRACT: NMDA receptors are important elements in pain signaling in the spinal cord dorsal horn.
The spinal superficial dorsal horn (SDH) contains neuronal circuits capable of modulating primary afferent information involved in pain processing.
This study investigated the effects of EA on neurotrophin-4 (NT-4) expression in L(6) spinal dorsal root ganglion (DRG) and associated segments of the spinal dorsal horn in cats subjected to unilateral removal of L(1)-L(5) and L(7)-S(2) DRG. NT-4 protein was normally present in the cytoplasm of the L(6) DRG neurons and L(3) and L(6) spinal dorsal horn neurons and glia. Adjacent ganglionectomy leads to a significant decrease in NT-4 expression in the L(6) DRG, but no change in the spinal dorsal horn.
Scavengers of reactive oxygen species (ROS) have been shown to produce a strong antinociceptive effect on persistent pain, and mitochondria are suggested to be the main source of ROS in the spinal dorsal horn. A large increase of mitochondrial superoxide in the spinal dorsal horn and a strong antinociceptive effect of ROS scavengers, phenyl-N-tert-butylnitrone (PBN) and 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPOL) were observed in antimycin A-treated mice.
GPR103 mRNA has been reported to be highly expressed in the superficial layers of the entire spinal cord and a high density of 26RFa binding sites was observed in the superficial layers of the dorsal horn. An immunohistochemical study revealed that GPR103-like immunoreactivity (LI) was observed in the superficial layers of spinal dorsal horn, that QRFP-LI was observed in the dorsal root ganglion and that intrathecal 26RFa suppressed the expression of Fos-LI induced by paw formalin injection in the superficial layers of the spinal dorsal horn.
A descending pathway reaching the dorsal horn in the spinal cord was postulated to mediate analgesic effects at the spinal cord level.
The effects of GABA, excitatory amino-acid receptors antagonists and a glial metabolism inhibitor on primary-afferent excitation in the spinal dorsal horn were studied by imaging the presynaptic excitation of high-threshold afferents in cord slices from young rats with a voltage-sensitive dye. Single-pulse stimulation of C fiber-activating strength to the dorsal root elicited compound action potential-like optical responses in the superficial dorsal horn.
We show that most retrogradely labeled INs are located dorsal to the MNs, in the ventral horn, the intermediate zone and the dorsal horn. IINs predominate in the dorsal horn.
It has prominent dorsally directed dendrites that enter the superficial laminae of the dorsal horn.
The authors hypothesize that the spatial activation and intensity of dorsal horn neuron responses to skin incision differ in immature and adult spinal cord. METHODS: Single wide-dynamic-range dorsal horn cell spike activity was recorded for a minimum of 2 h from anesthetized rat pups aged 7 and 28 days. CONCLUSIONS: Continuous recording from single dorsal horn cells both before and after injury shows that sensitization of receptive fields and of background and afferent-evoked spike activity at 1 h is greater in younger animals.
Inhibitory synaptic transmission within the dorsal horn of the spinal cord plays a key role in the processing of nociceptive signals, and mainly involves glycine.
By combining fluorescence-resonance-energy-transfer (FRET)-based cAMP measurements with Multi-Epitope-Ligand-Cartography (MELC), we showed that S1P decreased cAMP synthesis in excitatory dorsal horn neurons.
BDA (biotinylated dextran amine) labeling of the intact CST showed lesion-induced growth across the midline where CST collaterals increased their innervation density and extended fibers toward the ventral and the dorsal horn in response to forced limb use.
Cytokines related to acute or repetitive tissue injuries may be responsible for long-term activation of spinal cord glia and dorsal horn neurons, thus resulting in central sensitization.
Changes in glycinergic neurotransmission in the spinal cord dorsal horn are critically involved in the development of pathological pain.
BACKGROUND: Regulation of pain states is, in part, dependent upon plastic changes in neurones within the superficial dorsal horn. While a number of transcription factors including Methyl-CpG-binding protein 2 (MeCP2), Zif268 and Fos have been implicated in the regulation of dorsal horn neurone sensitization following injury, modulation of their activity by descending controls has not been investigated. RESULTS: Here, we describe how descending controls regulate MeCP2 phosphorylation (P-MeCP2), known to relieve transcriptional repression by MeCP2, and Zif268 and Fos expression in the rat superficial dorsal horn, after CFA injection into the hind paw. Serotonergic depletion of the lumbar spinal cord with 5,7 di-hydroxytryptamine creatinine sulphate (5,7-DHT) reduced the inflammation evoked P-MeCP2 in the superficial dorsal horn by 57%, and that of Zif268 and Fos by 37.5% and 30% respectively. CONCLUSION: We conclude that descending serotonergic pathways play a crucial role in regulating gene expression in the dorsal horn and mechanical sensitivity associated with an inflammatory pain state..
As measured by immunohistochemistry, microglia and astrocytes were activated in the spinal dorsal horn on day 7 of VCR administration.
In the conus medullaris the twin layers of CGRP-immunoreactive and IB4-labeled primary afferent fibers as well as the translucent portion of the superficial dorsal horn equivalent to the substantia gelatinosa discontinue before the complete removal of the dorsal horn. Parallel with these changes VGLUT1-immunoreactive myelinated primary afferent fibers arborize not only in the deep layers but also in the entire extension of the remaining dorsal horn, while scattered CGRP fibers still remains at the margin of and deep in the dorsal horn. PKCgamma-immunoreactive dorsal horn neurons discontinue parallel with the disappearance of the IB4-labeled nerve fibers. These observations suggest that in the dorsal horn certain neurons are linked to the substantia gelatinosa, while others are substantia gelatinosa-independent neurons..
It has prominent dorsally directed dendrites that enter the superficial laminae of the dorsal horn.
Calcium influx through neuronal voltage-sensitive calcium channels (VSCC(S)) mediates nociceptive information in the spinal dorsal horn.
Previously we reported that the cuff model of peripheral neuropathy, in which a 2 mm polyethylene tube is implanted around the sciatic nerve, exhibits aspects of neuropathic pain behavior in rats similar to those in humans and causes robust hyperexcitation of spinal nociceptive dorsal horn neurons. between the cuff and the cutaneous receptive field) decreased spontaneous baseline discharge of WDR dorsal horn neurons approximately 40% (n=18) and when applied subsequently proximal to the cuff, i.e. These results demonstrate that the hyperexcited state of spinal dorsal horn neurons observed in this model of peripheral neuropathy is not maintained by tonic descending facilitatory mechanisms. Rather, on-going afferent discharges originating from the sciatic nerve distal to, at, and proximal to the cuff maintain the synaptically-mediated gain in discharge of spinal dorsal horn WDR neurons and hyperresponsiveness of these neurons to cutaneous stimulation.
Western blotting and immunohistochemical fluorescence staining demonstrates that EphB1 receptor protein is significantly up-regulated in the spinal dorsal horn following escalating morphine treatment.
In mouse, Pax2 is required for correct specification of GABAergic interneurons in the dorsal horn, but it is not required for the neurotransmitter fates of other Pax2-expressing spinal neurons.
This study was done to determine 1) whether C2 SCS induced release of an analgesic neuropeptide in the dorsal horn of the thoracic (T4) spinal cord; 2) if one of the sources of this analgesic peptide was cervical propriospinal neurons and 3) if chemical inactivation of C2 neurons altered local T4 substance P (SP) release during concurrent C2 SCS and cardiac ischemia. CoAO increased the number of Fos-positive neurons in T4 dorsal horns but not in the intermediolateral columns (IML) while SCS (either alone or during CoAO) minimized this dorsal horn response to CoAO alone while inducing T4 IML neuronal recruitment.
Neurochemical characterization of the DRt-spinal pathway showed that delta-opioid receptors are positioned as to indirectly modulate the activity of non-projecting DRt neurons, whereas neurons expressing mu-opioid receptors project to the spinal dorsal horn or act as interneurons, the latter of which co-expressing GABA(B) receptors.
Effects of different parameters of hypothalamic paraventricular nucleus (PVN) electrical stimulation on somatic responses, in dorsal horn neurons were examined. In anaesthetized rats, single-unit extracellular recordings were made from dorsal horn lumbar segments, which receive afferent input from the toe and hind paw regions.
Immunocytochemical and electrophysiological evidence also implicates alpha3beta GlyRs as important mediators of glycinergic inhibitory neurotransmission in nociceptive sensory neuronal circuits in peripheral laminae of the spinal cord dorsal horn.
dorsal horn neurons express many different neuropeptides that modulate sensory perception like the sensation of pain. Inhibitory neurons of the dorsal horn derive from postmitotic neurons that express Pax2, Lbx1 and Lhx1/5, and diversify during maturation. We demonstrate here that a coordinate molecular mechanism determines inhibitory and peptidergic fate in the developing dorsal horn. We conclude that a transcriptional network operates in maturing dorsal horn neurons that coordinately determines transmitter and peptidergic fate..
The major ascending outputs from superficial spinal dorsal horn consist of projection neurons in lamina I, together with neurons in laminae III-IV that express the neurokinin 1 receptor (NK1r) and have dendrites that enter the superficial laminae. A projection from the cervical superficial dorsal horn to the posterior triangular nucleus (PoT) has recently been identified.
We show that NO-GC is distinctly expressed in neurons of the mouse dorsal horn, whereas its distribution in dorsal root ganglia is restricted to non-neuronal cells.
Whereas CCI induced microglial activation in both models, we observed a concomitant upregulation of IL-6 and ATF3 in the ipsilateral dorsal horn of the lumbar cord in SN-CCI rats but not in the ipsilateral spinal nucleus of the trigeminal nerve (Sp5c) in IoN-CCI rats. We show that IL-6 can upregulate OX-42 and ATF3 expression in cultured microglia and neurons from spinal cord, respectively, as well as in the dorsal horn after acute intrathecal administration of the cytokine.
CONCLUSIONS: These results suggest that the antiallodynic effect of Neurotropin is mediated via activation of descending pain inhibitory systems, such as the noradrenergic and serotonergic systems, which project from supraspinal sites to the spinal dorsal horn. In addition, activation of inhibitory GABAergic interneurons via 5-HT(3) receptors by serotonin released in the spinal dorsal horn may also be involved in the antiallodynic action of Neurotropin..
The number of cells in the superficial dorsal horn with nuclei that stained for pCREB was double on the surgical side and the ratio was reduced by nicotine in a dose-dependent manner. CONCLUSIONS: Our findings suggest that nicotine reduced nociceptive input to the superficial and deep dorsal horn.
Large-conductance calcium-activated potassium channels (BK channels) have been suggested to play a substantial role in synaptic transmission in the spinal cord dorsal horn. In the present experiments, we attempted to clarify the physiological significance of BK channels in the modulation of synaptic transmission in the superficial dorsal horn where nociceptive information is processed. Spontaneously occurring excitatory postsynaptic currents (sEPSCs) were recorded from the neurons located in the superficial dorsal horn of a mouse spinal cord slice, and the effects of iberiotoxin, a BK channel blocker, on sEPSCs were analyzed. These findings suggest that the BK channels that are located in presynaptic terminals control synaptic transmission in the superficial dorsal horn, and that functional downregulation of BK channels accompanies the neuropathic pain induced by peripheral nerve injury. Taken together, our present results indicate that BK channels play crucial roles in the synaptic transmission of nociceptive information in the superficial dorsal horn..
This commentary briefly reviews glial contributions and intracellular signaling mechanisms, both neuronal and glial, that provide the substrate for CNP after SCI, including the persistent glial production of factors that can maintain sensitization of dorsal horn neurons in segments remote from the spinal injury; ie. dorsal horn hyperexcitability to formerly non noxious stimuli that become noxious after SCI resulting in allodynia.
Previously, we demonstrated that stimulation of the paraventricular hypothalamic nucleus diminishes the nociceptive dorsal horn neuronal responses, and this decrease was mediated by oxytocin in the rat. In addition, we have proposed that oxytocin indirectly inhibits sensory transmission in dorsal horn neurons by exciting spinal inhibitory GABAergic interneurons. In anaesthetized rats, single-unit extracellular and juxtacellular recordings were made from dorsal horn lumbar segments, which receive afferent input from the toe and hind-paw regions. Additionally, in order to label the projecting dorsal horn neurons, we injected fluorescent retrograde neuronal tracers into the ipsilateral gracilis nucleus and contralateral ventroposterolateral thalamic nucleus.
Sixteen of 25 neurons were recorded in the marginal zone and the balance was located within the deep dorsal horn.
The synaptic vesicle protein synapsin II is specifically expressed in synaptic terminals of primary afferent nociceptive neurons and regulates transmitter release in the spinal cord dorsal horn. This was associated with decreased glutamate release in the dorsal horn of the spinal cord upon sciatic nerve injury or capsaicin application onto the sciatic nerve and reduced calcium signals in spinal cord slices upon persistent activation of primary afferents. Conversely, synapsin II knockout mice showed a stronger and longer-lasting increase of GABA in lamina II of the dorsal horn after nerve injury than wild type mice.
This study investigates the dorsal horn expression of the transporter GAT-1 and its functional involvement towards pain behaviour in the CCI model.
Intraplantar injection of cyclopentenone PGs stimulated c-fos expression in spinal neurons of the dorsal horn and evoked an instantaneous, robust, and transient nociceptive response in TRPA1(+/+) but not in TRPA1(-/-) mice.
We have previously reported that acute noxious mechanical stimulation of bone activates neurons throughout the dorsal horn of the lumbar spinal cord, and argued that the spinal mechanisms that mediate bone nociception are different to those that mediate cutaneous and visceral nociception. Spinal dorsal horn neurons activated by acute noxious mechanical stimulation of bone (bone drilling) were identified in these animals using Fos immunohistochemistry. Fluorogold and Fos-like immunoreactivity was not colocalized in any dorsal horn neurons projecting to the thalamus or gracile nucleus.
The preservation of EPP in dermatomes was examined relative to EPT to dissociate the involvement of the posterior (dorsal horn and ascending dorsal column) and anterior (decussating and ascending spinothalamic fibers) spinal cord according to different nerve fiber recruitment in the periphery.
Protein kinase C gamma (PKCgamma), which is concentrated in interneurons of the inner part of lamina II of the dorsal horn, has been implicated in injury-induced allodynia, a condition wherein pain is produced by innocuous stimuli.
METHODS: We used a model of adjuvant-induced arthritis (AIA) of the ankle and investigated the changes in expression of p-ERK in sensory afferent neurons in dorsal root ganglia (DRG) and spinal dorsal horn of TRPV1-knockout (KO) mice, compared to wild-type (WT) mice of the same genetic background, using multiple immunofluorescence.
The expression of glutamate transporters (GTs) in the spinal cord dorsal horn was also measured.
Although there is evidence that reduced inhibition in the spinal dorsal horn contributes to neuropathic pain, the mechanisms that underlie this are poorly understood. We have previously demonstrated that there is no loss of neurons from laminae I-III in the spared nerve injury (SNI) model [ Polgár E, Hughes DI, Arham AZ, Todd AJ (2005) Loss of neurons from laminas I-III of the spinal dorsal horn is not required for development of tactile allodynia in the SNI model of neuropathic pain. In this study we investigated whether there was a difference between ipsilateral and contralateral sides in the levels of GABA, the vesicular GABA transporter (VGAT), or the beta3 subunit of the GABA(A) receptor at synapses in the medial part of the superficial dorsal horn in this model. We found no difference in the intensity of immunolabeling for any of these markers on the two sides of the superficial dorsal horn. An alternative explanation for disinhibition after nerve injury is that it results from reduced excitatory drive to GABAergic dorsal horn neurons following loss of primary afferent input to these cells..
Treatment with the ultrapotent TRPV1 agonist resiniferotoxin (RTX) eliminated TRPV1-expressing dorsal root ganglion neurons and their central terminals in the spinal dorsal horn and significantly reduced the basal amplitude of glutamatergic excitatory postsynaptic currents (EPSCs) evoked from primary afferents. These data suggest that stimulation of mu-opioid receptors on non-TRPV1 afferent terminals causes extended inhibition of neurotransmitter release to spinal dorsal horn neurons.
injection of the sigma-1 receptor agonists PRE-084 (PRE) or carbetapentane (CAR) significantly decreased tail-flick latency (TFL) and increased the frequency of paw withdrawal responses to mechanical stimulation (von Frey filament, 0.6 g) as well as the amount of Fos expression in the spinal cord dorsal horn induced by noxious paw-pinch stimulation. PRE or CAR injection significantly increased pan-PKC as well as the PKCalpha, epsilon, and zeta isoforms in the dorsal horn.
Immunoreactivity was present in DRG cell bodies and central terminals in the dorsal horn of the spinal cord. In addition, the presence of Reg-2 in central axon terminals implicates Reg-2 as a possible modulator of second order dorsal horn cells..
METHODS: Electrophysiologic recordings of NMDA current were made from cultured rat dorsal horn neurons treated with remifentanil at various concentrations for 60 min.
In the present study, we tested the effects of five different omega-conotoxins, CVID, CVIB, MVIIA, MVIIC and GVIA, on excitatory synaptic transmission between primary afferents and dorsal horn superficial lamina neurons of rat spinal cord. The N-type VGCC antagonists CVID (200nM) and MVIIA (500nM) completely and irreversibly inhibited excitatory postsynaptic currents (EPSCs) in the dorsal horn superficial lamina. These results indicate that (i) the analgesic action of omega-conotoxins that antagonise N-type VGCCs may be attributed to inhibition of neurotransmission between primary afferents and superficial dorsal horn neurons, (ii) nociceptive synaptic transmission between primary afferents and superficial lamina neurons is mediated predominantly by N-type VGCCs, and (iii) in contrast to the irreversible inhibition by CVID, MVIIA and GVIA, the inhibition of excitatory monosynaptic transmission by CVIB is reversible..
We also demonstrated rAAV-GAD65 as a successful gene delivery vehicle in a chronic pain model by administrating rAAV-GAD65 to DRGs because GABA driven by GAD is a major inhibitory neurotransmitter in the dorsal horn of the spinal cord and also plays an important role in the ventral horn.
Experiments showed chromatolysis and a decreased response to calbindin D-28K associated with a significant increase of TUNEL-positive cells in the dorsal horn neurons.
In our experiments, expression of PV in the lumbar dorsal horn spinal cord was evaluated using densitometric analysis of immunohistological sections and Western-blot techniques in control and arthritic rats. There was a significant reduction of PV immunoreactivity in the superficial dorsal horn region ipsilateral to the arthritis after induction of the peripheral inflammation. Our results suggest that changes in expression of calcium binding proteins in spinal cord dorsal horn neurons may modulate nociceptive transmission..
Furthermore, Fos-LI- and NADPH-d-positive neurons were mainly found in the ipsilateral dorsal horn after injection of formalin, some of which were Fos-LI/NADPH-d double-labelled neurons.
Here we demonstrate that in the dorsal horn of the spinal cord, gliosis is accompanied by changes in glial amino acid transporters examined by immunoblot, immunohistochemistry and RT-PCR.
They respond to innocuous and/or noxious mechanical stimulation of the distal extremities, and some are prone to central sensitization or "windup." Morphologically, neurochemically, and functionally, therefore, these cells most closely resemble neurons in laminae III-VI in the dorsal horn.
RESULTS: Two weeks after CCI surgery, rats displayed significant mechanical allodynia and thermal hyperalgesia, and the spinal cord dorsal horn showed a significant increase in the number of pNR1 immunoreactive neurons. Importantly, IT clonidine, but not IT DAMGO or gabapentin, dose-dependently reduced CCI-induced pNR1 expression in all lamina of the spinal cord dorsal horn by 30 min after injection. In addition, IT injection of the alpha-2 adrenoceptor antagonist, idazoxan (40 microg/rat) 10 min before clonidine injection completely reversed clonidine's antihyperalgesic and antiallodynic effects, as well as clonidine's suppressive effect on CCI-induced NR1 phosphorylation in the spinal cord dorsal horn.
It was found that formalin test significantly up-regulated NOS expression and activity and NO production in the laminae I-II of the dorsal horn and the grey matter around the central canal in the lumbar spinal cord at 1 h after the formalin test. Selective inhibition of glia metabolism with intrathecal administration of FC (1 nmol) significantly inhibited the up-regulation in NOS expression and activity and NO production normally induced by the formalin test, which was represented with decreases in the number and density of the NADPH-d positive cells in the dorsal horn and grey matter around the central canal, and decrease in density of NADPH-d positive neuropil in the dorsal horn in formalin + FC group compared with formalin group.
The N-methyl-d-aspartate (NMDA) receptor in the spinal cord dorsal horn (SCDH) is one of the mechanisms involved in central sensitization during chronic pain.
In this study, we attempted to pharmacologically characterize the alteration in spinal transmission induced by partial sciatic nerve injury in terms of nociceptive behavior and phosphorylation of extracellular signal-regulated kinase (pERK) in the spinal dorsal horn. Moreover, Adelta- and C-, but not Abeta-fiber stimulations significantly increased the number of pERK-positive neurons in the superficial spinal dorsal horns of naïve mice, and corresponding antagonists used in the EPW test inhibited this increase. In mice with nerve injury, Abeta- as well as Adelta-fiber stimulations significantly increased the number of pERK-positive neurons in the superficial spinal dorsal horn, whereas C-fiber stimulation decreased this number.
Therefore, we focused our study on TNF-alpha protein synthesis and expression patterns in spinal dorsal horn of naives and rats under intrathecal challenge with LPS. Double immunofluorescence revealed that LPS-induced expression of TNF-alpha exclusively located in a subpopulation of microglia, which increased at 8 h in the rat spinal dorsal horn (the injected side).
This study investigated the effect of 5th and 6th lumbar nerve (L5/L6) spinal nerve ligation (SNL) on activated nuclear factor kappaB (NFkBa) in nuclear extracts from the lumbar dorsal horn of the rat, and its relationship to prostaglandin (PG)-dependent spinal hyperexcitability and allodynia 3 days later. This was preceded by an increase in NFkBa in the ipsilateral lumbar dorsal horn at 12 h which was still present 3 days after SNL.
Staining was dense in some regions of the CNS including spinal dorsal horn, anterior olfactory nucleus, anterior amygdala, basolateral (ventral) amygdala and cortical amygdala, and the piriform, perirhinal, insular and entorhinal cortices.
The retrograde tracer cholera toxin subunit B (CTb) was injected into the spinal dorsal horn, and medullary sections were processed by double immunocytochemistry for CTb and each receptor.
Moreover, our results indicate that neurosteroids, which are synthesized in the dorsal horn of the spinal cord and have limited side effects, may be of significant interest in order to treat pathological pain symptoms..
The results showed that: NCCs were observed in various regions of spinal cord of adult mice, but amount of NCCs was different in distinct region, the rank order of NCCs amount in various spinal cord regions was dorsal horn region greater than central canal greater than the ventral and lateral horn. NCCs in dorsal horn region mainly distributed in substantia gelatinosa, NCCs in central canal mainly distributed in ependymal zone, on the contrary, NCCs in ventral, lateral horn, medullae, nucleus regions of spinal cord were comparatively less.
The results showed that the number of neuronal NO synthase (nNOS) positive neurons significantly increased in superficial (I-II), deep (V-VI) dorsal horn laminae and the ventral gray laminae (VII-X), but not in the nucleus proprius (III and IV) of bilateral L4-L5 lumbar spinal cord after unilateral intraplantar injection of BmK venom from 2h to 7d.
Since cyclooxygenase-2 (COX-2) has been reported to increase in the spinal dorsal horn following spinal nerve ligation (SNL) and it may play a role in the neuropathic pain, we hereby tested the hypothesis that EA may affect COX-2 expression and hence neuropathic nociception after SNL. Immunostaining demonstrated suppression of COX-2 expression in the spinal L4-L6 dorsal horn after EA.
The laminar organization of dorsal horn and effects of descending impulses. 188, 403-423] of tonic descending inhibitory control of dorsal horn neurons, several studies have aimed to characterize the role of various brain centers in the control of nociceptive input to the spinal cord.
Central sensitization, similar to long-term potentiation in the hippocampus, refers to the increased synaptic efficacy established in somatosensory neurons in the dorsal horn of the spinal cord following tissue injury or nerve damage. In vivo patch-clamp recordings of rats 24 h after CFA injection showed that excitatory postsynaptic currents of dorsal horn neurons evoked by pinch stimuli to inflamed skin were inwardly rectified and inhibited by 60% by philanthotoxin-433, a selective inhibitor of the Ca2+-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor.
Mustard oil application to tooth pulp produces central sensitization in rat medullary dorsal horn (MDH) nociceptive neurons, which has been implicated in persistent pain mechanisms.
Immunocytochemical analyses indicate that the increases in p38 MAPK activation occurred in astrocytes, microglia, and dorsal horn neurons in the spinal cord rostral to the site of injury. Inhibiting the enzymatic activity of p38 MAPK dose dependently reverses the behavioral expression of at-level mechanical allodynia and also decreases the hyperexcitability seen in thoracic dorsal horn neurons after moderate SCI.
To gain insight into the cellular mechanism of 5-HT(3) receptors, we examined their expression in GABAergic and enkephalinergic (ENKergic) neurons in the spinal dorsal horn (SDH) using single-cell reverse transcription-polymerase chain reaction (RT-PCR).
Both immunohistochemical and real-time PCR analysis confirmed discrete NMDAR-2D subunit expression within the DRG and dorsal horn. Together, these findings seem to suggest that the NMDAR-2D receptor subunit is present within the cell body region of a population of small diameter sensory afferents and post-synaptically within second order dorsal horn neurons.
Immunohistochemistry showed that p38 was phosphorylated in DRG and spinal dorsal horn neurons at this time point.
Among these, the opioid peptides and their receptors in Arc-PAG-NRM-spinal dorsal horn pathway play a pivotal role in mediating acupuncture analgesia.
Spinal nerve ligation produced tactile allodynia along with a reduction of catalytic activity of the constitutive Ca(2+)-dependent NOS (eNOS and nNOS isoforms) in the ipsilateral dorsal horn, but not contralateral dorsal or ipsilateral or contralateral ventral, spinal cord at 1, 5, 10 and 15 days after surgery compared to naïve and sham-operated animals. Nerve ligation also induced a reduction of nNOS expression in the ipsilateral dorsal horn spinal cord at 10 and 15 days after surgery. Moreover, resveratrol significantly reversed the reduction of nNOS expression in the ipsilateral dorsal horn spinal cord. Results show that spinal nerve ligation leads to development of tactile allodynia along with a reduction in constitutive Ca(2+)-dependent NOS activity and nNOS isoform expression in the ipsilateral dorsal horn.
These findings indicate that loss of TRPV1-expressing afferent neurons leads to a substantial reduction in presynaptic delta-opioid receptors in the spinal dorsal horn.
The aim of the present study was to investigate the effects of chronic administration of morphine on the expression of an endogenous opioid peptide in the spinal dorsal horn.
Previous studies have shown that peripheral nerve injury in rats induces increased expression of the voltage gated calcium channel (VGCC) alpha-2-delta-1 subunit (Ca v alpha2 delta1) in spinal dorsal horn and sensory neurons in dorsal root ganglia (DRG) that correlates to established neuropathic pain states. To determine if injury discharges trigger Ca v alpha2 delta1 induction that contributes to neuropathic pain initiation, we examined allodynia onset and Ca v alpha2 delta1 levels in DRG and spinal dorsal horn of spinal nerve ligated rats after blocking injury induced neural activity with a local brief application of lidocaine on spinal nerves before the ligation. Similar pretreatment with the effective concentration of lidocaine diminished injury-induced increases of the Ca v alpha2 delta1 in DRG and abolished that in spinal dorsal horn specifically, and resulted in a delayed onset of tactile allodynia post-injury. Both dorsal horn Ca v alpha2 delta1 upregulation and tactile allodynia in the lidocaine pretreated rats returned to levels similar to that in saline pretreated controls 2 weeks post the ligation injury. These findings indicate that injury induced discharges regulate Ca v alpha2 delta1 expression in the spinal dorsal horn that is critical for neuropathic allodynia initiation.
In the present work we evaluate the role of BDNF in LTP of C-fiber evoked field potentials in spinal dorsal horn, a synaptic model of pain memory. The results suggest that BDNF play a crucial role in protein synthesis-dependent L-LTP in spinal dorsal horn via activation of ERK, p38 MAPK and NF-kappaB signal pathways..
Long term facilitation (LTF) of C-fiber-evoked firing of wide dynamic range neurons in the spinal dorsal horn in response to conditioning stimulation (CS) of afferent fibers is a widely studied cellular model of spinal nociceptive sensitization. The number of dorsal horn neurons expressing c-fos, but not zif268 or Arc, was significantly elevated after 3 Hz CS and increased proportionally with stimulation rate. This frequency-dependence is important for understanding how the afferent firing pattern affects neuronal plasticity and nociception in the spinal dorsal horn..
Our experiments demonstrate a novel role for group I metabotropic glutamate receptor (mGluR) subtypes 1 and 5 in generating a long-lasting synaptic excitation in the substantia gelatinosa (SG) and deep dorsal horn (DH) neurons of the rat spinal cord.
Neuropathic pain (NPP) due to sensory nerve injury is, in part, the result of peripheral sensitization leading to a long-lasting increase in synaptic plasticity in the spinal dorsal horn. Using a fluorescent tracer, sodium fluorescein, we confirmed that local DRG application results in minimal spread into the corresponding dorsal horn of the ipsilateral spinal cord.
Botulinum toxin A (20 U) significantly decreased inflammatory cell accumulation, and cyclooxygenase-2 expression in the prostate, ventral horn and dorsal horn of the L6 spinal cord (93.5%, 89.4%, 90.5% and 77.5%, respectively).
The specificity of this innervation has been suggested to be the result both of differential sensitivity to chemorepellants expressed in the ventral spinal cord and of the function of Ig-like neural cell adhesion molecules in the dorsal horn. Focussing on the pathfinding of TrkA+ NGF-dependent axons, we demonstrate for the first time that their axons project prematurely into the dorsal horn of both L1 and TAG-1 knockout mice.
Some varicose fibers in the spinal cord dorsal horn and intermediate gray matter that expressed DYN-ir also expressed DOR-ir.
The delayed development of contralateral allodynia correlated with an increase in OX-42, but not GFAP immunoreactivity in the contralateral dorsal horn.
Under an in vivo condition, chronic morphine exposure also induced posttranscriptional down-regulation of the glutamate transporter EAAC1, which was prevented by MG-132, and transcriptional up-regulation of PTEN and Nedd4 within the spinal cord dorsal horn.
Following paw incision and at spinal L5 segment GFAP expression was increased in laminae I-II and Iba1 in deep laminae on day 1, in the entire dorsal horn on day 4 and dissipated on day 7 after paw incision in parallel with the allodynia. L5 nerve transection induced mechanical allodynia from day 1 to 7 which correlated with Iba-1 increases on day 1, 4 (entire dorsal horn) and day 7 after nerve injury (deep laminae of the dorsal horn) at spinal L5 segment. Conversely, GFAP increased at later time points from day 4 (deep laminae) and on day 7 (entire dorsal horn).
Unilateral lesioning of the spinal dorsal horn with the excitotoxin quisqualic acid (QUIS) leads to robust degeneration of dorsal horn grey matter, and robust pain-related symptoms, such as cutaneous hypersensitivity, persist long after injury. A possible mechanism that underlies the pain-related symptoms is the disruption of dorsal horn inhibitory neuron function, leading to decreased inhibition of nociceptive neurons. The expression of the immediate-early gene product Fos in the dorsal horn ipsilateral to formalin injection was similar between QUIS- and sham-lesioned rats. In QUIS-lesioned rats, however, there was a marked absence of dorsal horn neurons, particularly GABAergic neurons, compared to sham-lesioned rats. The prolonged nociceptive response observed with a unilateral QUIS lesion may be due to generalized changes in dorsal horn neuron function including a loss of inhibitory neuron function..
Previous studies have focused considerable attention on the directly damaged primary afferents and their influence on the activity of the dorsal horn neurons.
Intraplantar administration of ABT-102 blocks heat-evoked firing of wide dynamic range and nociceptive-specific neurons in the spinal cord dorsal horn of the rat.
In the hindbrain, Lmx1b-expressing neurons were primarily observed in the raphe nuclei, parabrachial nuclei, principal sensory trigeminal nucleus, nucleus of the solitary tract, and laminae I-II of the medullary dorsal horn as well as spinal dorsal horn. as well as the medullary and spinal dorsal horns, suggesting that Lmx1b-expressing cells in these areas are excitatory neurons.
We previously reported that vanilloid receptor type 1 (VR1, or TRPV1) was up-regulated in dorsal root ganglion (DRG) and the spinal dorsal horn after chronic inflammatory pain produced by complete Freund's adjuvant (CFA) injection into the plantar of rat hind paw. With extracellular electrophysiological recording, the effect of CPZ on noxious electrical or heat stimulation evoked responses of wide dynamic range (WDR) neurons in the deep layers of the spinal dorsal horn was evaluated.
In the present study we sought to (i) characterize anatomical and cellular distribution and localization of cPLA(2)IVA in dorsal horn of rat spinal cord, (ii) verify efficacy and selectivity of intrathecal (IT) delivery of an antisense oligonucleotide (AS) targeting rat cPLA(2)IVA mRNA on spinal expression of this enzyme, and (iii) examine the effect of down-regulation of spinal cPLA(2)IVA on peripheral tissue injury-induced pain behavior. Here we demonstrate that cPLA(2)IVA is constitutively expressed in rat spinal cord, predominantly in dorsal horn neurons and oligodendrocytes but not in astrocytes or microglia.
Also increased phosphorylation of p38 MAP kinase occurred in the L5 dorsal horn of allodynic rats. For below-level allodynia after SCI, TNF-alpha and IL-1beta increased in the L5 dorsal horn by 7 dpo and returned to baseline by 35 dpo.
In the spinal dorsal horn, orexins have been shown to be concentrated in the superficial laminae.
BACKGROUND: Recent evidence suggests that oxytocin (OT), secreted in the superficial spinal cord dorsal horn by descending axons of paraventricular hypothalamic nucleus (PVN) neurons, produces antinociception and analgesia. RESULTS: We show that OT released during PVN stimulation specifically activates a subpopulation of lamina II glutamatergic interneurons which are localized in the most superficial layers of the dorsal horn of the spinal cord (lamina I-II).
After chronic morphine treatment, a marked increase in TRPV1 immunoreactivity (IR) was detected in L4 dorsal root ganglion (DRG) neurons, spinal cord dorsal horn, and sciatic nerve.
The inflammatory mediators released by activated glial cells, such as tumor necrosis factor-alpha and interleukin-1beta can not only cause neurodegeneration in these disease conditions, but also cause abnormal pain by acting on spinal cord dorsal horn neurons in injury conditions.
Raclopride, injected into the NAc shell region, attenuated the antinociceptive effect of N(2)O in the formalin test, and blocked the suppressive effect of N(2)O on the formalin-induced c-Fos expression in the dorsal horn of the spinal cord by N(2)O.
BACKGROUND: The presence of A(2A) receptors in the dorsal horn of the spinal cord remains controversial. In this study, we sought to establish the presence of adenosine A(2A) receptors in the lamina II of the rat lumbar dorsal horn neurons and investigated whether the activation of A(2A) receptors is able to modulate NMDA receptor currents. CONCLUSIONS: These results demonstrate the presence of A(2A) receptor on neurons from the substantia gelatinosa of the rat lumbar dorsal horn and the inhibition of NMDA-induced currents by the application of a selective A(2A) receptor agonist.
We hypothesized that depression of dorsal horn neuronal responses to noxious stimulation would correlate with the magnitude of effect of benzene (BNZ), o-difluorobenzene, and hexafluorobenzene (HFB) on NMDA receptors. A 5-s noxious mechanical stimulus was then applied to the hindpaw receptive field of nociceptive dorsal horn neurons, and single-neuron responses were recorded at 0.8 and 1.2 MAC. RESULTS: In intact rats, depression of responses of dorsal horn neurons to noxious stimulation by peri-MAC increases in BZN, o-difluorobenzene, and HFB correlated directly with their in vitro capacity to block NMDA receptors. CONCLUSIONS: The findings in intact rats suggest that NMDA blockade contributes to the depression of dorsal horn neurons to nociceptive stimulation by fluorinated aromatic anesthetics.
In the dorsal horn of the spinal cord, AT1 immunostainining and angiotensin binding were both prominent.
The authors also examined effects of MLR stimulation on responses of nociceptive dorsal horn neurons and limb force responses to tail clamp. MLR stimulation inhibited noxious stimulus evoked responses of dorsal horn neurons by approximately 80%. CONCLUSIONS: Because electrical stimulation of the MLR elicits movement independent of dorsal horn activation, the immobilizing properties of isoflurane and halothane are largely independent of action in the dorsal horn.
OBJECTIVES: We evaluated the longitudinal changes in contralateral mechanical allodynia, expression of tumor necrosis factor (TNF)-alpha and glial fibrillary acidic protein (GFAP)-positive satellite cells in the contralateral dorsal root ganglion (DRG), and expression of astrocytes and microglia in the contralateral spinal dorsal horn after hemilateral spinal nerve injury in rats. Expression of TNF-alpha and GFAP in bilateral L5 DRGs and expression of GFAP and ionized calcium-binding adaptor molecule-1 (Iba-1) in bilateral L5 spinal dorsal horns were studied using immunohistochemistry and immunoblotting. In the contralateral spinal dorsal horn, GFAP-positive astrocytes significantly increased for 21 days, but Iba-1 was not significant.
In the somatosensory system, myriads of primary afferents, conveying information from different body locations and sensory modalities, get organized in the dorsal horn of the spinal cord so that spinal multisensory circuits receive topographically ordered information. Thus, far from being inborn and stereotypic, the dorsal horn of the spinal cord now appears to be a highly adaptive brain-body interface..
injection of the Sig-1 R agonists, PRE-084 or carbetapentane dose dependently enhanced pNR1 expression in the murine dorsal horn.
This review considers the ion channels that underlie transduction of nociceptive energies in the periphery, that are involved in impulse initiation and propagation in peripheral sensory neurones, and that participate in pre- and post-synaptic actions in the spinal cord dorsal horn, in light of their susceptibility to local anaesthetics.
Activation of mitogen-activated protein kinases (MAPKs) in dorsal root ganglia (DRG) and the spinal dorsal horn contributes to inflammatory pain by transcription-dependent and -independent means. Injection of complete Freund's adjuvant (CFA) into a hindpaw produced persistent inflammation and sustained ERK5 activation in DRG and the spinal dorsal horn.
The aim of this short review was to summarize the knowledge about TRPV1 receptors in the spinal cord dorsal horn, preferentially from morphological and electrophysiological studies on spinal cord slices and from in vivo experiments.
Central sensitization, increased sensitivity in spinal cord dorsal horn neurons after injuries, plays an essential role in the induction and maintenance of chronic pain. Furthermore, all the PICs increased cAMP response element-binding protein (CREB) phosphorylation in superficial dorsal horn neurons and produced heat hyperalgesia after spinal injection. Together, our data have demonstrated that PICs induce central sensitization and hyperalgesia via distinct and overlapping synaptic mechanisms in superficial dorsal horn neurons either by increasing excitatory synaptic transmission or by decreasing inhibitory synaptic transmission.
Our data suggests that icilin modulates the mechanosensitivity of dorsal horn neurones. The differing effects of ice and icilin on dorsal horn neurones indicate different mechanisms of action..
Glucose-sensitive neurons in the lateral hypothalamic area produce orexin-A (OxA) as well as orexin-B (OxB) and send their axons to the spinal dorsal horn, which predominantly expresses orexin receptor-1 (OX-1), showing a higher sensitivity to OxA.
The effect of SCS was assessed with von Frey filaments in rats displaying tactile hypersensitivity after partial ligation of the sciatic nerve and both SCS-responding and non-responding as well as normal rats were subjected to microdialysis in the dorsal horn. SCS produced significantly increased release of ACh in the dorsal horn in rats responding to SCS whereas the release was unaffected in the non-responding animals. In conclusion, the attenuating effect of SCS on pain related behavior is associated with the activation of the cholinergic system in the dorsal horn and mediated via muscarinic receptors, particularly M(4,) while nicotinic receptors appear not to be involved..
The cold thermal afferent circuit from cutaneous thermal receptors ascends via second-order thermosensory neurons in the dorsal horn of the spinal cord to activate neurons in the lateral parabrachial nucleus, which drive GABAergic interneurons in the preoptic area to inhibit warm-sensitive, inhibitory output neurons of the preoptic area.
In this study, using lumbar spinal cord tissue from rats with L(5)/L(6) spinal nerve ligation (SNL), we demonstrated that SNL injury induces MOR linkage to G(s) in the damaged (ipsilateral) spinal dorsal horn. The MOR-G(s) coupling observed in response to SNL may in part contribute to the excitatory neurotransmission in spinal dorsal horn in neuropathic pain states.
Activity in descending systems from the brainstem modulates nociceptive transmission through the dorsal horn. Intrathecal injection of the neurotoxin saporin conjugated to SP (SP-SAP) into the lumbar spinal cord results in the selective ablation of NK(1) receptor expressing (NK(1)+ve) neurones in the superficial dorsal horn (lamina I/III). Loss of these NK(1)+ve neurones attenuates excitability of deep dorsal horn neurones due to a disruption of both intrinsic spinal circuits and a spino-bulbo-spinal loop, which activates a descending excitatory drive, mediated through spinal 5HT(3) receptors. Intrathecal application of atipamezole dose dependently facilitated the mechanically evoked neuronal responses of deep dorsal horn neurones to low intensity von Frey hairs (5-15 g) and noxious thermal (45-50 degrees C) evoked responses in SAP control animals indicating a physiological alpha2-adrenoceptor control. These data suggest that activity within noradrenergic pathways have a dependence on dorsal horn NK(1)+ve cells.
These neurons project axons throughout the rostrocaudal extent of the spinal cord, terminating predominantly in the dorsal horn.
This study aims to analyse the expression of GABA, its synthesizing enzyme glutamic acid decarboxylase (GAD) and the potassium chloride cotransporter (KCC2), in the spinal dorsal horn of streptozotocin (STZ)-induced diabetic rats. Densitometric quantification was performed in the superficial dorsal horn (laminae I, II and III) of immunoreacted sections and in the immunoblots.
Spinally-projecting serotonergic neurons in the LH have not been identified, suggesting that the LH innervates brainstem serotonergic neurons in the rostral ventromedial medulla (RVM), known to modify nociception in the spinal cord dorsal horn.
This neutralizes substance P in the spinal cord dorsal horn by increasing naturally occurring opioids such as enkephalins.
The present study was undertaken to further examine the ultrastructural localization of SST(2A) receptor in lamina II of the spinal dorsal horn and the role of SST(2A) receptor in thermal hyperalgesia following Complete Freund's Adjuvant (CFA)-induced inflammation.
We show that ephrinB-EphB receptor signaling plays a critical role is induction and maintenance of neuropathic pain by regulating neural excitability and synaptic plasticity in the dorsal root ganglion (DRG) and the spinal dorsal horn (DH).
Allodynia was associated with an increase in the number of microglial cells in the dorsal horn of the spinal cord. The expression of the chemokine CX3CL1 (fractalkine) and its receptor CX3CR1 were also higher in EAN than in control dorsal horns suggesting spinal microglia and CX3CL1/CX3CR1 may play a role in the pain-like behaviour..
RESULTS: We found that BV injection resulted in a quick activation of p38, predominantly in the L4/L5 spinal dorsal horn ipsilateral to the inflammation from 1 hr to 7 d post-injection. Activated ERK1/2 was observed exclusively in neurons in the L4/L5 dorsal horn from 2 min to 1 d, peaking at 2 min after BV injection. p-ERK1/2 and p-p38 were expressed in neurons in distinct regions of the L4/L5 dorsal horn; p-ERK1/2 was mainly in lamina I, while p-p38 was mainly in lamina II of the dorsal horn. CONCLUSION: The results indicate that differential activation of p38 and ERK1/2 in the dorsal horn may contribute to the generation and development of BV-induced pain hypersensitivity by different mechanisms..
The number of p-p38 MAPK-immunoreactive (IR) cells was significantly increased in the L5 dorsal horn and the gracile nucleus ipsilateral to the injury at days 3-21 after SNL. Increased immunofluorescence labeling for OX-42 indicated that microglial cells were activated by SNL in the L5 dorsal horn and the gracile nucleus ipsilateral to the injury. These results demonstrate that SNL activates p38 MAPK pathway in microglia in the gracile nucleus as well as in the spinal cord dorsal horn.
The A7 catecholamine cell group consists of noradrenergic (NAergic) neurons that project to the dorsal horn of the spinal cord.
We have now examined the signaling pathways that are responsible for the postsynaptic modulatory actions of bradykinin on glutamatergic action and transmission in superficial dorsal horn neurons. B(2) receptors are coexpressed in dorsal horn neurons with protein kinase A (PKA) and the delta isoform of protein kinase C (PKC), and we find that the augmentation by bradykinin of AMPA and NMDA receptor-mediated currents in lamina II neurons requires coactivation of both PKC and PKA. We conclude that bradykinin, by activating multiple kinases in dorsal horn neurons, potentiates glutamatergic synaptic transmission to produce pain hypersensitivity..
Indeed, anatomical, cellular and biochemical investigations have shown that the SC dorsal horn (DH), a pivotal structure in nociception, contains various active steroidogenic enzymes such as cytochrome P450side-chain-cleavage, cytochrome P450c17, 3beta-hydroxysteroid dehydrogenase, 5alpha-reductase and 3alpha-hydroxysteroid oxido-reductase.
OBJECTIVE: Dorsal root entry zone (DREZ) operations came into medical practice after the demonstration of increased electrical activity in the dorsal horn of the spinal cord and brainstem in patients with deafferentation of the central nervous system after injury to these areas.
Hoxb genes are expressed at high levels in the dorsal horn of the spinal cord. Although spinal ganglia were normal, a lower postmitotic neural count was found in the dorsalmost laminae at lumbar levels around birth, leading to a smaller dorsal horn and a correspondingly narrowed projection field of nociceptive and thermoceptive afferents. Because none of the neuronal markers used was unexpressed in the adult dorsal horn, absence of Hoxb8 does not impair neuronal differentiation. The data therefore suggest that a lower number of neurons in the upper spinal laminae and neuronal disorganization in the dorsal horn underlie the sensory defects including the excessive grooming of the Hoxb8 mutant..
PalGly potently inhibited heat-evoked firing of nociceptive neurons in rat dorsal horn.
In the spinal cord, the c-kit receptor was detected in the superficial layer of the dorsal horn and co-localized there with CGRP in central terminals of DRG neurons.
We found that microglia showed a uniform distribution throughout the CNS, and peripheral nerve injury selectively activated microglia in the spinal cord dorsal horn and related ventral horn.
Wind-up is a progressive, frequency-dependent increase in the excitability of trigeminal and spinal dorsal horn wide dynamic range (WDR) nociceptive neurons evoked by repetitive stimulation of primary afferent nociceptive C-fibres.
Using immunohistochemical studies, we first show that CCL2 is constitutively expressed by primary afferent neurons and their processes in the dorsal horn of the spinal cord.
After 7 days of treatment and during ongoing treatment single unit extracellular recordings were made from the lumbar deep dorsal horn under urethane anesthesia.
We examined whether different itch signals converge on the same dorsal horn neurons in mice. These stimuli induced Fos expression in cells in the superficial dorsal horn.
Sensory signals are transmitted from the periphery by primary afferent fibres into the dorsal horn of the spinal cord, where these afferents synapse with intrinsic spinal dorsal horn neurones. During nociceptive transmission, the output of the spinal cord is dependent on various spinal mechanisms which can either increase or decrease the activity of dorsal horn neurones.
The expression of the 5-HT2A receptor mRNA in the nucleus of raphe magnus (NRM), ventrolateral periaqueductal gray (vlPAG) and spinal dorsal horn of mono-arthritic rats after a ten-day treatment with tramadol was measured with in situ hybridization. Expression of the 5-HT2A receptor mRNA in NRM, ipsilateral vlPAG, and the ipsilateral spinal dorsal horn of arthritic rats was significantly increased after tramadol treatment.
Aberrant sprouting of primary afferent fibers and synaptogenesis within incorrect dorsal horn laminae leads to the development and maintenance of chronic pain as well as autonomic dysreflexia.
Vinpocetine, a derivative of vincamine, widely used in the clinical pharmacotherapy of cerebral circulatory diseases, inhibits retrograde axoplasmic transport of nerve growth factor (NGF) in the peripheral nerve, resulting in transganglionic degenerative atrophy (TDA) in the related ipsilateral superficial spinal dorsal horn, as shown in our previous publications. Nociception, induced by intraplantar injection of formalin, was mitigated by vinpocetine; increased expression of c-fos in the ipsilateral, segmentally related upper dorsal horn was also prevented.
Long-term potentiation (LTP)-like changes in synaptic transmission between nociceptive C-fibers and spino-periaqueductal grey projection neurons as well as a loss of inhibitory control by GABAergic and glycinergic spinal dorsal horn neurons have repeatedly been proposed as underlying principles.
P2X receptor-mediated sensory inputs can be either innocuous or nociceptive, depending on which dorsal horn regions receive these inputs. We provide a brief review of P2X receptor-mediated purinergic sensory pathways to different regions in the dorsal horn.
Furthermore, Western blot and RT-PCR analysis revealed a significant downregulation of Bax protein and its mRNA, but an upregulation of Bcl-2 in the dorsal horn of L(3) and L(6) cords at both 7 and 14 dpo.
The lower thresholds and increased excitability of dorsal horn neurons in the neonatal rat suggest that inhibitory processing is less efficient in the immature spinal cord. To address this issue we examined monosynaptic GABAergic inputs onto superficial dorsal horn neurons using whole cell patch-clamp recordings made in spinal cord slices at a range of postnatal ages (P3, P10, and P21). These properties may affect the integration of synaptic inputs within developing superficial dorsal horn neurons and thus contribute to their larger receptive fields and enhanced afterdischarge..
These studies suggest that Tlx1 and Tlx3 operate high in the regulatory hierarchy that coordinates specification of dorsal horn pain-modulatory peptidergic neurons..
Literature highlights that serotonergic descending pathways are implicated in somatosensory functions in the spinal cord and that serotonin (5-HT) in the dorsal horn might play a role in motor function through proprioceptive feedback. We hypothesized that 5-HT release in dorsal horn might represent an important factor in the completion of locomotion by facilitation of the spinocerebellar tract and/or by modulation of spinal reflex pathways. Microdialysis in combination with HPLC was used to measure concentrations of neurotransmitters in the lumbar dorsal horn before, during, and after a treadmill running exercise. Our results show a significant 41% increase of 5-HT release within the dorsal horn during the exercise. The present study demonstrates that dorsal horn 5-HT release might modulate locomotion..
The purpose of the present study was to test whether there is any anatomical evidence to support the suggestion that terminating unmyelinated (C) fibres of injured and adjacent uninjured nerves interact at the level of the spinal dorsal horn. Results with both tracers showed that the central terminals of nerve L4 were concentrated in both L4 and L3 segments of the dorsal horn with clear although reduced levels of labelling in L2 and L5. These results suggest an intermingling of primary afferents of adjacent nerves at the level of the spinal dorsal horn.
At the 2-hour time point, all the rats were deeply anesthetized and perfused intracardially; and then, the spinal cord was removed for analysis of c-Fos protein-like immunoreactive neurons (FLIN) at the dorsal horn in the L4-L6 segments. (2) Both in the superficial and deep laminae at the dorsal horn, the amount of FLIN of group NS was much less than that of the remaining groups. (3) Correlation analysis showed that the correlation coefficient between the sum of NBI in one hour and the expression of c-Fos in the superfacial or deep lamina of dorsal horn was positive. CONCLUSION: Pre-intrathacal lornoxicam can successfully inhibit nociceptive behavior and c-Fos expression in spinal dorsal horn of formalin test rats.
The mean optical density (OD) of Sema3A immunoreactivity in dorsal horn was measured and the number of NP-1 positive medium-small sized neurons in spared DRG was counted. 37 +/- 0.87) (P < 0.05), but kept the level along to 14th day group (0.27 +/- 0.09); in L5 segment, the expression of Sema3A decrea sed in 7th day group (0.26 +/- 0.11) (P < 0.05), and then recovered to normal level in 14th day group (0.33 +/- 0.09); in L6 segment, OD values in dorsal horn had no changes to all groups.
We show that approximately 90% of the PKCgamma cells in the gracile nucleus and 60% in the dorsal horn were immuno-positive for the AMPA receptor subunit glutamate 2/3 (GluR2/3).
Substance P immunoreactive (IR) positive product of the spinal dorsal horn (L3-L5) was detected by immunohistochemical method and expressed as integrated optical density (IOD). Compared with model group, IOD values of SP in the spinal dorsal horn in EX-B2 , GB34 and EX-B2 + GB34 groups were significantly lower (P < 0.05). There were no significant differences among the 3 EA groups in the expression of SP in the spinal dorsal horn.
Our results also demonstrated that SNL induced a marked and long-term (>21 days) activation of astrocytes in the ipsilateral spinal dorsal horn.
In this study, we investigated postnatal changes in Rexed's laminae and distribution of nociceptive afferents in the dorsal horn of the rat lumbar spinal cord at postnatal days 0, 5, 10, 15, 20, and 60. In absolute values, the overall width of the bands of intense CGRP and IB4 labeling increased with age but decreased as a percentage of the overall thickness of the dorsal horn with maturation. First, the size of the different laminae does not grow evenly across the dorsal horn. These findings have implications for comparing data obtained in immature and mature tissues with respect to localization of structures in the dorsal horn..
STUDY DESIGN: This study was aimed at investigating changes in the dorsal horn of the lumbar cord induced by mechanical compression using an in vivo model. OBJECTIVE: To determine the effect of axonal flow disturbance in the dorsal horns induced by nerve root compression. SUMMARY OF BACKGROUND DATA: Few studies have looked at changes of synapses within the dorsal horn caused by disturbance of axonal flow and the axon reaction as a result of mechanical compression of the dorsal root. Morphologic changes of the synapses in the dorsal horns secondary to the nerve fiber degeneration were examined by light and electron microscope. Changes on immuno-staining for substance P, calcitonin gene-related peptide, and somatostatin in the dorsal horn were also examined. RESULTS: Light microscope observation conducted 1 week after compression of the nerve roots revealed Wallerian degeneration of the myelinated nerve in the dorsal horn, and fluorescence microscope observation of these areas demonstrated edema formation resulting from damage of the blood-spinal cord barrier. CONCLUSION: It is important to recognize that compressive disturbance of the nerve roots caused Wallerian degeneration not only at the site of compression of nerve roots but also at the synapses of spinal cord dorsal horns..
The number of MitoSox positive dorsal horn neurons was increased significantly after capsaicin treatment. This study suggests that ROS mediates the development and maintenance of capsaicin-induced hyperalgesia in mice, mainly through central sensitization and that the elevation of spinal ROS is most likely due to increased production of mitochondrial superoxides in the dorsal horn neurons..
Immunohistochemistry results showed that the increase in phospho-ERK1/2 expression occurred at the region of the superficial dorsal horn and grey commisure of the spinal cord.
We examined the possibility of a differential spatial control in the endogenous production of 3alpha5alpha-reduced steroids and its consequences on GABA(A) receptor-mediated miniature IPSCs (mIPSCs) in laminas II and III-IV of the rat spinal cord dorsal horn (DH).
Compared to exuberant synovial hypertrophy and inflammatory cell infiltration seen in arthritic rats treated with CFA only or CFA and HSV-beta-gal, the CFA- and HSV-ENK-treated arthritic rats had: (i) striking preservation of synovial membrane cytoarchitecture with minimal inflammatory cell infiltrates; (ii) significantly improved nociceptive behavioural responses to mechanical and thermal stimuli; (iii) normalized Fos staining in lumbar dorsal horn; and (iv) significantly increased met-ENK staining in ipsilateral synovial tissue, lumbar DRG and spinal cord.
Double labelling with the neuronal marker, NeuN, showed that PNNs were present surrounding approximately 30% of motoneurons in the ventral horn, 50% of large interneurons in the intermediate grey and 20% of neurons in the dorsal horn.
NNLA treatment effectively reduced nNOS-IR in both the dorsal horn and the dorsal column, and decreased Ca2+-dependent NOS activity in the lower lumbar segments.
Intrathecal administration of the neurotoxin for IB4-positive nociceptors, IB4-saporin, markedly attenuated IB4 staining in the dorsal horn of the spinal cord and completely prevented oxaliplatin-induced hyperalgesia.
Mice receiving saline exhibited punctate expression of both eGFP (GLT-1 promoter activation) and DsRed (GLAST promoter activation) in the dorsal horn of the spinal cord, which was decreased ipsilateral to nerve injury on day 12. Propentofylline administration reinstated promoter activation on the injured side as evidenced by an equal number of eGFP (GLT-1) and DsRed (GLAST) puncta in both dorsal horns.
Although repetitive stimuli applied to the dorsal root did not induce any slow responses, ones focally applied to the spinal dorsal horn produced slow inhibitory postsynaptic currents (IPSCs) at a holding potential of -50 mV in about 30% of the SG neurones recorded.
In this study, we evaluated whether propentofylline, a methylxanthine derivative, modulates spinal glial activation and GABAergic inhibitory tone by modulation of glutamic acid decarboxylase (GAD)(65), the GABA synthase enzyme, in the spinal dorsal horn following spinal cord injury (SCI). Western blotting and immunohistochemical data demonstrated that the expression level of GAD(65) protein significantly decreased on both sides of the lumbar dorsal horn (L4/5) after SCI (p<0.05). In addition, astrocytes and microglia showed soma hypertrophy as determined by increased soma area and increased GFAP and CD11b on both sides of the lumbar dorsal horn compared to sham controls, respectively (p<0.05). treatment of PPF significantly prevented the decrease of GAD(65) expression in both sides of the lumbar dorsal horn following SCI (p<0.05).
RESULTS: Double labeling studies of SSeCKS with CNPase in the dorsal horn and Pzero in the periphery showed that SSeCKS immunoreactivity was observed predominantly in association with unmyelinated primary sensory fibers. In capsaicin treated rats, SSeCKS immunoreactivity was essentially obliterated in the dorsal horn while in dorsal root ganglia quantitative analysis revealed a 43% reduction in the number of SSeCKS-labeled cells. This attenuation is concomitant with a decrease in fluoride-resistant acid phosphatase labeled fibers in the spinal cord dorsal horn and small neuronal somata in sensory ganglia.
After 2 h of intermittent electrical stimulation of the hind paw of the rat, the number of Fos immunoreactive (Fos-IR) neurons in the dorsal horn was measured quantitatively.
Our hypothesis in this study was that a deep thoracic incision causes COX-1 and COX-2 upregulation in the dorsal horn coincident with pain-related behavior, and that specific cell types contribute to this increase in COX expression. There was an increase in both COX-1 and COX-2 immunoreactivity in the thoracic dorsal horn at 4 h postsurgery on the ipsilateral side of surgery animals compared to the ipsilateral side of control animals, contralateral side of surgery animals or contralateral side of control animals. CONCLUSIONS: A unilateral deep thoracic wound produces pain-related behavior and, at the same time, ipsilateral upregulation of microglial COX-1 and neuronal COX-2 in the thoracic dorsal horn..
Formalin-induced c-Fos expression could be dose-dependently inhibited by BmK AS in superficial (I-II), the nucleus proprius (III and IV) and deep (V-VI) dorsal horn laminae, but not in the ventral gray laminae (VII-X) of lumbar spinal cord.
Adrenergic alpha2C receptors are present in opioid-containing terminals in the dorsal horn, where they could modulate opioid release. Opioid release was evoked from rat spinal cord slices by incubating them with the sodium channel opener veratridine in the presence of peptidase inhibitors (actinonin, captopril and thiorphan), and was measured in situ through the internalization of mu-opioid receptors in dorsal horn neurons. These results show that alpha2C receptors inhibit the release of opioids in the dorsal horn.
CONCLUSION: Using proteomic analysis, we identified eight GFAP protein spots that were up-regulated in the dorsal horn of morphine-tolerant rat spinal cords.
It is widely thought that, after peripheral injury, some low-threshold mechanoreceptive (LTMR) afferents "sprout" into pain-specific laminae (I-II) of the dorsal horn and are responsible for chronic pain states such as mechanical allodynia. Here we show that, in the thoracic spinal cord of naïve adult mouse, all myelinated nociceptors gave rise to terminal projections throughout the superficial dorsal horn laminae (I-II). Most (70%) of these fibers had large-diameter axons with recurving flame-shaped central arbors that projected throughout the dorsal horn laminae I-V. After peripheral nerve axotomy, we found that LTMR afferents with narrow, uninflected somal action potentials did not sprout into superficial laminae of the dorsal horn.
About 40% of the MPTA neurons that project to the lumbar spinal cord also have collaterals at cervical levels, and about 60% of those with projections to the ventral horn also have projections to the dorsal horn (at cervical levels).
On the other hand, no NPFF-ir cells could be detected in the septal region and dorsal horn of the spinal cord in Pseudemys.
Induction of Fos protein was used to localize spinal dorsal horn and hypothalamic neurons activated by noxious heating of the hind paw dorsum at rates known to preferentially activate C- or A-heat nociceptors. The majority of dorsal horn heat-activated neurons were located in laminae I and II.
It was found that ERK was activated not only in the superficial layers but also in deep layers of L4-L5 spinal cord dorsal horn, which started at 2 min, peaked at 30-60 min and almost disappeared at 4h following intraplantar injection of BmK venom. Thus, activation of ERK in spinal cord dorsal horn, partially mediated by NMDA and non-NMDA receptor, potentially contributes to BmK venom-induced pain-related behaviors..
The effect of the non-selective, 1-aminoindan-1,5-dicarboxylic acid (AIDA), and selective (3,4-dihydro-2H-pyrano[ 2,3-b]quinolin-7-yl)-(cis-4-methoxycyclohexyl) methanone (JNJ16259685), metabotropic glutamate subtype 1 (mGlu1) receptor antagonists, on rat sciatic nerve chronic constrictive injury (CCI)-induced hyperalgesia, allodynia, spinal dorsal horn apoptosis, and gliosis was examined at 3 and 7 days post-injury. RT-PCR analysis showed increased expression of bax, apoptotic protease-activating factor-1 (apaf-1), nestin, GFAP, and caspase-7 mRNA in the dorsal horn spinal cord by 3 days post-CCI. We report here that despite inhibiting CCI-induced over-expression of pro-apoptotic genes in the spinal cord dorsal horn, the selective mGlu1 receptor antagonist JNJ16259685 exerted only a slight and transient allodynic effect.
The increased expression is predominately located in the medium- and small-sized DRG neurons, the superficial layers of spinal dorsal horn (DH) neurons, and the IB4 positive nociceptive terminals.
Immunohistochemical labeling of sensory afferents in the spinal cord dorsal horn showed prevention of the reduction in expression of substance P at one month postlesion in group ES.
However, in dorsal horn, the mRNA and protein for SSeCKS expression were significantly increased at 1 day for its mRNA level and 3 days for its protein level, and then gradually declined to the baseline level, ultimately up-regulated again from 7 to 14 days.
RESULTS: Both mechanical and chemical stimulus to the ipsilateral masseter induced increasing neuronal c-fos expression in the trigeminal nucleus and in the cervical spinal dorsal horn in occlusal interference and mechanical stimulus group and occlusal interference and chemical stimulus group (P < 0.05).
The substantia gelatinosa (SG) of the dorsal horn of the spinal cord is a recipient zone for unmyelinated sensory neurons in adults.
These beneficial effects of GA immunization therapy coincided with the attenuation of expression of the chemotactic fractalkine chemokine (CX3CL1) in the dorsal horn of the lumbar spinal cord (L4-L5) in response to CFA treatment, assessed by DNA microarray and confirmed immunocytochemically (ICC).
Peripheral capsaicin treatment induces molecular changes that sensitize the responses of nociceptive neurons in the spinal dorsal horn.
Nerve injury induced a striking increase in the expression of TAK1 in the ipsilateral dorsal horn, and TAK1 was increased in hyperactive astrocytes, but not in neurons or microglia.
Previous evidence suggests that dorsal horn neurons with ascending projections may be more susceptible to depression by general anesthetics than local spinal interneurons. In this study we evaluated the effects of volatile and injectable general anesthetics on lumbar dorsal horn neurons with and without ascending projections. METHODS: Thirty-seven adult male rats underwent laminectomies at C1, for placement of a stimulating electrode, and T13/L1, for extracellular recording from the spinal cord dorsal horn. CONCLUSIONS: Our findings suggest, at peri-MAC concentrations, these general anesthetics do not preferentially depress lumbar dorsal horn neurons with ascending projections compared to those with no identifiable ascending projections..
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