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Biomedical subjects

H G Schaible

Publications and source records attributed to H G Schaible.

At least 19 recordsLinked to original sources
PubMed2007

Peripheral and central mechanisms of pain generation.

Pain research has uncovered important neuronal mechanisms that underlie clinically relevant pain states such as inflammatory and neuropathic pain. Importantly, both the peripheral and the central nociceptive system contribute significantly to the generation of pain upon inflammation and nerve injury. Peripheral nociceptors are sensitized during inflammation, and peripheral nerve fibres develop ectopic discharges upon nerve injury or disease. As a consequence a complex neuronal response is evoked in the spinal cord where neurons become hyperexcitable, and a new balance is set between excitation and inhibition. The spinal processes are significantly influenced by brain stem circuits that inhibit or facilitate spinal nociceptive processing. Numerous mechanisms are involved in peripheral and central nociceptive processes including rapid functional changes of signalling and long-term regulatory changes such as up-regulation of mediator/receptor systems. Conscious pain is generated by thalamocortical networks that produce both sensory discriminative and affective components of the pain response.

Afferent Pathways↗
PubMed2002

[Neuroendocrine-immunologic mechanisms in rheumatic diseases--a congress report].

Neuro-endocrine immune mechanisms play an important immunomodulatory role for rheumatic diseases as evidenced by long-recognized effects of glucocorticoids, gender, pregnancy, hemiparalysis, and stress on various clinical and epidemiological aspects. Recently, some regulatory pathways have been identified between the neuroendocrine and immune systems which seem to be altered in these diseases. Cooperation between the autonomic nervous system and the hypothalamic pituitary adrenal axis (HPA axis) is important to dampen the reaction of the immune system. In chronic inflammatory diseases such as rheumatic diseases these systems have become deficient. Moreover, hyperexcitability of sensory nerves due to peripheral and central neuronal sensitization can support the local inflammatory process.

Arousal↗
PubMed2001

Spinal prostaglandins are involved in the development but not the maintenance of inflammation-induced spinal hyperexcitability.

Prostaglandins (PGs) are local mediators of several functions in the CNS. Both primary afferent neurons and intrinsic cells in the spinal cord produce PGs, with a marked upregulation during peripheral inflammation. Therefore, the significance of spinal PGs in the neuronal processing of mechanosensory information was herein investigated. In anesthetized rats, the discharges of spinal nociceptive neurons with input from the knee joint were extracellularly recorded. Topical administration of prostaglandin E(2) (PGE(2)) to the spinal cord facilitated the discharges and expanded the receptive field of dorsal horn neurons to innocuous and noxious pressure applied to the knee joint, the ankle, and the paw, thus mimicking inflammation-induced central sensitization. Conversely, topical administration of the PG synthesis inhibitor indomethacin to the spinal cord before and during development of knee joint inflammation attenuated the generation of inflammation-induced spinal neuronal hyperexcitability. However, after development of inflammation, the responses of spinal neurons to mechanical stimuli were only reduced by systemic indomethacin but not by indomethacin applied to the spinal cord. Thus, spinal PG synthesis is important for the induction and initial expression but not for the maintenance of spinal cord hyperexcitability. Spinal PGE(2) application facilitated dorsal horn neuronal firing elicited by ionophoretic delivery of NMDA, suggesting that an interaction of PGs and NMDA receptors may contribute to inflammation-induced central sensitization. However, after development of inflammation, spinal indomethacin failed to reduce responses to ionophoretic delivery of NMDA or AMPA, suggesting that such an interaction is not required for the maintenance of central sensitization.

Action Potentials↗
PubMed2001

Effect of brain-derived neurotrophic factor on the release of substance P from rat spinal cord.

Brain-derived neurotrophic factor (BDNF) can produce hyperalgesia in the adult rat. Here we assessed whether changes in the spinal release of the nociceptive peptide substance P (SP) contributes to this effect. Antibody-coated microprobes revealed a significant basal release of SP in the dorsal horn in vivo that was increased following acute knee inflammation. Microinjection of BDNF into the grey matter (0.5 microl, 10(-5) M) altered SP release neither in rats with normal knees nor in rats with inflamed knee joints. In the lumbar dorsal horn slice preparation in vitro, superfusion with BDNF (100 ng/ml) could reduce SP release evoked by electrical dorsal root stimulation without modyfing SP basal outflow. It is unlikely, therefore, that enhanced spinal SP release mediates the hyperalgesic effect of BDNF.

Animals↗
PubMed2001

Prostaglandins and cyclooxygenases [correction of cycloxygenases] in the spinal cord.

The spinal cord is one of the sites where non-steroidal anti-inflammatory drugs (NSAIDs) act to produce analgesia and antinociception. Expression of cyclooxygenase(COX)-1 and COX-2 in the spinal cord and primary afferents suggests that NSAIDs act here by inhibiting the synthesis of prostaglandins (PGs). Basal release of PGD(2), PGE(2), PGF(2alpha) and PGI(2) occurs in the spinal cord and dorsal root ganglia. Prostaglandins then bind to G-protein-coupled receptors located in intrinsic spinal neurons (receptor types DP and EP2) and primary afferent neurons (EP1, EP3, EP4 and IP). Acute and chronic peripheral inflammation, interleukins and spinal cord injury increase the expression of COX-2 and release of PGE(2) and PGI(2). By activating the cAMP and protein kinase A pathway, PGs enhance tetrodotoxin-resistant sodium currents, inhibit voltage-dependent potassium currents and increase voltage-dependent calcium inflow in nociceptive afferents. This decreases firing threshold, increases firing rate and induces release of excitatory amino acids, substance P, calcitonin gene-related peptide (CGRP) and nitric oxide. Conversely, glutamate, substance P and CGRP increase PG release. Prostaglandins also facilitate membrane currents and release of substance P and CGRP induced by low pH, bradykinin and capsaicin. All this should enhance elicitation and synaptic transfer of pain signals in the spinal cord. Direct administration of PGs to the spinal cord causes hyperalgesia and allodynia, and some studies have shown an association between induction of COX-2, increased PG release and enhanced nociception. NSAIDs diminish both basal and enhanced PG release in the spinal cord. Correspondingly, spinal application of NSAIDs generally diminishes neuronal and behavioral responses to acute nociceptive stimulation, and always attenuates behavioral responses to persistent nociception. Spinal application of specific COX-2 inhibitors sometimes diminishes behavioral responses to persistent nociception.

Animals↗
PubMed2001

Is there a correlation between spreading depression, neurogenic inflammation, and nociception that might cause migraine headache?

The time course of propagation of scotoma and blood flow changes during migraine aura parallels the phenomenon of cortical spreading depression (CSD). It was proposed that CSD generates a sterile neurogenic inflammation in the meninges, which may then lead to the activation or sensitization of nociceptors, thus generating headache. We performed rat experiments in which the effect of CSD on plasma extravasation in the dura mater and on neuronal activity in deep laminae of the trigeminal nucleus was assessed in vivo. CSD did not alter dural plasma extravasation measured by means of bovine serum albumin-coupled flourescein (n = 17 rats) compared to the CSD-free contralateral side. In an in vitro model, the application of KCl to the dura at concentrations extracellularly found during CSD did not alter the release of calcitonin gene-related peptide and prostaglandin E2 from the dura. In 33 rats, neither single CSDs nor a series of CSDs altered ongoing neuronal activity or mechanical and/or thermal sensitivity of the deeply located neurons to stimulation of their receptive fields in the dura mater. These results are at variance with data that showed increased c-Fos labeling in superficial laminae of the trigeminal nucleus following CSD. They do not suggest that CSD initiates migraine headache via neurogenic inflammation.

Animals↗
PubMed2000

Monoarticular antigen-induced arthritis leads to pronounced bilateral upregulation of the expression of neurokinin 1 and bradykinin 2 receptors in dorsal root ganglion neurons of rats.

STATEMENT OF FINDINGS: This study describes the upregulation of neurokinin 1 and bradykinin 2 receptors in dorsal root ganglion (DRG) neurons in the course of antigen-induced arthritis (AIA) in the rat knee. In the acute phase of AIA, which was characterized by pronounced hyperalgesia, there was a substantial bilateral increase in the proportion of lumbar DRG neurons that express neurokinin 1 receptors (activated by substance P) and bradykinin 2 receptors. In the chronic phase the upregulation of bradykinin 2 receptors persisted on the side of inflammation. The increase in the receptor expression is relevant for the generation of acute and chronic inflammatory pain.

Animals↗
PubMed2000

Differential effects of calcitonin gene-related peptide and calcitonin gene-related peptide 8-37 upon responses to N-methyl-D-aspartate or (R, S)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate in spinal nociceptive neurons with knee joint input in the rat.

Calcitonin gene-related peptide is involved in the spinal processing of nociceptive input from the knee joint and in the generation and maintenance of joint inflammation-evoked hyperexcitability of spinal cord neurons. The present study examined whether this peptide influences the excitation of nociceptive spinal cord neurons by agonists at the N-methyl-D-aspartate and the non-N-methyl-D-aspartate [(R, S)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)/kainate] receptors, both of which are essential for the excitation and hyperexcitability of spinal cord neurons. In anaesthetized rats extracellular recordings were made from dorsal horn neurons with knee input, and compounds were administered ionophoretically close to the neurons recorded. When calcitonin gene-related peptide was administered the responses of the neurons to the application of both N-methyl-D-aspartate and AMPA were increased. The coadministration of the antagonist calcitonin gene-related peptide 8-37 had no effect on the responses to N-methyl-D-aspartate, but it prevented the enhancement of the responses to N-methyl-D-aspartate by calcitonin gene-related peptide. By contrast, the administration of calcitonin gene-related peptide 8-37 enhanced the responses of the neurons to AMPA, and it did not antagonize but rather increased the effects of calcitonin gene-related peptide on these responses. The data suggest that the facilitatory role of calcitonin gene-related peptide on the development and maintenance of inflammation-evoked hyperexcitability is caused at least in part by the modulation of the activation of the dorsal horn neurons through their N-methyl-D-aspartate and non-N-methyl-D-aspartate receptors. The different effects of calcitonin gene-related peptide 8-37 on the respones to N-methyl-D-aspartate and AMPA suggest that different intracellular pathways may facilitate the activation of N-methyl-D-aspartate and ionotropic non-N-methyl-D-aspartate receptors.

Animals↗
PubMed2000

Inhibition of noxious stimulus-induced spinal prostaglandin E2 release by flurbiprofen enantiomers: a microdialysis study.

Peripheral noxious stimuli have been shown to induce prostaglandin (PG) E2 release at the site of inflammation and in the spinal cord. The antiinflammatory and antinociceptive effects of cyclooxygenase-inhibiting drugs are thought to depend on the inhibition of PG synthesis. R-Flurbiprofen, however, does not inhibit cyclooxygenase activity in vitro but still produces antinociceptive effects. To find out whether R-flurbiprofen acts via inhibition of spinal PG release, concentrations of PGE2 and flurbiprofen in spinal cord tissue were assessed by microdialysis. The catheter was transversally implanted through the dorsal horns of the spinal cord at level L4. R- and S-flurbiprofen (9 and 27 mg kg(-1), respectively) were administered intravenously 10-15 min before subcutaneous injection of formalin into the dorsal surface of one hindpaw. Flurbiprofen was rapidly distributed into the spinal cord with maximal concentrations after 30-45 min. Baseline PGE2 dialysate concentrations were 100.6 +/- 6.4 pg ml(-1) (mean +/- SEM). After formalin injection they rose about threefold with a maximum of 299.4 +/- 68.4 pg ml(-1) at 7.5 min. After approximately 1 h PGE2 levels returned to baseline. Both flurbiprofen enantiomers completely prevented the formalin-induced increase of spinal PGE2 release and reduced PGE2 concentrations below basal levels. S- and R-flurbiprofen at 9 mg kg(-1) produced a minimum of 15.8 +/- 5.2 and 27.7 +/- 14.9 pg ml(-1), respectively, and 27 mg kg(-1) S- and R-flurbiprofen resulted in 11.7 +/- 1.7 and 9.3 +/- 4.7 pg ml(-1), respectively. PGE2 levels remained at the minimum up to the end of the observation period at 5 h. When 27 mg kg(-1) R-flurbiprofen was injected intravenously without subsequent formalin challenge, baseline immunoreactive PGE2 concentrations were not affected. S-Flurbiprofen (27 mg kg(-1)), however, led to a moderate reduction (approximately 40%). The data suggest that antinociception produced by R-flurbiprofen is mediated at least in part by inhibition of stimulated spinal PGE2 release and support the current view that increased spinal PGE2 release significantly contributes to nociceptive processing.

Animals↗
PubMed2000

How do we manage chronic pain?

Pain is an important symptom of acute damage and chronic inflammatory diseases such as rheumatoid arthritis. This chapter briefly summarizes the neuronal mechanisms of the peripheral and central sensitization of nociceptive neurones which are thought to be important in the generation and maintenance of inflammatory pain. Chronic pain in particular not only results from the neurobiological process of nociception, but is also influenced by psychological and social factors. The principles of current drug treatment are herein presented within the framework of neuroanatomy, neurophysiology and neuropharmacology, and options for the future are mentioned. A description is offered on how non-steroidal anti-inflammatory drugs and opioids interfere with peripheral and central pain mechanisms, and the rationale for using non-opioidergic and opioidergic analgesics is outlined. The importance of physical and psychosocial therapy is also addressed.

Analgesics, Opioid↗
PubMed1999

Localization of the neurokinin 1 receptor on a subset of substance P-positive and isolectin B4-negative dorsal root ganglion neurons of the rat.

Dorsal root ganglion (DRG) neurons that express the neurokinin 1 (NK1) receptor were further characterized immunocytochemically using double-labeling techniques. DRG neurons were isolated from adult rats and cultured for 1-4 days. NK1 receptors on the surface of the neurons were labeled with substance P-gold. Non-peptidergic neurons were labeled with the surface marker isolectin B4 from Griffonia simplicifolia (IB4). Substance P-immunoreactivity was determined using an antibody to substance P. NK1 receptors were not identified on non-peptidergic neurons. The vast majority of the neurons with NK1 receptors showed substance P-immunoreactivity suggesting that NK1 receptors are autoreceptors in many dorsal root ganglion neurons.

Animals↗
PubMed1999

Expression of neurokinin-1 receptors on cultured dorsal root ganglion neurons from the adult rat.

The expression of neurokinin-1 receptors in isolated dorsal root ganglion neurons of adult rats was investigated using substance P covalently bound to a 1.4-nm gold particle. Binding of substance P-gold was determined in neurons after 0.8, 1.8 or 3.8 days under culture conditions. Substance P-gold binding sites were identified in 9.5 +/- 1.8% of the neurons that were cultured for 0.8 days. The proportion of neurons with substance P-gold binding sites increased to 21.5 +/- 3.6% after 1.8 days in culture and returned to the initial values (9.2 +/- 2.1%) after 3.8 days in culture. Binding of substance P-gold was suppressed by co-administration of [Sar9, Met(O2)11] substance P, a specific agonist at the neurokinin-1 receptor, but not by co-administration of [beta-Ala8] Neurokinin A (4-10), an agonist at the neurokinin-2 receptor, and senktide, an agonist at the neurokinin-3 receptor. This indicates that substance P-gold was bound specifically to neurokinin-1 receptors. Double-labelling with RT97, an antibody that selectively labels somata of A-fibres revealed that substance P binding sites were present in small neurons with myelinated and unmyelinated axons. These data show that a proportion of dorsal root ganglion neurons of adult rat in culture exhibit neurokinin-1 receptors. A transient increase in the proportion of neurons expressing neurokinin-1 receptors after 1.8 days in culture suggests that the expression of neurokinin-1 receptors is subjected to regulation.

Animals↗
PubMed1999

The intraspinal release of prostaglandin E2 in a model of acute arthritis is accompanied by an up-regulation of cyclo-oxygenase-2 in the spinal cord.

In anaesthetized rats, the intraspinal release of immunoreactive prostaglandin E2 was measured using antibody microprobes. We addressed the question of whether the release of immunoreactive prostaglandin E2 is altered during development of acute inflammation in the knee evoked by intra-articular injections of kaolin and carrageenan. We also examined cyclo-oxygenase-1 and cyclo-oxygenase-2 protein levels in the spinal cord during the development of inflammation using the same model of arthritis. Densitometric analysis of microprobes showed that basal release of immunoreactive prostaglandin E2 in the period 175-310 min after kaolin was slightly higher than in the absence of inflammation. A pronounced enhancement of basal release of immunoreactive prostaglandin E2 was observed 430-530 min after kaolin. Enhanced levels of immunoreactive prostaglandin E2 were observed throughout the dorsal and ventral horns. Release of immunoreactive prostaglandin E2 was not altered further by the application of innocuous and noxious pressure onto the inflamed knee. Western blot analysis revealed that cyclo-oxygenase-2 but not cyclo-oxygenase-1 protein levels were elevated in the spinal cords of animals with inflammation compared to normal animals. This effect was evident as early as 3 h after the induction of arthritis. The maximum elevation of cyclo-oxygenase-2 protein levels (six-fold) was observed 12 h after the induction of arthritis. The results show that there is a tonic release of immunoreactive prostaglandin E2 from the spinal cord following the induction of arthritis, which is accompanied by enhanced expression of cyclo-oxygenase-2 protein in the spinal cord. We suggest that intraspinal prostaglandins may play a role in inflammation-evoked central sensitization of spinal cord neurons.

Acute Disease↗
PubMed1999

Effects of omega-agatoxin IVA, a P-type calcium channel antagonist, on the development of spinal neuronal hyperexcitability caused by knee inflammation in rats.

Both N- and P-type high-threshold calcium channels are located presynaptically in the CNS and are involved in the release of transmitters. To investigate the importance of P-type calcium channels in the generation of inflammation-evoked hyperexcitability of spinal cord neurons, electrophysiological recordings were made from wide-dynamic-range neurons with input from the knee joint in the anesthetized rat. The responses of each neuron to innocuous and noxious pressure onto the knee and the ankle were continuously assessed before and during the development of an inflammation in the knee joint induced by the injections of K/C into the joint cavity. The specific antagonist at P-type calcium channels omega-agatoxin was administered into a 30-microl trough on the spinal cord surface above the recorded neuron. In most neurons the application of omega-agatoxin before induction of inflammation slightly enhanced the responses to pressure onto the knee and ankle or left them unchanged. Two different protocols were then followed. In the control group (13 rats) only Tyrode was administered to the spinal cord during and after induction of inflammation. In these neurons the responses to mechanical stimuli applied to both the inflamed knee and to the noninflamed ankle showed a significant increase over 4 h. In the experimental group (12 rats) omega-agatoxin was applied during knee injection and in five 15-min periods up to 180 min after kaolin. This prevented the increase of the neuronal responses to innocuous pressure onto the knee and to innocuous and noxious pressure onto the ankle; only the responses to noxious pressure onto the knee were significantly enhanced during development of inflammation. Thus the development of inflammation-evoked hyperexcitability was attenuated by omega-agatoxin, and this suggests that P-type calcium channels in the spinal cord are involved in the generation of inflammation-evoked hyperexcitability of spinal cord neurons. Finally, when omega-agatoxin was administered to the spinal cord 4 h after the kaolin injection, i.e., when inflammation-evoked hyperexcitability was fully established, the responses to innocuous and noxious pressure onto the knee were reduced by 20-30% on average. The shift in the effect of omega-agatoxin, from slight facilitation or no change of the responses before inflammation to inhibition in the state of hyperexcitability, indicates that P-type calcium channels are important for excitatory synaptic transmission involved in the maintenance of inflammation-evoked hyperexcitability.

Animals↗
PubMed1998

The effects of S- and R-flurbiprofen on the inflammation-evoked intraspinal release of immunoreactive substance P--a study with antibody microprobes.

Using antibody coated microprobes in anesthetized rats, we studied the intraspinal release of immunoreactive substance P during development of kaolin/carrageenan-induced inflammation in the knee joint, and the effects of S- and R-flurbiprofen on inflammation-evoked intraspinal release of immunoreactive substance P once inflammation was established. During the first 6 h after induction of acute inflammation, the basal release and the release of immunoreactive substance P evoked by innocuous pressure applied to the knee showed increases (n=4 rats). An intravenous dose of 9 mg/kg S-flurbiprofen (a potent inhibitor of cyclooxygenases that is anti-inflammatory and antinociceptive) did not significantly alter the pattern of inflammation-evoked release of immunoreactive substance P within 2 h although this dose reduced the responses of spinal cord neurons to pressure applied to the inflamed knee joint within 15 min to about 15% of the predrug value (Neugebauer et al., J. Pharmacol. Exp. Ther. 275 (1995) 618-628). The subsequent i.v. injection of 27 mg/kg S-flurbiprofen significantly changed the pattern of release of immunoreactive substance P showing a reduction of the level of immunoreactive substance P in the dorsal horn within 1 h (n=4 rats). The release of immunoreactive substance P was also reduced after the i.v. injection of 27 mg/kg R-flurbiprofen that is also antinociceptive but less anti-inflammatory (n=5 rats). These data show that both S- and R-flurbiprofen reduce the inflammation-evoked intraspinal release of immunoreactive substance P within hours. However, the reduction of release of immunoreactive substance P does not seem to be a prerequisite for the initial antinociceptive action of non-steroidal anti-inflammatory drugs. It may be rather important in the long term range.

Animals↗
PubMed1998

Spinal application of omega-conotoxin GVIA, an N-type calcium channel antagonist, attenuates enhancement of dorsal spinal neuronal responses caused by intra-articular injection of mustard oil in the rat.

Administration of the N-type calcium channel antagonist omega-conotoxin GVIA to the spinal cord reduces spinal neuronal responses to innocuous and noxious pressure applied to the knee, both in rats with normal knees and in rats in which a knee inflammation has induced a state of hyperexcitability in spinal neurons (Neugebauer et al. 1996, J Neurophysiol 76: 3740-3749). In the present experiments we studied whether the development of hyperexcitability of spinal neurons induced by intra-articular injection of mustard oil, an excitant of C-fibres, can be influenced by spinal pretreatment with omega-conotoxin GVIA. In anaesthetized rats, responses of wide-dynamic-range neurons were recorded in the spinal dorsal horn when standardized stimulation with innocuous and noxious pressure was applied to the knee and ankle joints. Injection of mustard oil into the knee joint cavity caused an initial neuronal discharge followed by an early (peaking at about 15 min) and a late (after 60 min) facilitation of responses to innocuous and noxious stimulation of the knee. Responses to ankle stimulation showed only the late facilitation. When omega-conotoxin GVIA (20 microl, 1 microM) was applied into a small trough onto the spinal cord above the recording site the responses to articular stimulation were reduced. Furthermore, when mustard oil was injected while omega-conotoxin GVIA was on the spinal cord, the early increase in the neuronal responses to innocuous pressure on the knee and the late increase in responses to noxious pressure on the ankle were significantly smaller than those observed in rats not treated with omega-conotoxin GVIA; the drop in the responses to noxious pressure on the knee was not significant. Thus the spinal application of omega-conotoxin GVIA reduced but did not completely prevent the fast and slow development of neuronal hyperexcitability of spinal cord neurons produced by a prompt and strong excitation of afferent C-fibres. This suggests that N-type calcium channels are important for the development of spinal cord hyperexcitability.

Animals↗