PubMed Health⌕ Search

Biomedical subjects

Jürgen Sandkühler

Publications and source records attributed to Jürgen Sandkühler.

At least 19 recordsLinked to original sources
PubMed2007

Xenon blocks the induction of synaptic long-term potentiation in pain pathways in the rat spinal cord in vivo.

BACKGROUND: Xenon's (Xe) mechanisms for producing anesthesia and analgesia are not fully understood. We tested the effect of Xe equilibrated in a lipid formulation or normal saline on spinal C-fiber-evoked potentials and on the induction of synaptic long-term potentiation (LTP). METHODS: C-fiber-evoked field potentials were recorded in the superficial lumbar spinal cord in response to supramaximal electrical stimulation of the sciatic nerve. Anesthesia was maintained with isoflurane in one-third O2 and two-thirds N2O. Xe equilibrated at a concentration of 600 microL/mL of Lipofundin MCT(R) 20%, (n = 5) or solvent alone (n = 3), and Xe equilibrated at a concentration of 100 microL/mL of normal saline (n = 7) or saline alone (n = 7) was given IV under apnea. High-frequency stimulation of the sciatic nerve was applied 60 min after the injection of Xe-containing formulations or solvents [to induce LTP]. RESULTS: High-frequency stimulation potentiated C-fiber-evoked potentials to 156% +/- 14% (mean +/- sem) of control. Low-dose Xe in saline 0.9% blocked the induction of LTP. High-dose Xe equilibrated in MC(R) 20% showed no additional effect when compared with the solvent, which blocked the induction of LTP. CONCLUSION: Low-dose Xe in saline 0.9% revealed no antinociceptive, but preventive, action in spinal pain pathways.

Animals↗
PubMed2006

Group I metabotropic glutamate receptor-induced Ca(2+)-gradients in rat superficial spinal dorsal horn neurons.

Here, we investigated changes in the free cytosolic Ca(2+) concentration ([Ca(2+)](i)), induced by the pharmacological activation of metabotropic glutamate receptors (mGluRs), in nociceptive neurons of the superficial spinal dorsal horn. Microfluorometric Ca(2+) measurements with fura-2 in a lumbar spinal cord slice preparation from young rats were used. Bath application of the specific group I mGluR agonist (S)-3,5-dihydroxyphenylglycine ((S)-3,5-DHPG) resulted in a distinct increase of [Ca(2+)](i) in most of the neurons in superficial dorsal horn. In contrast, activation of groups II or III mGluRs by DCG-IV or l-AP4, respectively, failed to evoke any significant change in [Ca(2+)](i). The effect of (S)-3,5-DHPG was mediated by both group I subtypes mGluR1 and mGluR5, since combined pre-treatment with the subtype antagonists (S)-4-CPG and MPEP was necessary to abolish the [Ca(2+)](i) increase. Depleting intracellular Ca(2+) stores with CPA or inhibiting IP(3)-receptors with 2-APB, respectively, reduced the (S)-3,5-DHPG-evoked [Ca(2+)](i) increase significantly. Inhibition of voltage-dependent L-type Ca(2+) channels (VDCCs) by verapamil or nicardipine reduced the (S)-3,5-DHPG-induced [Ca(2+)](i) rise likewise. Thus, in rat spinal cord, (S)-3,5-DHPG enhances Ca(2+) signalling in superficial dorsal horn neurons, mediated by the release of Ca(2+) from IP(3)-sensitive intracellular stores and by an influx through L-type VDCCs. This may be relevant to the processing of nociceptive information in the spinal cord.

Analysis of Variance↗
PubMed2006

Effects of the NMDA-receptor antagonist ketamine on perceptual correlates of long-term potentiation within the nociceptive system.

We recently reported perceptual correlates of long-term potentiation (LTP) of synaptic strength within the nociceptive system demonstrating the functional relevance of LTP for human pain sensation. LTP is generally classified as NMDA-receptor dependent or independent. Here we show that low doses of the NMDA-receptor antagonist ketamine (0.25 mg/kg) prevented the long-term increase in perceived pain to electrical test stimuli, which was induced by high-frequency electrical stimulation (HFS) of nociceptive afferents. Whereas in a control experiment HFS led to a stable increase in perceived pain by 51% for the entire observation period of 1h HFS given 4 min after i.v. ketamine was ineffective. In contrast, HFS induced a two-fold increase of pinprick-evoked pain surrounding the HFS site (secondary neurogenic hyperalgesia) in both experiments. Pain evoked by light tactile stimuli (allodynia) was also unaffected by ketamine. These data support the concept that homotopic hyperalgesia to electrical stimulation of the conditioned pathway is a perceptual correlate of NMDA-receptor sensitive homosynaptic LTP in the nociceptive system, e.g. in the spinal cord. Although secondary neurogenic hyperalgesia and allodynia are induced by the same HFS protocol, they involve additional NMDA-receptor insensitive mechanisms of heterosynaptic facilitation.

Adult↗
PubMed2006

Physiological properties of spinal lamina II GABAergic neurons in mice following peripheral nerve injury.

Aberrant GABAergic inhibition in spinal dorsal horn may underlie some forms of neuropathic pain. Potential, but yet unexplored, mechanisms include reduced excitability, abnormal discharge patterns or altered synaptic input of spinal GABAergic neurons. To test these hypotheses, we quantitatively compared active and passive membrane properties, firing patterns in response to depolarizing current steps and synaptic input of GABAergic neurons in spinal dorsal horn lamina II of neuropathic and of control animals. Transgenic mice were used which expressed enhanced green fluorescent protein (EGFP) controlled by the GAD67 promoter, thereby labelling one-third of all spinal GABAergic neurons. In all neuropathic mice included in this study, chronic constriction injury of one sciatic nerve led to tactile allodynia and thermal hyperalgesia. Control mice were sham-operated. Membrane excitability of GABAergic neurons from neuropathic or sham-treated animals was indistinguishable. The most frequent firing patterns observed in neuropathic and sham-operated animals were the initial burst (neuropathic: 46%, sham-treated: 42%), the gap (neuropathic: 31%, sham-treated: 29%) and the tonic firing pattern (neuropathic: 16%, sham-treated: 24%). The synaptic input from dorsal root afferents was similar in neuropathic and in control animals. Thus, a reduced membrane excitability, altered firing patterns or changes in synaptic input of this group of GABAergic neurons in lamina II of the spinal cord dorsal horn are unlikely causes for neuropathic pain.

Animals↗
PubMed2006

Synaptic amplifier of inflammatory pain in the spinal dorsal horn.

Inflammation and trauma lead to enhanced pain sensitivity (hyperalgesia), which is in part due to altered sensory processing in the spinal cord. The synaptic hypothesis of hyperalgesia, which postulates that hyperalgesia is induced by the activity-dependent long-term potentiation (LTP) in the spinal cord, has been challenged, because in previous studies of pain pathways, LTP was experimentally induced by nerve stimulation at high frequencies ( approximately 100 hertz). This does not, however, resemble the real low-frequency afferent barrage that occurs during inflammation. We identified a synaptic amplifier at the origin of an ascending pain pathway that is switched-on by low-level activity in nociceptive nerve fibers. This model integrates known signal transduction pathways of hyperalgesia without contradiction.

Animals↗
PubMed2005

Signal transduction pathways of group I metabotropic glutamate receptor-induced long-term depression at sensory spinal synapses.

Activation of spinal group I metabotropic glutamate receptors (mGluRs) may have antinociceptive or pro-nociceptive effects in different pain models. Pharmacological activation of group I mGluRs leads to long-term depression (LTD) of synaptic strength between Adelta-fibers and neurons in lamina II of spinal dorsal horn of the rat. Here, we studied the signal transduction pathways involved. Synaptic strength between Adelta-fibers and lamina II neurons was assessed by perforated whole-cell patch-clamp recordings in a spinal cord-dorsal root slice preparation of young rats. Bath application of the specific group I mGluR agonist (S)-3,5-dihydroxyphenylglycine [(S)-3,5-DHPG] produced an LTD of Adelta-fiber-evoked responses. LTD induction by (S)-3,5-DHPG was prevented, when intracellular Ca(2+) stores were depleted by thapsigargin or cyclopiazonic acid (CPA). Preincubation with ryanodine to inhibit Ca(2+)-induced Ca(2+) release had no effect on LTD-induction by (S)-3,5-DHPG. In contrast, pretreatment with 2-aminoethoxydiphenyl borate (2-APB), an inhibitor of inositol-1,4,5-trisphosphate (IP(3))-sensitive Ca(2+) stores prevented LTD induction. Preincubation with the specific protein kinase C (PKC) inhibitors bisindolylmaleimide I (BIM) or chelerythrine, respectively, had no effect. Inhibition of L-type VDCCs by verapamil or nifedipine prevented LTD-induction by (S)-3,5-DHPG. The presently identified signal transduction cascade may be relevant to the long-term depression of sensory information in the spinal cord, including nociception.

Animals↗
PubMed2005

Synaptic input of rat spinal lamina I projection and unidentified neurones in vitro.

Spinal lamina I projection neurones that transmit nociceptive information to the brain play a pivotal role in hyperalgesia in various animal models of inflammatory and neuropathic pain. Consistently, activity-dependent long-term potentiation can be induced at synapses between primary afferent C-fibres and lamina I projection neurones but not unidentified neurones in lamina I. The specific properties that enable projection neurones to undergo long-term potentiation and mediate hyperalgesia are not fully understood. Here, we have tested whether lamina I projection neurones differ from unidentified neurones in types or strength of primary afferent input and/or action potential-independent excitatory and inhibitory input. We used the whole-cell patch-clamp technique to record synaptic currents in projection and unidentified lamina I neurones in a transverse lumbar spinal cord slice preparation from rats between postnatal day 18 and 37. Lamina I neurones with a projection to the parabrachial area or the periaqueductal grey were identified by retrograde labelling with a fluorescent tracer. The relative contribution of NMDA receptors versus AMPA/kainate receptors to C-fibre-evoked excitatory postsynaptic currents of lamina I neurones significantly decreased with age between postnatal day 18 and 27, but was independent of the supraspinal projection of the neurones. We did not find a significant contribution of kainate receptors to C-fibre-evoked excitatory postsynaptic currents. Lamina I projection and unidentified neurones possessed functional GABAA and glycine receptors but received scarce action potential-independent spontaneous GABAergic and glycinergic inhibitory input as measured by miniature inhibitory postsynaptic currents. The miniature excitatory postsynaptic current frequencies were five times higher in projection than in unidentified neurones. The predominance of excitatory synaptic input to projection neurones, taken together with the previous finding that their membranes are more easily excitable than those of unidentified neurones, may facilitate the induction of synaptic long-term potentiation.

Action Potentials↗
PubMed2005

Opioids and central sensitisation: I. Preemptive analgesia.

Opioids are powerful analgesics when used to treat acute pain and some forms of chronic pain. A large body of literature has shown that opioids can, in addition, also prevent (this review) or induce and perhaps reverse, some forms central sensitisation in in vitro and in vivo animal models of pain. However, the concept of central sensitisation is, at present, ambiguous and the usefulness of opioids as preemptive analgesics in human pain patients is still not clear.

Analgesics, Opioid↗
PubMed2005

Long-range oscillatory Ca2+ waves in rat spinal dorsal horn.

Synchronous activity of large populations of neurons shapes neuronal networks during development. However, re-emergence of such activity at later stages of development could severely disrupt the orderly processing of sensory information, e.g. in the spinal dorsal horn. We used Ca2+ imaging in spinal cord slices of neonatal and young rats to assess under which conditions synchronous activity occurs in dorsal horn. No spontaneous synchronous Ca2+ transients were detected. However, increasing neuronal excitability by application of 4-aminopyridine after pretreatment of the slice with blockers of (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate, gamma-aminobutyric acid (GABA)(A) and glycine receptors evoked repetitive Ca2+ waves in dorsal horn. These waves spread mediolaterally with a speed of 1.0 +/- 0.1 mm/s and affected virtually every dorsal horn neuron. The Ca2+ waves were associated with large depolarizing shifts of the membrane potential of participating neurons and were most likely synaptically mediated because they were abolished by blockade of action potentials or N-methyl-D-aspartate (NMDA) receptors. They were most pronounced in the superficial dorsal horn and absent from the ventral horn. A significant proportion of the Ca2+ waves spread to the contralateral dorsal horn. This seemed to be enabled by disinhibition as primary afferent-induced dorsal horn excitation crossed the midline only when GABA(A) and glycine receptors were blocked. Interestingly, the Ca2+ waves occurred under conditions where AMPA/kainate receptors were blocked. Thus, superficial dorsal horn NMDA receptors are able to sustain synchronous neuronal excitation in the absence of functional AMPA/kainate receptors.

4-Aminopyridine↗
PubMed2004

Physiological, neurochemical and morphological properties of a subgroup of GABAergic spinal lamina II neurones identified by expression of green fluorescent protein in mice.

The processing of sensory, including nociceptive, information in spinal dorsal horn is critically modulated by spinal GABAergic neurones. For example, blockade of spinal GABA(A) receptors leads to pain evoked by normally innocuous tactile stimulation (tactile allodynia) in rats. GABAergic dorsal horn neurones have been classified neurochemically and morphologically, but little is known about their physiological properties. We used a transgenic mouse strain coexpressing enhanced green fluorescent protein (EGFP) and the GABA-synthesizing enzyme GAD67 to investigate the properties of a subgroup of GABAergic neurones. Immunohistochemistry showed that EGFP-expressing neurones accounted for about one-third of the GABAergic neurones in lamina II of the spinal dorsal horn. They constituted a neurochemically rather heterogeneous group where 27% of the neurones coexpressed glycine, 23% coexpressed parvalbumin and 14% coexpressed neuronal nitric oxide synthase (nNOS). We found almost no expression of protein kinase Cgamma (PKCgamma) in EGFP-labelled neurones but a high costaining with PKCbetaII (78%). The whole-cell patch-clamp technique was used to intracellularly label and physiologically characterize EGFP- and non-EGFP-expressing lamina II neurones in spinal cord slices. Sixty-two per cent of the EGFP-labelled neurones were islet cells while the morphology of non-EGFP-labelled neurones was more variable. When stimulated by rectangular current injections, EGFP-expressing neurones typically exhibited an initial bursting firing pattern while non-EGFP-expressing neurones were either of the gap or the delayed firing type. EGFP-expressing neurones received a greater proportion of monosynaptic input from the dorsal root, especially from primary afferent C-fibres. In conclusion, EGFP expression defined a substantial but, with respect to the measured parameters, rather inhomogeneous subgroup of GABAergic neurones in spinal lamina II. These results provide a base to elucidate the functional roles of this subgroup of GABAergic lamina II neurones, e.g. for nociception.

Action Potentials↗
PubMed2004

Perceptual correlates of nociceptive long-term potentiation and long-term depression in humans.

Long-term potentiation (LTP) and long-term depression (LTD) of synaptic strength are ubiquitous mechanisms of synaptic plasticity, but their functional relevance in humans remains obscure. Here we report that a long-term increase in perceived pain to electrical test stimuli was induced by high-frequency electrical stimulation (HFS) (5 x 1 sec at 100 Hz) of peptidergic cutaneous afferents (27% above baseline, undiminished for >3 hr). In contrast, a long-term decrease in perceived pain (27% below baseline, undiminished for 1 hr) was induced by low-frequency stimulation (LFS) (17 min at 1 Hz). Pain testing with punctate mechanical probes (200 microm diameter) in skin adjacent to the HFS-LFS conditioning skin site revealed a marked twofold to threefold increase in pain sensitivity (secondary hyperalgesia, undiminished for >3 hr) after HFS but also a moderate secondary hyperalgesia (30% above baseline) after strong LFS. Additionally, HFS but not LFS caused pain to light tactile stimuli in adjacent skin (allodynia). In summary, HFS and LFS stimulus protocols that induce LTP or LTD in spinal nociceptive pathways in animal experiments led to similar LTP- and LTD-like changes in human pain perception (long-term hyperalgesia or hypoalgesia) mediated by the conditioned pathway. Additionally, secondary hyperalgesia and allodynia in adjacent skin induced by the HFS protocol and, to a minor extent, also by the LFS protocol, suggested that these perceptual changes encompassed an LTP-like heterosynaptic facilitation of adjacent nociceptive pathways by a hitherto unknown mechanism.

Adult↗
PubMed2004

Low doses of fentanyl block central sensitization in the rat spinal cord in vivo.

BACKGROUND: mu-Opioid receptor agonists are strong analgesics. However, their usefulness for preemptive analgesia is controversial. The authors tested antinociceptive and preemptive properties of fentanyl as a mu-opioid receptor agonist in a model of spinal nociception in vivo. METHODS: C fiber-evoked potentials were recorded in the superficial laminae I-II of the rat lumbar spinal cord with glass microelectrodes in response to electrical stimulation of the sciatic nerve. High-frequency stimulation was applied on the sciatic nerve to induce long-term potentiation of C fiber-evoked field potentials, a form of central sensitization. To test the effect of fentanyl on acute nociception, fentanyl was infused intravenously at increasing doses (6-192 microg.kg(-1).h(-1)). One hour after start of infusion, high-frequency stimulation was applied to evaluate effects of fentanyl on the induction of long-term potentiation. RESULTS: In the absence of fentanyl, high-frequency stimulation potentiated C fiber-evoked field potentials to 149 +/-12% of controls (mean +/-SEM; n = 6) for at least 1 h. Increasing doses of fentanyl led to a significant reduction of C fiber-evoked potentials in a dose-dependent manner. The induction of long-term potentiation was blocked by low doses of fentanyl (infusion 12-48 microg.kg(1).h(-1)). At high doses, fentanyl did not block the induction of long-term potentiation (infusion 96-192 microg.kg(-1).h(-1)). CONCLUSIONS: : Low doses of fentanyl block the synaptic form of central sensitization in the rat spinal cord in vivo, but higher doses do not have this effect.

Animals↗
PubMed2003

Distinctive membrane and discharge properties of rat spinal lamina I projection neurones in vitro.

Most lamina I neurones with a projection to the brainstem express the neurokinin 1 receptor and thus belong to a small subgroup of lamina I neurones that are necessary for the development of hyperalgesia in rat models of persisting pain. These neurones are prone to synaptic plasticity following primary afferent stimulation in the noxious range while other nociceptive lamina I neurones are not. Here, we used whole-cell patch-clamp recordings from lamina I neurones in young rat spinal cord transverse slices to test if projection neurones possess membrane properties that set them apart from other lamina I neurones. Neurones with a projection to the parabrachial area or the periaqueductal grey (PAG) were identified by retrograde labelling with the fluorescent tracer DiI. The properties of lamina I projection neurones were found to be fundamentally different from those of unidentified, presumably propriospinal lamina I neurones. Two firing patterns, the gap and the bursting firing pattern, occurred almost exclusively in projection neurones. Most spino-parabrachial neurones showed the gap firing pattern while the bursting firing pattern was characteristic of spino-PAG neurones. The underlying membrane currents had the properties of an A-type K(+) current and a Ca(2+) current with a low activation threshold, respectively. Projection neurones, especially those of the burst firing type, were more easily excitable than unidentified neurones and received a larger proportion of monosynaptic input from primary afferent C-fibres. Intracellular labelling with Lucifer yellow showed that projection neurones had larger somata than unidentified neurones and many had a considerable extension in the mediolateral plane.

Animals↗
PubMed2003

Partial correlation analysis for the identification of synaptic connections.

In this paper, we investigate the use of partial correlation analysis for the identification of functional neural connectivity from simultaneously recorded neural spike trains. Partial correlation analysis allows one to distinguish between direct and indirect connectivities by removing the portion of the relationship between two neural spike trains that can be attributed to linear relationships with recorded spike trains from other neurons. As an alternative to the common frequency domain approach based on the partial spectral coherence we propose a new statistic in the time domain. The new scaled partial covariance density provides additional information on the direction and the type, excitatory or inhibitory, of the connectivities. In simulation studies, we investigated the power and limitations of the new statistic. The simulations show that the detectability of various connectivity patterns depends on various parameters such as connectivity strength and background activity. In particular, the detectability decreases with the number of neurons included in the analysis and increases with the recording time. Further, we show that the method can also be used to detect multiple direct connectivities between two neurons. Finally, the methods of this paper are illustrated by an application to neurophysiological data from spinal dorsal horn neurons.

Action Potentials↗
PubMed2003

Induction of long-term potentiation of C fibre-evoked spinal field potentials requires recruitment of group I, but not group II/III metabotropic glutamate receptors.

In superficial layers of the lumbar spinal dorsal horn, N-methyl-D-aspartate-dependent long-term potentiation (LTP) of C fibre-evoked field potentials, a synaptic model of central sensitisation and hyperalgesia, ensues the application of electrical high-frequency, high-intensity conditioning stimulation to the sciatic nerve. In order to investigate the putative involvement of the G protein-coupled metabotropic glutamate receptors (mGluRs) in the induction of this form of LTP, we applied a series of mGluR antagonists exhibiting distinct group-specific activity profiles to the spinal lumbar enlargement, prior to conditioning stimulation. The group I (mGluR1/5) and group II (mGluR2/3) mGluR antagonist (S)-alpha-methyl-4-carboxyphenylglycine or the selective mGluR1/5 antagonist (S)-4-carboxyphenylglycine consistently impaired the development of spinal LTP. However, potentiation occurred in the presence of the inactive enantiomer (R)-alpha-methyl-4-carboxyphenylglycine. LTP proved insensitive to the selective mGluR2/3 antagonists (2S)-alpha-ethylglutamic acid and LY341495, either spinally or intravenously delivered. LTP could also be induced in the presence of the selective group III (mGluR4/mGluR6-mGluR8) mGluR antagonist (RS)-alpha-methylserine-O-phosphate. However, none of the mGluR-active compounds alone noticeably altered the amplitudes of C fibre-evoked field potentials in the absence of conditioning stimulation. These findings suggest that the induction of LTP of C fibre-evoked field potentials in the spinal dorsal horn by high-frequency, high-intensity stimulation of afferent C fibres requires a group-specific mGluR recruitment, activation of mGluR1/5 but not that of mGluR4/6-8 and mGluR2/3 being a requisite step.

Action Potentials↗
PubMed2003

Epileptiform activity in rat spinal dorsal horn in vitro has common features with neuropathic pain.

Neuropathic pain and epileptic seizures bear several similarities, among them is the response to anticonvulsant drugs. It has therefore been hypothesized that epileptiform activity of nociceptive spinal dorsal horn neurons may contribute to paroxysmal forms of neuropathic pain. We used patch-clamp and field potential recordings from young rat spinal cord slices to test if nociceptive dorsal horn structures are indeed able to sustain epileptiform activity. Application of the convulsant 4-aminopyridine (100 microM) evoked epileptiform activity that was most pronounced in superficial dorsal horn and involved nociceptive lamina I neurons with a projection to the brain. The epileptiform activity was dependent on fast excitatory and inhibitory synaptic transmission through ionotropic glutamate receptors and GABA(A) receptors. During epileptiform activity, previously silent polysynaptic pathways from primary afferent C-fibers to superficial dorsal horn neurons were opened. Stimulation of primary afferents at Adelta- and C-fiber intensity interfered with the epileptiform rhythm, suggesting that both affect the same dorsal horn structures. Similar to neuropathic pain, spinal dorsal horn epileptiform activity was much less reduced by classical analgesics than by anticonvulsant agents.

4-Aminopyridine↗