[Visceral pain]. / Viszeraler Schmerz.

Chronic visceral pain is an unresolved neurobiological, medical and socioeconomic challenge. Up to 20% of the adult population suffer from chronic visceral pain and abdominal complaints constitute a prevalent symptom also in children and adolescents. Existing treatment approaches are often unsuccessful and patients typically suffer from multiple somatic and psychological symptoms. This complex situation requires integrative treatment approaches. This review summarizes current basic and clinical research on acute and chronic visceral pain with a focus on research groups in Germany. Despite significant clinical and scientific advances, a number of questions remain open calling for more funding to support research to elucidate the complex pathophysiology of chronic visceral pain and to develop and test new treatment approaches. Research support should focus on interdisciplinary concepts and methodology using expertise from multiple disciplines. The field would also benefit from a broader integration of visceral pain into teaching curricula in medicine and psychology and should aim to motivate young clinicians and scientists to strive for a career within this important and highly fascinating area.

[Neurobiology of visceral pain]. / Neurobiologie viszeraler Schmerzen.

Visceral pain is diffusely localized, referred into other tissues, frequently not correlated with visceral traumata, preferentially accompanied by autonomic and somatomotor reflexes, and associated with strong negative affective feelings. It belongs together with the somatic pain sensations and non-painful body sensations to the interoception of the body. (1) Visceral pain is correlated with the excitation of spinal (thoracolumbar, sacral) visceral afferents and (with a few exceptions) not with the excitation of vagal afferents. Spinal visceral afferents are polymodal and activated by adequate mechanical and chemical stimuli. All groups of spinal visceral afferents can be sensitized (e.g., by inflammation). Silent mechanoinsensitive spinal visceral afferents are recruited by inflammation. (2) Spinal visceral afferent neurons project into the laminae I, II (outer part IIo) and V of the spinal dorsal horn over several segments, medio-lateral over the whole width of the dorsal horn and contralateral. Their activity is synaptically transmitted in laminae I, IIo and deeper laminae to viscero-somatic convergent neurons that receive additionally afferent synaptic (mostly nociceptive) input from the skin and from deep somatic tissues of the corresponding dermatomes, myotomes and sclerotomes. (3) The second-order neurons consist of excitatory and inhibitory interneurons (about 90 % of all dorsal horn neurons) and tract neurons activated monosynaptically in lamina I by visceral afferent neurons and di- or polysynaptically in deeper laminae. (4) The sensitization of viscero-somatic convergent neurons (central sensitization) is dependent on the sensitization of spinal visceral afferent neurons, local spinal excitatory and inhibitory interneurons and supraspinal endogenous control systems. The mechanisms of this central sensitization have been little explored. (5) Viscero-somatic tract neurons project through the contralateral ventrolateral tract and presumably other tracts to the lower and upper brain stem, the hypothalamus and via the thalamus to various cortical areas. (6) Visceral pain is presumably (together with other visceral sensations and nociceptive as well as non-nociceptive somatic body sensations) primarily represented in the posterior dorsal insular cortex (primary interoceptive cortex). This cortex receives in primates its spinal synaptic inputs mainly from lamina I tract neurons via the ventromedial posterior nucleus of the thalamus. (7) The transmission of activity from visceral afferents to second-order neurons in spinal cord is modulated in an excitatory and inhibitory way by endogenous anti- and pronociceptive control systems in the lower and upper brain stem. These control systems are under cortical control. (8) Visceral pain is referred to deep somatic tissues, to the skin and to other visceral organs. This referred pain consists of spontaneous pain and mechanical hyperalgesia. The mechanisms underlying referred pain and the accompanying tissue changes have been little explored.

Neurophysiological tests and neuroimaging procedures in non-acute headache (2nd edition).

BACKGROUND AND PURPOSE: A large number of instrumental investigations are used in patients with non-acute headache in both research and clinical fields. Although the literature has shown that most of these tools contributed greatly to increasing understanding of the pathogenesis of primary headache, they are of little or no value in the clinical setting. METHODS: This paper provides an update of the 2004 EFNS guidelines and recommendations for the use of neurophysiological tools and neuroimaging procedures in non-acute headache (first edition). Even though the period since the publication of the first edition has seen an increase in the number of published papers dealing with this topic, the updated guidelines contain only minimal changes in the levels of evidence and grades of recommendation. RESULTS: (i) Interictal EEG is not routinely indicated in the diagnostic evaluation of patients with headache. Interictal EEG is, however, indicated if the clinical history suggests a possible diagnosis of epilepsy (differential diagnosis). Ictal EEG could be useful in certain patients suffering from hemiplegic or basilar migraine. (ii) Recording evoked potentials is not recommended for the diagnosis of headache disorders. (iii) There is no evidence warranting recommendation of reflex responses or autonomic tests for the routine clinical examination of patients with headache. (iv) Manual palpation of pericranial muscles, with standardized palpation pressure, can be recommended for subdividing patient groups but not for diagnosis. Pain threshold measurements and EMG are not recommended as clinical diagnostic tests. (v) In adult and pediatric patients with migraine, with no recent change in attack pattern, no history of seizures, and no other focal neurological symptoms or signs, the routine use of neuroimaging is not warranted. In patients with trigeminal autonomic cephalalgia, neuroimaging should be carefully considered and may necessitate additional scanning of intracranial/cervical vasculature and/or the sellar/orbital/(para)nasal region. In patients with atypical headache patterns, a history of seizures and/or focal neurological symptoms or signs, MRI may be indicated. (vi) If attacks can be fully accounted for by the standard headache classification (IHS), a PET or SPECT scan will normally be of no further diagnostic value. Nuclear medical examinations of the cerebral circulation and metabolism can be carried out in subgroups of patients with headache for the diagnosis and evaluation of complications, when patients experience unusually severe attacks or when the quality or severity of attacks has changed. (vii) Transcranial Doppler examination is not helpful in headache diagnosis. CONCLUSION: Although many of the examinations described in the present guidelines are of little or no value in the clinical setting, most of the tools, including thermal pain thresholds and transcranial magnetic stimulation, have considerable potential for differential diagnostic evaluation as well as for the further exploration of headache pathophysiology and the effects of pharmacological treatment.

Visceral nociceptors: a new world order?

There has been a long-standing controversy as to whether or not internal organs are innervated by a special category of 'visceral nociceptor'. Recent experimental studies on the afferent supply of some viscera have thrown new light on this issue by demonstrating the presence of several categories of visceral sensory receptor, including high-threshold receptors, 'silent' nociceptors and intensity-encoding receptors. Advances in the understanding of how the CNS processes nociceptive signals have also helped to clarify the issue. The authors of this report, originally having different points of view, present here a common and closer approach to the visceral nociceptor controversy.

Characteristics of function-specific pathways in the sympathetic nervous system.

The autonomic nervous system enables all of our body systems to operate in an external environment that is both physically and emotionally challenging. Despite voluntary and involuntary interventions, the composition of the internal environment is maintained. Autonomic dysfunction, particularly in aging people, reveals the importance of this efferent neural control for the wellbeing of our bodies and minds. Although the sympathetic component of this system has been widely thought to be concerned only with the body's response to stress, we discuss here how a range of neuroscientific techniques has started to reveal the specialized properties of functional pathways in the sympathetic system at molecular, cellular and integrative levels. The diversity observed is not compatible with a simple neuroendocrine role of this system.

Axotomized and intact muscle afferents but no skin afferents develop ongoing discharges of dorsal root ganglion origin after peripheral nerve lesion.

After peripheral nerve lesions, some axotomized afferent neurons develop ongoing discharges that originate in the dorsal root ganglion (DRG). We investigated in vivo which functional types of afferent neurons contributed to this ectopic activity. Six to twelve days after the gastrocnemius soleus (GS) nerve supplying skeletal muscle and the sural (SU) nerve supplying skin had been transected (experimental group E1), 20.4% of afferent neurons with myelinated axons projecting into the GS nerve produced ongoing discharges of irregular or bursting pattern. In contrast, all SU neurons were silent. Additional transection of peroneal and tibial nerves (group E2) induced ongoing activity in a similar percentage of GS neurons (22.1%), but their mean discharge frequency was higher (6.0 vs 2.7 Hz), and more of them exhibited bursting discharges (63 vs 17%). When the GS nerve had been left intact while tibial, peroneal, and SU nerve had been transected (group E3), 18.8% of unlesioned GS neurons developed ongoing discharges at a mean frequency of 6.1 Hz; most of them exhibited a bursting pattern. Without a preceding nerve lesion, almost no GS neuron (1.1%) fired spontaneously. Most afferent neurons with ongoing activity had an axonal conduction velocity of 5-30 m/sec indicating that some of these neurons may have had nociceptive function. These findings provide the first evidence that after peripheral nerve injury both axotomized as well as intact afferent neurons supplying skeletal muscle but not skin afferents generate ongoing activity within the DRG, probably because of a yet unknown signal in the DRG triggered by axotomy.

Attenuation of neurogenic vasoconstriction by nitric oxide in hindlimb microvascular beds of the rat in vivo.

There is evidence that sympathetic nerve activity leads to endothelium-derived nitric oxide release, which in turn attenuates neurogenic vasoconstriction. Here we tested in vivo (1) whether the magnitude of the vasoconstriction induced by N(G)-nitro-L-arginine methyl ester given systemically is altered when ongoing sympathetic activity is abolished by sectioning the lumbar sympathetic trunk, and (2) whether hindlimb sympathetic vasoconstriction elicited by electrical stimulation of the lumbar sympathetic trunk is enhanced after inhibition of nitric oxide synthesis. Blood flow in the microvascular beds of hairless skin and skeletal muscle of the rat hindlimb was measured with laser Doppler flowmetry. Sectioning the lumbar sympathetic trunk resulted in an increase of blood flow in both tissues, indicating that tonic neurogenic vasoconstriction was abolished. Inhibition of nitric oxide synthesis resulted in vasoconstriction in both vascular beds. This vasoconstriction was more pronounced after abolition of sympathetic activity than with intact sympathetic supply in skin but was smaller in skeletal muscle. The vasoconstriction elicited by graded electrical stimulation of the centrally sectioned lumbar sympathetic trunk with frequencies less than 5 Hz was significantly enhanced after blockade of nitric oxide in skeletal muscle but not in skin microvasculature. These findings suggest that under physiological conditions, sympathetic nerve impulses directly promote the release of nitric oxide in skeletal muscle but not in cutaneous blood vessels. Therefore, basal nitric oxide release is probably in part dependent on sympathetic activity in skeletal muscle, whereas it appears to be mainly due to flow-dependent shear stress in hairless skin microvasculature.

On the fate of sympathetic and sensory neurons projecting into a neuroma of the superficial peroneal nerve in the cat.

Cell bodies of sympathetic and sensory axons projecting via the superficial peroneal (SP) nerve supplying hairy skin of the distal hindlimb have been labeled retrogradely with horseradish peroxidase (HRP) on both sides of three cats in which the left SP nerve had been cut and ligated about 5 months previously. Three SP nerves from unoperated cats have also been studied. The location, size, and numbers of labeled somata have been determined from serial sections of lumbosacral dorsal root and sympathetic chain ganglia after standard histochemical processing. The numbers of myelinated fibers in each nerve have also been counted. The segmental distributions of both sympathetic and sensory cell bodies were identical bilaterally in each operated animal, but the number of labeled neurons was reduced on the lesioned side. There were only about 31% of sympathetic and about 51% of sensory somata relative to the numbers on the contralateral side. The average total number of neurons labeled from SP nerves in unoperated animals was about 8% higher than on the control side of operated animals. The average number of myelinated fibers in the neuromatized nerves was not reduced with respect to that in the contralateral nerve and both of these were not significantly different from the number in unoperated animals. The dimensions of samples of labeled sympathetic and sensory somata were reduced on the side with the neuroma, both in comparison with the contralateral side and with unlabeled neurons at the same levels. The mean cross-sectional area of profiles of sympathetic ganglion cells was 76% of the control; of sensory ganglion cells, 65% of the control. Assuming that HRP labeling was not impaired, we conclude that large numbers of neurons with unmyelinated axons had degenerated in the neuromatized cutaneous nerves.

Afferent and sympathetic neurons projecting into lumbar visceral nerves of the male rat.

The cell bodies of thoracolumbar sensory and sympathetic pre- and postganglionic neurons that project to the colon and pelvic organs of the male rat were labeled retrogradely with horseradish peroxidase (HRP) in order to study numbers, segmental distribution, and location of the somata of these neurons quantitatively. HRP was applied to one hypogastric nerve (HGN), to the lumbar colonic nerves (LCN) and to the intermesenteric nerve (IMN). In order to estimate the significance of the branching of one axon into both hypogastric nerves a double-labeling technique with fluorogold and HRP was used. About 2640 neurons project into the two HGN added together (800 afferent, 1320 pre-, and 520 postganglionic), 4650 neurons into the LCN (360 afferent, 0 pre- and 4290 postganglionic), and 5990 into the IMN (1500 afferent, 1250 pre-, and 3240 postganglionic). About 4190 sympathetic postganglionic prevertebral neurons innervate the colon and pelvic organs, 1900 are located in the inferior mesenteric ganglion and 2290 in ganglia of the IMN. Considering the efferent component, the HGN mainly are preganglionic and the LCN exclusively postganglionic nerves. Branching of one axon into both HGN is a rare event and quantitatively negligible (less than 3%). Afferent neurons of all three nerves were found in the dorsal root ganglia (DRG) T12-L2 with the maximum in L1 and L2. The distribution of afferent neurons projecting into the LCN is shifted slightly more rostrally compared to neurons projecting into the HGN. The IMN distribution is located in a position in between. Preganglionic neurons projecting into the IMN are located in the spinal cord segments T12-L3 with the maximum in L1 and L2.(ABSTRACT TRUNCATED AT 250 WORDS)

Sympathetic and afferent somata projecting in hindlimb nerves and the anatomical organization of the lumbar sympathetic nervous system of the rat.

The anatomy of the sympathetic pathways from the spinal cord to the lumbar sympathetic trunk and the inferior mesenteric ganglion was studied systematically in the rat. Details of the arrangements of white and gray rami communicantes, sympathetic trunk ganglia, the intermesenteric nerve, and the lumbar splanchnic nerves are summarized. A modified nomenclature for the segmental ganglia of the paravertebral sympathetic chain is proposed. Cell bodies of sensory and sympathetic axons projecting to the skin and skeletal muscle of the rat hindlimb were labeled retrogradely with horseradish peroxidase (HRP) in order to study numbers, segmental distribution, and location of the somata of these neurons quantitatively. HRP was applied to the nerves supplying skeletal muscle (gastrocnemius-soleus, GS), hairy skin (sural, SU; saphenous, SA) and to a mixed nerve (tibial, TI). All sensory somata and 96.4% of the sympathetic cell bodies were located ipsilaterally. Sensory somata were commonly restricted to two adjacent dorsal root ganglia (usually L3-4 for SA; L4-5 for GS, TI; L5-6 for SU). Although the sympathetic somata were more widely distributed rostrocaudally (four to six segments), their maximum was always located one or two segments more cranially than the sensory outflow, i.e., corresponding to the rami communicantes grisei. From the data, it is estimated that 420 sympathetic and 530 afferent neurons project into GS, 590 and 3,610 into SU, 920 and 3,750 into SA, and 1,070 and 5,760 into TI. These absolute neuron numbers are compared with electron microscopic fiber counts from the literature.

Identification of distinct topographical distributions of lumbar sympathetic and sensory neurons projecting to end organs with different functions in the cat.

A comparison has been made between the lumbar sensory and sympathetic pre- and postganglionic neurons that project in the lumbar splanchnic nerves and those that project in the caudal lumbar sympathetic trunk of the cat. The neuron cell bodies have been labeled retrogradely with horseradish peroxidase applied to the central end of their cut axons near the inferior mesenteric ganglion on one side, and the results have been compared with those obtained after labeling the contralateral lumbar sympathetic trunk of the same animal (Jänig and McLachlan, '86). The numbers, segmental distribution, location, and size of the labeled somata have been determined quantitatively. The data for individual animals confirm in every way those previously reported for separate experiments in different groups of animals. In addition, similar experiments were performed in which the neurons projecting in the white rami of either L4 or L5 were labeled. This procedure labeled populations of neurons that overlapped both splanchnic and paravertebral populations. Consideration of the spatial distributions and numbers of sensory and preganglionic neurons with destinations in somatic and visceral domains has enabled us to describe the different topography of these neuron populations with respect to function.

The cell bodies of origin of sympathetic and sensory axons in some skin and muscle nerves of the cat hindlimb.

Cell bodies of sensory and sympathetic axons projecting to skin and skeletal muscle of the cat hindlimb have been labeled retrogradely with horseradish peroxidase (HRP) in order to study location, size, and numbers of the somata of these neurons. HRP was applied to the freshly transected axons of nerves supplying hairy skin (superficial peroneal, SP; sural, Su), hairy and hairless skin of the paw (medial plantar, MP), or skeletal muscle (gastrocnemius-soleus, GS). Serial sections of lumbosacral dorsal root and sympathetic ganglia were studied after standard histochemical processing. Additionally, the numbers of myelinated fibers in the same nerves were determined. All sensory somata and 99.4% of sympathetic cell bodies were located ipsilaterally. Sensory somata were commonly restricted to two adjacent dorsal root ganglia (usually L6-7 for SP, MP; L7-S1 for Su, GS). Although sympathetic somata were more widely distributed rostrocaudally, their maximum frequency always occurred in the segmental ganglia immediately rostral to the sensory outflows, i.e., corresponding to rami communicantes grisei. Dimensions of sympathetic somata varied little between populations projecting to different tissues and were unimodally distributed. The size distributions of sensory somata were characterized by a peak between 10 and 20 microns radius, similar to sympathetic somata, and a varying smaller number of cells ranging up to 60 microns radius. Each nerve had a characteristic distribution profile of afferent somata. A population of very small cells was only present in GS, while the largest sensory somata in GS and MP were bigger than those in SP and Su. Numerical analysis of the data disclosed the characteristic composition of both myelinated and unmyelinated fibers in each nerve studied.

The sympathetic and sensory components of the caudal lumbar sympathetic trunk in the cat.

The cell bodies of the lumbar sensory and sympathetic pre- and postganglionic neurons that project in the caudal lumbar sympathetic trunk of the cat have been labeled retrogradely with horseradish peroxidase applied to the central end of their cut axons. The application was made just proximal to the segmental ganglion that sends its gray rami to the L7 spinal nerve, and so identified the sympathetic outflow concerned primarily with the vasculature of the hindlimb and tail. The numbers, segmental distribution, location, and size of the labeled somata have been determined quantitatively. Labeled cell bodies were found ipsilaterally, but the segmental distributions of the different cell types were not matched. Afferent cell bodies lay in dorsal root ganglia L1-L5 (maximum L4), preganglionic cell bodies in spinal segments T10-L5 (maximum L2/3), and postganglionic cell bodies in ganglia L2-L5 (maximum L5). Both numbers and dimensions of labeled dorsal root ganglion cells were variable between experiments (maximum about 1,000); the majority were small relative to the entire population of sensory neurons. Labeled preganglionic cell bodies were located right across the intermediate region of the spinal cord, extending from the lateral part of the dorsolateral funiculus to the central canal. The highest density of labeled neurons lay at the border between the white and gray matter (corresponding to the intermediolateral cell column) with smaller proportions medially in L1-L2, and laterally in caudal L4-L5. Medial preganglionic neurons were generally larger than those lying in lateral positions. From the data, it is estimated that about 650 afferent, about 4,500 preganglionic, and some 2,500 postganglionic neurons project in each lumbar sympathetic trunk distal to the ganglion L5 in the cat.

The afferent and sympathetic components of the lumbar spinal outflow to the colon and pelvic organs in the cat. I. The hypogastric nerve.

The cell bodies of the lumbar sensory and sympathetic pre- and postganglionic neurons that project to the pelvic organs in the hypogastric nerve of the cat have been labeled retrogradely with horseradish peroxidase applied to the central end of their cut axons. The numbers, segmental distribution, location, and size of these labeled somata have been determined quantitatively. Afferent and preganglionic cell bodies were located bilaterally in dorsal root ganglia and spinal cord segments L3-L5, with the maximum numbers in L4. Very few cells lay rostral to L3. Afferent cell bodies were generally very small in cross-sectional area relative to the entire population in the dorsal root ganglia. Most of the preganglionic cell bodies lay clustered just medial to the region of the intermediolateral column and extended caudally well beyond its usual limit in the upper part of L4. These neurons were, on the average, larger than the cells of the intermediolateral column itself, with the largest cells lying in the most medial positions. Most of the post-ganglionic somata were in the ipsilateral distal lobe of the inferior mesenteric ganglion, while some (usually less than 10%) lay in accessory ganglia along the lumbar splanchnic nerves and in paravertebral ganglia L3-L5. Postganglionic somata in the inferior mesenteric ganglion were larger than both labeled and unlabeled ganglion cells in the paravertebral ganglia. From the data, it is estimated that about 1,300 afferent neurons, about 1,700 preganglionic neurons, and about 17,000 postganglionic neurons project in each hypogastric nerve in the cat.

The afferent and sympathetic components of the lumbar spinal outflow to the colon and pelvic organs in the cat. II. The lumbar splanchnic nerves.

The cell bodies of the lumbar sensory and sympathetic pre- and postganglionic neurons that project to the inferior mesenteric ganglion in the lumbar splanchnic nerves of the cat have been labeled retrogradely with horseradish peroxidase applied to the central end of their cut axons near the inferior mesenteric ganglion. The numbers, segmental distribution, location, and size of these labeled somata have been determined quantitatively. After all the lumbar splanchnic nerves on one side of an animal were labeled, most labeled cell bodies were situated ipsilaterally in dorsal root ganglia, ganglia of the lumbar sympathetic trunk, and spinal cord segments L2-L5, with the maximum numbers in L3 and L4. A few labeled somata lay contralaterally or rostral to L2. After labeling of only one lumbar splanchnic nerve, the majority of cell bodies were found in the labeled segment, but a few were also present up to three segments rostral or caudal. These variations could always be attributed to extraspinal connections usually via the lumbar sympathetic trunk. Cross-sectional areas of labeled afferent somata were small relative to those of the entire population of dorsal root ganglion cells. Preganglionic cell bodies were labeled in the intermediate gray matter extending from its lateral border ventrolaterally across to the central canal. Two regions of high density were observed: one laterally just medial to the edge of the white matter and the other lateral to the central canal. The dorsolateral group lay somewhat medial and caudal to the usual limits of the intermediolateral column. Labeled preganglionic neurons were on the average larger than the unlabeled cells in the inferior mesenteric ganglion, with the group lying medially being larger than those that were laterally positioned. From the data, it is estimated that about 4,600 afferent axons, about 4,600 preganglionic axons, and about 2,800 postganglionic axons travel in the lumbar splanchnic nerves to the inferior mesenteric ganglion of the cat.

The afferent and sympathetic components of the lumbar spinal outflow to the colon and pelvic organs in the cat. III. The colonic nerves, incorporating an analysis of all components of the lumbar prevertebral outflow.

The cell bodies of the lumbar sensory and sympathetic pre- and postganglionic neurons that project to the colon along the inferior mesenteric artery of the cat have been labeled retrogradely with horseradish peroxidase applied to the central end of their cut axons. The numbers, segmental distribution, location, and size of these labeled somata have been determined quantitatively. Afferent cell bodies were symmetrically distributed bilaterally in dorsal root ganglia T13-L5, with the maximum number (about 80%) in L3 and L4 and most of the rest in L2. Labeled afferent somata were small relative to the entire population of DRG cells. Occasionally a few preganglionic somata were labeled in the intermediate zone of L3 and L4 spinal cord segments. Postganglionic cell bodies were labeled bilaterally in the proximal lobes of the inferior mesenteric ganglion (70-95%), in accessory ganglia of the intermesenteric nerve and of the lumbar splanchnic nerves, and in lumbar paravertebral ganglia. The segmental distribution in the lumbar sympathetic trunk was symmetrical on both sides and was the same as that of the afferent cells. Labeled postganglionic cell bodies in both the IMG and the accessory ganglia were larger than labeled and unlabeled ganglion cells in the paravertebral ganglia. From these data, it is estimated that about 2,100 afferent neurons and about 29,000 postganglionic neurons project in the lumbar colonic nerves. In conjunction with equivalent data for the hypogastric and lumbar splanchnic nerves, the results provide a quantitative and spatial description of the afferent and efferent components of the lumbar innervation of the colon and pelvic viscera.

Discharge pattern of afferent fibers from a neuroma.

Discharge properties of afferent units from experimentally produced stump neuromata in the superficial peroneal nerve of the cat hind limb were investigated electrophysiologically. The superficial peroneal nerves were cut and ligated 6-245 days before the experiments. Myelinated and chiefly unmyelinated axons were analyzed. The following results were obtained: (1) 3.9 +/- 3% (mean +/- S.D.) of axons from early neuromata (days 6-27) and 13.4 +/- 10.7% of axons from old neuromata (more than 50 days after nerve severance) showed ongoing activity. The rate of ongoing activity was usually below 1 imp/sec (73%) and rarely above 4 imp/sec and its pattern, in most cases, was irregular. Some myelinated afferents had regular or irregular bursting patterns. (2) Mechanical stimulation of the neuroma excited 19.4 +/- 9.6% of the axons from young neuromata and 32.8 +/- 14.9% of the axons from old neuromata. Part of these mechanosensitive units exhibited pronounced after-discharges. Some 20% of the units which could be excited, probably ephaptically, by stimulation of other afferent fibers in the common peroneal nerve were excited by pressure applied to the neuroma. (3) About 20-40% of the units with ongoing activity (3-5% of all axons) responded weakly to intravenous injections of adrenaline and noradrenaline and to repetitive stimulation of the lumbar sympathetic trunk. (4) Recording from distally cut fiber bundles showed that part of the axons could be activated by electrical stimulation of the nerve distal to the recording site and by mechanical stimulation of the neuroma. Most of these axons were unmyelinated. This result indicates that afferent axons either branch or interact ephaptically a long distance proximal to the neuroma in the neuroma nerve. (5) The results are discussed with respect to similar results obtained on afferent fibers from experimentally produced neuromata of the sciatic nerve of mice and rats.

Reflexes in sympathetic vasoconstrictor neurones arising from urinary bladder afferents are not amplified early after inflammation in the anaesthetised cat.

Pathophysiological processes in the viscera can lead to pain and hyperalgesia and exaggerated motility-regulating reflexes. This may be due to sensitisation of visceral afferents (peripheral sensitisation), which has repeatedly been shown to occur as a consequence of e.g. inflammation, and/or to sensitisation of dorsal horn neurones (central sensitisation), which is less well documented in the visceral domain. As an indicator of peripheral sensitisation, we previously analysed the responses of sacral spinal afferents after inflammation of the urinary bladder. Here, we studied reflexes in sympathetic vasoconstrictor neurones supplying skeletal muscle and skin elicited by bladder distension stimuli (vesico-sympathetic reflexes) before and after induction of bladder inflammation. Our aim was to test whether these vesico-sympathetic reflexes are amplified after inflammation in a way that would support a major functional role for post-inflammatory central sensitisation processes. Bladder inflammation was induced in anaesthetised cats by instillation of turpentine or mustard oil and vesico-sympathetic reflexes were studied 1 and 2 h after induction of the inflammation. Inflammation enhanced on-going activity in vasoconstrictor neurones supplying skeletal muscle (after 1 h to 187.6+/-36.8%, mean+/-SEM, P<0.01, and after 2 h to 139.1+/-12.9%, P<0.05, of baseline activity) and decreased it in most sympathetic neurones supplying skin (to 91.7+/-12.5%, P>0.05, and to 71.6+/-11.3%, P<0.05, respectively, of baseline activity). Relative to the altered baseline activity vesico-sympathetic reflexes to graded distension of the inflamed bladder were quantitatively unchanged with a tendency to be diminished. Thus, the changes in on-going sympathetic vasoconstrictor activity and the distension-evoked reflexes directly mirrored the afferent input from the inflamed urinary bladder into the spinal cord, i.e. no increase of the gain of these reflexes was observed. These results suggest that in the first 2 h of inflammation, peripheral sensitisation processes play the main role for hyperalgesia and hyperreflexia of the urinary bladder. In contrast, central sensitisation appears to be of little importance during this time period.

Dynamic mechanical allodynia in humans is not mediated by a central presynaptic interaction of A beta-mechanoreceptive and nociceptive C-afferents.

Recently, Cervero and Laird (NeuroReport, 7 (1996) 526-528; Pain, 68 (1996) 13-23) proposed a new pathophysiological mechanism of dynamic mechanical allodynia in skin. Using the capsaicin pain model in humans, they showed that light mechanical stimulation within an area of secondary mechanical allodynia induces vasodilatation measured by laser-Doppler flowmetry. They suggested that the low-threshold A beta-mechanoreceptive fibres depolarize the central terminals of nociceptive primary afferent neurons via interneurons. Consequently, the vasodilatation is produced by impulses conducted antidromically in nociceptive C-axons. The allodynia was proposed to result from depolarization of central terminals of primary afferent neurons with C-fibres with activation of nociceptive dorsal horn neurons. In order to extend these findings, we used the same experimental approach but additionally stimulated the A beta-fibres electrically to evoke secondary allodynia during simultaneous monitoring skin blood flow. Twenty microlitres of a 0.5% capsaicin solution was injected intradermally into the dorsal forearm. Skin sites that demonstrated dynamic mechanical allodynia but were not located within the area of primary hyperalgesia and flare were investigated. Ten mm away from a laser-Doppler probe, dynamic mechanical allodynia was induced for 1 min (1) by moving a cotton swab and (2) by electrically stimulating the afferent nerve endings transdermally. Increasing stimulus intensities were applied (0.3-4 mA, 40 Hz, pulse duration 0.2 ms). After intracutaneous injection of capsaicin, light mechanical stimulation elicited a burning painful sensation (numeric analogue scale (NAS) 1.5-3) and concomitant movement artefacts at the laser signal. Antidromic vasodilatation was never observed. In this area of dynamic allodynia, electrical stimulation at stimulus intensities that were not painful before capsaicin injection (A beta-stimulation) was now able to elicit a burning painful sensation (NAS 1.5-3). No change in blood flow was detected. When the stimulus intensities were increased reaching levels that were also painful before capsaicin treatment (C-fibre stimulation), an increase in blood flow could be induced showing the time course of an axon reflex vasodilatation. In conclusion, electrical stimulation of A beta-fibres in allodynic skin does not induce antidromic vasodilatation. Consequently, interaction of A beta-mechanoreceptive fibres and nociceptive C-fibres at a presynaptic level is unlikely to produce antidromically conducted impulses and therefore cannot explain the pathophysiology of mechanical allodynia. Alternatively, it is much more likely that under pathophysiological conditions, activity in A beta-fibres may activate nociceptive second-order neurons, i.e. in the spinal cord.