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Biomedical subjects

K Messlinger

Publications and source records attributed to K Messlinger.

34 records · Page 2Linked to original sources
PubMed1996

Lack of a role for substance P in the control of dural arterial flow.

The role of the neuropeptide substance P (SP) in the control of dural arterial blood flow was examined in barbiturate-anaesthetised rats. The parietal skull was trephinised and the blood flow in branches of the medial meningeal artery was monitored with a laser Doppler flowmeter. Electrical stimulation of the dura mater encephali at a parasagittal site with pulses of 0.5 ms (10-20 V, 5-10 Hz, 30 s) caused a transient increase in dural blood flow which was reproducible in size with repetitive stimulation. Neither the basal flow nor the stimulus-evoked flow was significantly changed by topical administration of SP, the SP analog septide, or the NK1 antagonist RP 67580. It is concluded that SP released from dural nerve fibres upon local stimulation does not play an important role in the regulation of dural arterial flow.

Animals↗
PubMed1995

The opioid antagonist naloxone does not alter discharges of nociceptive afferents from the acutely inflamed knee joint of the cat.

Recent studies have shown peripheral antinociceptive effects of opiates in inflamed tissue. To test whether the afferent activity during an acute inflammation may also be suppressed by endogenous opioids, we studied whether the application of the opioid antagonist naloxone would alter the afferent discharges from the cat knee joint inflamed by kaolin and carrageenin. After i.a. bolus administration of naloxone (3 micrograms/kg and 1 mg/kg) close to the joint, neither the ongoing activity nor the responses to noxious and innocuous movements significantly changed in group III or group IV units. Since naloxone did not unmask opioidergic activity under these conditions, we conclude that the development of increased activity in joint afferents during an acute kaolin/carrageenin-induced inflammation is not tonically suppressed by endogenous opioids.

Afferent Pathways↗
PubMed1995

Fine sensory innervation of the knee joint capsule by group III and group IV nerve fibers in the cat.

Afferent group III and IV nerve fibers of the knee joint markedly differ in their responsiveness to mechanical stimulation, which may be reflected in the structure and location of their terminals. Therefore, in sympathectomized cats, the fine afferent innervation of the knee joint capsule was studied via ultrastructural three-dimensional reconstructions over distances of up to 300 microns. Small peripheral nerves and "free" (noncorpuscular) sensory nerve endings were found in a superficial layer of the outer fibrous part of the capsule, in the patellar retinaculum, and in the outer and inner surface layers of the medial collateral and patellar ligaments. Group III nerve fibers showed a proximal myelinated portion inside the nerve, an intermediate portion that lacks a myelin sheath and is only surrounded by perineurium, and a distal portion outside of the perineurium that forms the sensory ending proper. Group IV fibers showed only two distinct portions, an intraperineurial (proximal) and an extraperineurial (distal) portion without any further morphological differences. Outside of the perineurium, a network formed by Schwann cells ("Schwann cell reticulum") provides a pathway for the distal portion of the sensory axons. No distinct subgroups of the sensory terminal fibers could be defined according to the configuration of the Schwann cells and the nerve fiber terminals. Sensory terminals were located adjacent to different structures such as venous and lymphatic vessels, fat cells, and collagenous fibers. Distinct parts of the same terminal nerve fiber were found in close contact to a vessel wall; others were surrounded by dense collagenous tissue. Close to sensory endings, mast cells and mast cell-like cells were frequently found, indicating a functional relationship.

Animals↗
PubMed1995

A new combination of methods for the localization, identification, and three-dimensional reconstruction of the sensory endings of articular afferents characterized by electrophysiology.

A combination of methods is described to identify and reconstruct corpuscular and non-corpuscular sensory endings of group II and group III nerve fibers following functional examination by electrophysiology. Afferent units activated by electrical stimulation of the medial articular nerve of the cat's knee were analyzed by single fiber recordings and characterized by their responsiveness to mechanical stimuli. The receptive fields of the units were closely demarcated by fine needles when the responses elicited by insertion of the needles were being recorded. After fixation, the tissue around the demarcated field was dissected and histologically processed. Series of semithin sections were cut from the embedded tissue blocks containing the receptive fields. Corpuscular endings of group II fibers and peripheral myelinated group III nerve fibers, presumably corresponding to the characterized units, were identified by light microscopy of semithin sections and localized within the demarcated area. Non-corpuscular endings were identified by electron microscopy of ultrathin sections cut in alternation with, or after re-embedding of, semithin sections. Morphometric analysis of ultrathin section series allowed the measurement of parameters such as the mean axon diameter and the organelle content of the sensory endings. The methods described are appropriate for collecting data that correlate the structural and functional characteristics of sensory endings in deep tissues.

Animals↗
PubMed1995

Increase of meningeal blood flow after electrical stimulation of rat dura mater encephali: mediation by calcitonin gene-related peptide.

1. The dura mater encephali of the rat was exposed and the blood flow around branches of the medial meningeal artery was monitored with a laser Doppler flowmeter. Changes in the meningeal blood flow (MBF) following electrical stimulation of the dura mater at a parasagittal site were registered. The effects of human calcitonin gene-related peptide (h-alpha CGRP) and the CGRP antagonist (h-alpha CGRP8-37) on the MBF were tested. 2. Electrical stimulation with rectangular pulses of 0.5 ms, 10-20 V, 5-10 Hz and a duration of 30 s caused an increase of the MBF in 14 out of 16 rats tested. The increases were dependent on stimulus strength and frequency. 3. The increase in MBF was inhibited in a dose-dependent manner by topical application of 0.1 ml of h-alpha CGRP8-37 at concentrations of 10(-7) - 10(-5) M. The highest dose abolished the increase in MBF. 4. Topical administration of 0.1 ml of h-alpha CGRP at a concentration of 10(-4) M increased the basal MBF by 15% on average. 5. It is suggested that the increase in MBF following electrical stimulation of the dura mater is mediated by the release of CGRP. The contribution of the dural afferent and sympathetic and parasympathetic efferent nerve fibres to this response are discussed.

Animals↗
PubMed1995

Calcitonin gene related peptide released from dural nerve fibers mediates increase of meningeal blood flow in the rat.

The parietal dura mater encephali of the rat was shown by immunohistochemistry to be densely innervated by calcitonin gene related peptide (CGRP) immunoreactive nerve fibers spreading around the medial meningeal artery and its branches. Electrical stimulation of the dural surface (10-20 V, 5-10 Hz, 10-30 min) caused a depletion of CGRP-immunopositive fibers, suggesting a release of CGRP. The dural blood flow around branches of the medial meningeal artery was also monitored with a laser Doppler flowmeter. Short periods (30 s) of electrical stimulation with parameters that presumably released CGRP form nerve fibers caused a repeatable and constant increase of the blood flow for 1-2 min. This evoked increase could dose dependently be inhibited by topical application of the CGRP antagonist hCGRP8-37. Accordingly, administration of hCGRP increased the basal blood flow. We conclude that stimulation of trigeminal afferents innervating the dura mater releases CGRP from peptidergic afferent terminals, thereby causing vasodilatation and increasing the meningeal blood flow, an important element of neurogenic inflammation.

Animals↗
PubMed1994

Mitochondria in fine afferent nerve fibres of the knee joint in the cat: a quantitative electron-microscopical examination.

The distribution of mitochondria, their content and concentration (expressed as the ratio of the mean volume of mitochondria and the surface of the sensory axon) were determined in group-III and -IV nerve fibres innervating the knee joint capsule in the cat. Mitochondria mainly accumulated in axonal swellings ("beads") and end bulbs of the terminal branches. Between single nerve fibres, marked differences in the content and the concentration of mitochondria were obtained in proximal portions (inside of the perineurium) and in distal portions (unmyelinated sensory endings). In group-III nerve fibres, the mitochondrial concentration ranged from 0.005 to 0.030 microns 3/microns 2 (proximal portion) and from 0.016 to 0.080 microns 3/microns 2 (distal portion). In unmyelinated group-IV nerve fibres, the values also showed a broad variation ranging from 0.001 to 0.011 microns 3/microns 2 (proximal portion) and from 0.003 to 0.019 microns 3/microns 2 (distal portion). The wide range of mitochondrial concentrations may reflect different energy consumption during receptive processes: nerve fibres with a low mechanical threshold and a high probability of excitatory events may be rich in mitochondria, whereas fibres with a high mechanical threshold and a low probability of excitatory events may be poor in mitochondria.

Animals↗
PubMed1993

Bradykinin B1 and B2 receptor antagonists do not change the ongoing activity of slowly conducting articular afferents in the inflamed knee joint of the cat.

Arthritic hyperalgesia and pain result from an increased activity of nociceptive afferents that may be induced and maintained by inflammatory mediators like bradykinin (BK). The B1 receptor antagonist des-Arg9-Leu8-BK and the B2 receptor antagonists Thi5,8-D-Phe7-BK and Hoe 140 were used to study the involvement of BK receptors in the generation of ongoing afferent activity in the cat's knee joint that was inflamed by kaolin and carrageenin. After i.a. bolus administration of BK receptor antagonists (26-260 micrograms) close to the joint, the ongoing activity did not significantly vary in any group III or group IV unit. We conclude that activation of BK receptors by endogenous BK is probably not the mechanism that is responsible for the increased ongoing activity of articular afferents in the inflamed joint.

Animals↗
PubMed1993

Innervation of the dura mater encephali of cat and rat: ultrastructure and calcitonin gene-related peptide-like and substance P-like immunoreactivity.

Ultrastructural, immunocytochemical, and immunoelectron microscopical examinations are reported that describe the morphology of putative sensory nerve endings in the dura mater encephali of the rat and the cat. Morphometrical measurements and reconstructions showed that in the cat the mean diameter of axons, the bare area of axolemma, and the content of mitochondria and vesicles are highly variable in dural nerve endings. Nerve fibers with a high volume density of mitochondria are thought to be sensory, while nerve fibers containing many small vesicles are considered autonomic. There is, however, a broad overlap of mitochondria-rich and vesicle-rich nerve fibers in the dura, so that discrimination between sensory and autonomic endings by these characteristics frequently fails. Whole-mount preparations treated cytochemically for detection of substance P- and calcitonin gene-related peptide-like immunoreactivity in the rat and the cat showed a network of immunopositive nerve fibers in the vicinity of dural blood vessels. Most of these peptidergic and probably sensory nerve fibers were found terminating in the dural connective tissue far from vessels. Calcitonin gene-related peptide-positive nerve fibers were much more abundant than substance P-positive fibers. Immunoelectron microscopic preparations revealed that calcitonin gene-related peptide- and substance P-like immunoreactivity is found in a small proportion of generally thin unmyelinated nerve fibers. These proportions were very similar in the rat and the cat. Summarizing the recent literature, the morphological characteristics of putative sensory nerve fibers in the dura mater are discussed in relation to their possible functional significance for neurogenic inflammation and nociception.

Animals↗
PubMed1993

The effects of phorbol ester on slowly conducting afferents of the cat's knee joint.

The effects of beta-phorbol 12,13-dibutyrate (PDBu) on the discharge properties of slowly conducting knee joint afferents (group III and group IV fibers) were studied to determine the role of protein kinase C in nociception. Extracellular single unit recordings were made from small filaments dissected from the medial articular nerve in cats anesthetized with alpha-chloralose. PDBu was applied intra-arterially close to the joint in concentrations of 10(-6) up to 10(-4) M. The afferents were classified as low-threshold and high-threshold units with regard to their sensitivity to passive noxious and innocuous movements of the knee joint. Following PDBu application, an excitation occurred in 28% of the group III and in 40% of the group IV fibers. An enhancement of responses to passive movements of the joint (sensitization) occurred in 37% of group III and 19% of group IV afferents. In summary, 37.5% of the low-threshold and 50% of the high-threshold fibers proved to be sensitive to PDBu. Most of the PDBu-positive units responded also to bradykinin, whereas only a few PDBu-positive units were sensitive to prostaglandin I2 and E2. We conclude from these results that, in a distinct population of slowly conducting joint afferents, protein kinase C is likely to be involved in the process of transduction. Thus, pain and hyperalgesia may be mediated at least partly by intracellular mechanisms that are linked to protein kinase C.

Animals↗
PubMed1992

Inflammatory mediators and nociception in the joint: excitation and sensitization of slowly conducting afferent fibers of cat's knee by prostaglandin I2.

The effects of prostaglandin I2 on the discharge properties of fine articular afferents (group III and group IV fibers) in the cat were examined by extracellular recordings from single units dissected from the medial articular nerve of the knee joint. Prostaglandin I2 was applied intra-arterially close to the joint in doses of 0.3-30 micrograms per 0.3 ml bolus injection, and its effects on the spontaneous activity as well as on discharges evoked by mechanical and chemical stimulation (bradykinin) were monitored. Prostaglandin E2 was also applied and the effects of prostaglandins I2 and E2 on particular units were compared. An excitatory effect of prostaglandin I2 was observed in 49% of 37 group III and in 37% of 27 group IV units. A sensitization to passive movements of the joint occurred in 71% of 31 group III and 48% of 21 group IV units. Sixty-seven per cent of 32 units (groups III and IV) were both excited and sensitized by prostaglandin I2 to movements of 27% were sensitized but not excited. In 64% of 11 group III and 63% of eight group IV units studied the responses to bradykinin were enhanced by prostaglandin I2. Prostaglandin E2 had qualitatively similar effects as prostaglandin I2 but excited and sensitized a lower proportion of articular afferents. Forty-one per cent of the units were sensitive to both prostaglandins but 26% of the fibers were only sensitive to prostaglandin I2. None of the units was exclusively sensitive to prostaglandin E2. In general, the excitatory and sensitizing effects of prostaglandin E2 had a longer duration than those exerted by prostaglandin I2. We conclude that prostaglandin I2 increases the sensitivity to mechanical stimuli as well as to chemical stimulation by bradykinin in the majority of articular group III and group IV fibers. Moreover, in a large proportion of articular afferents, prostaglandin I2 had an excitatory effect. Thus, prostaglandin I2 may be an inflammatory mediator which is important for inflammation-evoked activity in slowly conducting afferents and it may participate in the development of arthritic hyperalgesia and pain.

Afferent Pathways↗
PubMed1991

Nociception and pain.

In recent years, progress in the treatment of pain has been strongly influenced by new insights into the mechanisms underlying pain and nociception. The following article briefly reviews some recent reports which make a significant contribution to our knowledge of the structure and function of nocisensors, the neuropeptides involved in the nociceptive system, and the spinal and supraspinal central mechanisms of nociception.

Afferent Pathways↗
PubMed1990

Ultrastructural three-dimensional reconstruction of group III and group IV sensory nerve endings ("free nerve endings") in the knee joint capsule of the cat: evidence for multiple receptive sites.

The noncorpuscular endings ("free nerve endings") of thinly myelinated group III and nonmyelinated group IV afferent nerve fibers have been examined in the knee joint capsule of sympathectomized cats by transmission electron microscopy and three-dimensional reconstruction of series of semi- and ultrathin sections. The sensory ending is the most distal part of a group III or IV nerve fiber that consists only of the sensory axon and associated Schwann cells but lacks a myelin sheath and is not surrounded by perineurium. The sensory axon divides into several branches and forms a terminal tree. The branches run either as single fibers or within small Remak bundles in parallel to sensory axons of other endings; they spread along vessel walls and also extend into dense connective tissue. Each sensory axon consists of a series of spindle-shaped thick segments ("beads") connected by waist-like thin segments. Thus all axons of sensory endings have a string-of-beads appearance, which resembles that of efferent sympathetic nerve fibers. The beads of the sensory axon and the end bulb at its tip show the same ultrastructural features which are characteristic of receptive sites: an accumulation of mitochondria and glycogen particles and various vesicles in the axoplasm and "bare" areas of axolemma that are not covered by Schwann cell processes. Group III and group IV sensory endings differ in the length of their branches (up to 200 microM in group III vs. more than 300 microM in group IV), number of beads per 100 microM axon length (about seven vs. nine or ten), mean diameter of axons (0.9-1.5 microM vs. 0.3-0.6 microM), and the presence of a neurofilament core consisting of bundles of parallel microfilaments only in group III. In conclusion, we propose that the sensory part of noncorpuscular "free nerve endings" is formed by the entire terminal tree of group III or group IV nerve fibers and that the beads in the course of the sensory axon represent multiple receptive sites.

Animals↗
PubMed1989

Serial sectioning, electron microscopy, and three-dimensional reconstruction of fine nerve fibres and other extended objects.

Two different techniques for three-dimensional reconstructions of nerve fibres or other extended fine tissue structures were developed to study the afferent innervation of the cat's knee-joint capsule. The re-embedding technique starts with series of semithin sections for light microscopic reconstructions. In a second step, selected semithin sections can be re-embedded for ultramicrotomy to examine ultrastructural details. This method offers the possibility to investigate fine structures over a distance of several hundred micrometres without any loss of ultrastructural information. The serial section-ESI technique is based on the electron spectroscopic imaging of semithin sections. Small tissue blocks are cut into series of either semithin or alternate semi- and ultrathin sections which can be directly used for a complete ultrastructural investigation. Finally, true-to-scale three-dimensional reconstructions are performed by graphical techniques or computer-aided methods.

Afferent Pathways↗
PubMed1988

Morphological characteristics of the innervation of the cat's knee joint.

The peripheral and central terminals of primary afferents of the cat's knee joint were studied with light- and electron microscopy (including HRP-transport methods). The majority of these afferent fibres are unmyelinated or thinly myelinated. In the periphery, they terminate in non-corpuscular endings. A dense network of branching nerve fibres surround the blood vessels to terminate at the vessel walls or in the adjacent dense collagenous tissue. Besides the terminals the fibres show preterminal bulges which are assumed to represent additional transduction sites. This implies that the whole distal fibre portion has a receptive function. The spinal projection is located in lamina I and V-VII of the dorsal horn. This location parallels that of muscular and visceral fibres, pointing to the possibility of a common projection pattern for deep somatic afferent fibres in the spinal cord of the cat.

Animals↗