[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.

Enhanced pain and autonomic responses to ambiguous visual stimuli in chronic Complex Regional Pain Syndrome (CRPS) type I.

Cortical reorganisation of sensory, motor and autonomic systems can lead to dysfunctional central integrative control. This may contribute to signs and symptoms of Complex Regional Pain Syndrome (CRPS), including pain. It has been hypothesised that central neuroplastic changes may cause afferent sensory feedback conflicts and produce pain. We investigated autonomic responses produced by ambiguous visual stimuli (AVS) in CRPS, and their relationship to pain. Thirty CRPS patients with upper limb involvement and 30 age and sex matched healthy controls had sympathetic autonomic function assessed using laser Doppler flowmetry of the finger pulp at baseline and while viewing a control figure or AVS. Compared to controls, there were diminished vasoconstrictor responses and a significant difference in the ratio of response between affected and unaffected limbs (symmetry ratio) to a deep breath and viewing AVS. While viewing visual stimuli, 33.5% of patients had asymmetric vasomotor responses and all healthy controls had a homologous symmetric pattern of response. Nineteen (61%) CRPS patients had enhanced pain within seconds of viewing the AVS. All the asymmetric vasomotor responses were in this group, and were not predictable from baseline autonomic function. Ten patients had accompanying dystonic reactions in their affected limb: 50% were in the asymmetric sub-group. In conclusion, there is a group of CRPS patients that demonstrate abnormal pain networks interacting with central somatomotor and autonomic integrational pathways.

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.

[Clinical findings in patients with chronic complex regional pain syndrome]. / Klinische Auffälligkeiten bei Patienten mit chronischem komplexen regionalen Schmerzsyndrom (sympathische Reflexdystrophie/Kausalgie).

PURPOSE: What are the clinical findings in patients with chronic complex regional pain syndrome (CRPS)? METHODS: Bedside examination was performed in 40 patients with CRPS and a mean illness duration of 43 months. To evaluate motor and autonomic disturbances, rating scales were developed and applied. Quantitative sensory testing (QST) was conducted in 24 patients. RESULTS: Clinical examination revealed sensory abnormalities in 93% of patients examined (in 56% limited to the affected limb, in 7% in the upper quadrant of the body, in 30% hemisensory impairment of the ipsilateral body side), and 60% of the patients suffered from mechanical allodynia in the affected limb. Patients with generalized sensory impairment had a significantly longer illness duration, pain intensity and significantly higher frequency of mechanical allodynia/hyperalgesia than patients with sensory deficits limited to the limb affected. In patients with generalized sensory abnormalities, QST revealed significant changes of cold, warm and touch thresholds on the ipsilateral compared to the contralateral body side. Mild/moderate motor abnormalities could be demonstrated in 45% of patients, tremor (50%), impaired joint movements, 45%, and 40% of patients revealed autonomic disturbances. CONCLUSION: In chronic CRPS, among clinical symptoms and signs, pain and sensory impairment play a major role. Mechanical allodynia reveals the highest level of subjective disability among all symptoms. With respect to hemisensory impairment, functional disturbances of central pain processing in the nucleus ventralis posterior of the thalamus are postulated.

Neurophysiological tests and neuroimaging procedures in non-acute headache: guidelines and recommendations.

The use of instrumental examinations in headache patients varies widely. In order to evaluate their usefulness, the most common instrumental procedures were evaluated, on the basis of evidence from the literature, by an EFNS Task Force (TF) on neurophysiological tests and imaging procedures in non-acute headache patients. The conclusions of the TF regarding each technique are expressed in the following guidelines for clinical use. 1 Interictal electroencephalography (EEG) is not routinely indicated in the diagnostic evaluation of headache patients. 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 and basilar migraine. 2 Recording of evoked potentials is not recommended for the diagnosis of headache disorders. 3 There is no evidence to justify the recommendation of autonomic tests for the routine clinical examination of headache patients. 4 Manual palpation of pericranial muscles, with standardized palpation pressure, can be recommended for subdividing patient groups but not for diagnosis. Pressure algometry and electromyography (EMG) cannot be recommended as clinical diagnostic tests. 5 In adult and paediatric patients with migraine, with no recent change in attack pattern, no history of seizures, and no other focal neurological signs or symptoms, the routine use of neuroimaging is not warranted. In patients with atypical headache patterns, a history of seizures and/or focal neurological signs or symptoms, magnetic resonance imaging (MRI) may be indicated. 6 If attacks can be fully accounted for by the standard headache classification [International Headache Society (IHS)], a positron emission tomography (PET) or single-photon emission computerized tomography (SPECT) and scan will generally be of no further diagnostic value. 7 Nuclear medicine examinations of the cerebral circulation and metabolism can be carried out in subgroups of headache patients for diagnosis and evaluation of complications, when patients experience unusually severe attacks, or when the quality or severity of attacks has changed. 8 Transcranial Doppler examination is not helpful in headache diagnosis. Although many of the examinations described are of little or no value in the clinical setting, most of the tools have a vast potential for further exploring the pathophysiology of headaches and the effects of pharmacological treatment.

Blockade of nociceptive inhibition of plasma extravasation by opioid stimulation of the periaqueductal gray and its interaction with vagus-induced inhibition in the rat.

We have previously shown that stimulation of cutaneous or visceral nociceptors suppresses inflammation measured as bradykinin-induced synovial plasma extravasation in the knee joint of the rat. This suppression occurs through the activation of a spinal as well as a supraspinal reflex pathway leading to activation of the adrenal medullae and probably the release of epinephrine. These nociceptive-neuroendocrine reflex pathways are tonically inhibited by activity in abdominal vagal afferents acting through an inhibitory descending pathway projecting through the dorsolateral funiculus (DLF) ipsilateral to the cutaneous afferent nociceptive input. Here we investigated whether the descending inhibitory pathway acted upon by vagal afferents is also modulated by the periaqueductal gray (PAG), similar to other bulbo-spinal pathways acting on spinal nociceptive transmission. Injection of morphine sulfate (10 nmol) in the ventrolateral PAG significantly inhibited the nociceptive-neuroendocrine reflex pathways, an effect that was significantly less after removal of vagal afferents (i.e. after release from tonic inhibition maintained by vagal afferents). Interruption of the DLF ipsilateral to the nociceptive input removed the inhibitory effect of vagal afferents and partly reduced the inhibition produced by morphine injected in the PAG. From these investigations we conclude that PAG-induced inhibition of the nociceptive-neuroendocrine reflex pathways is mediated through the DLF ipsilateral to the nociceptive input, involving the same descending inhibitory pathway that relays afferent vagal inhibition, and through other spinal and possibly supraspinal pathways.

Relationship between pain and autonomic phenomena in headache and other pain conditions.

Involvement of the (efferent) autonomic nervous system in the generation of pain is ongoing matter of debate. Based on clinical and experimental observations, there are good arguments that the sympathetic nervous system may be involved in pain following trauma, with and without nerve lesion, at an extremity, such as in complex regional pain syndrome type I and II. However, the mechanisms involved are in many cases still unclear. In various types of headache there is no convincing evidence that the sympathetic nervous system is involved in the generation of pain, although these pains may be accompanied by considerable autonomic reactions which are dependent on activity in sympathetic neurons. Migraine and headaches with autonomic symptoms are accompanied by autonomic reactions which are dependent on activity in cranial parasympathetic neurons. Whether parasympathetic neurons innervating cranial blood vessels are involved in activation or sensitization of trigemino-vascular afferents is discussed and needs experimental verification.

Neurophysiological analysis of target-related sympathetic pathways--from animal to human: similarities and differences.

The sympathetic nervous system regulates many different target tissues in the somatic and visceral domains of the body in a differentiated manner, indicating that there exist separate sympathetic pathways that are functionally defined by their target cells. Signals generated by central integration and channelled through the preganglionic neurons into the final sympathetic pathways are precisely transmitted through the para- and prevertebral ganglia and at the neuroeffector junctions to the effector cells. Neurophysiological recordings of activity in postganglionic neurons in skin and muscle nerves using microneurography in human subjects and in skin, muscle and visceral nerves, using conventional recording techniques in anaesthetized animals, clearly show that each type of sympathetic neuron exhibits a discharge pattern that is characteristic for its target cells and, therefore, its function. These findings justify labelling the neurons as muscle vasoconstrictor, cutaneous vasoconstrictor, sudomotor, lipomotor, cardiomotor, secretomotor neurons, etc. The discharge patterns monitor aspects of the central organization of the respective sympathetic system in the neuraxis and forebrain. They can be dissected into several distinct reflexes (initiated by peripheral and central afferent inputs) and reactions connected to central signals (related to respiration, circadian and other rhythms, command signals generated in the forebrain, etc). They are functional markers for the sympathetic final pathways. These neurophysiological recordings of the discharge patterns from functionally identified neurons of sympathetic pathways in the human and in animals are the ultimate reference for all experimental investigations that aim to unravel the central organization of the sympathetic systems. The similarities of the results obtained in the in vivo studies in the human and in animals justify concluding that the principles of the central organization of sympathetic systems are similar, if not identical, at least in the neuraxis, in both species. Future progress in the analysis of the central neuronal circuits that are associated with the different final sympathetic pathways will very much depend on whether we are able to align the human models and the animal models. Human models using microneurography have the advantage to work under awake conditions. The activity in the postganglionic neurons can be correlated with various other (afferent, centrally generated) signals, effector responses, perceptions, central changes monitored by imaging methods, etc. However, human models have considerable limitations. Animal models can be divided into in vivo models and various types of reduced in vitro models. Animal models allow using various methodological approaches (e.g., neurophysiological, pharmacological, modern anatomical tracing methods; behavioural animal models; transgenic animals), which cannot be used in the human. Interaction of the research performed in the human and animals will allow to design animal models that are relevant for diseases in which the sympathetic nervous systems is involved and to trace down the underlying pathophysiological mechanisms. The scientific questions to be asked are formulated on the basis of clinical observations resulting in testable hypotheses that are investigated in the in vivo human and animal models. Results obtained in the in vivo models lead to the formulation of hypotheses that are testable in reduced in vivo and particularly in vitro animal models. Microneurographic recordings from sympathetic postganglionic fibres in the human will keep its place in the analysis of the sympathetic nervous system in health and disease although only relatively few laboratories in the world will be able to keep the standards and expertise to use this approach. Experimental investigation of the organization of the sympathetic nervous system in animal models has changed dramatically in the last 15 years. The number of in vitro models and the methodological diversity have increased. In vivo experimentation on larger animals has almost disappeared and has been replaced by experimentation on rats, which became the species for practically all types of studies on the central organization of the sympathetic nervous system.

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.

[Visceral pain--a neglected phenomenon in pain therapy and research?]. / Bauchschmerzen - ein Stiefkind der Schmerztherapie und Forschung?

The topic "visceral pain"is hardly covered in basic research and pain therapy. After low back pain, headache and musculosceletal pain is abdominal pain the 4th frequent chronic pain syndrome in the general population with considerable direct and indirect disease related costs.An interdisciplinary multimodal treatment of chronic abdominal pain syndromes is rarely practiced in clinical care.

[Physiology and pathophysiology of visceral pain]. / Physiologie und Pathophysiologie viszeraler Schmerzen.

Visceral pain is diffusely localized, referred to deep somatic tissues, skin and viscera, frequently not correlated with an actual trauma, commonly correlated with strong negative affective reactions and accompanied by strong protective autonomic and motor reactions. It is correlated with the excitation of spinal (thoraco-lumbar, sacral) visceral afferents and (with a few exceptions) not with the excitation of vagal afferents. Spinal visceral afferents are polymodal and can be excited by physical and chemical stimuli. All groups of visceral afferents can be sensitized (e.g.by inflammation). Normally silent (mechanically insensitive) visceral afferents are recruited by inflammation. Individual visceral afferent neurons project in laminae I and V of the dorsal horn over several segments, medio-lateral over the entire width of the dorsal horn and to the contralateral side. Their activity is synaptically transmitted, in these and deeper laminae, to viscero-somatic convergent neurons which receive additional afferent synaptic input from skin and deep somatic tissues of the corresponding dermatomes,myotomes and sclerotomes. The mechanism of sensitization of viscerosomatic convergent neurons (central sensitization) during sensitization of spinal visceral afferents is unclear.Viscero-somatic tract neurons project to lower and upper brain stem,hypothalamus and via the thalamus to various cortex areas. Visceral nociception and pain is presumably (together with other visceral sensations and homeostatic regulations of autonomic body functions) primarily represented in the insula in the context of interoception. The insula obtains its main peripheral afferent input from lamina I neurons via the Nucleus ventromedialis posterior of the thalamus. The transmission of visceral impulses in the spinal cord is modulated by the endogenous control systems in the brain stem which are in turn under the control of cortex and limbic system.

Spino-bulbo-spinal pathway mediating vagal modulation of nociceptive-neuroendocrine control of inflammation in the rat.

Stimulation of nociceptors by intradermal capsaicin produces depression of bradykinin (BK)-induced synovial plasma extravasation (PE) that is markedly enhanced by subdiaphragmatic vagotomy. This depression is mediated by the adrenal medullae, a propriospinal pathway between the afferent nociceptive input and preganglionic neurones projecting to the adrenal medullae, and a spino-bulbo-spinal pathway. Here we investigated the role of spinal ascending and descending pathways in the interaction between noxious and vagal afferent inputs, leading to inhibition of BK-induced PE mediated by the adrenal medullae. Nociceptors in the paw were activated by capsaicin and depression of BK-induced PE was measured in rats with intact or cut subdiaphragmatic vagus nerves. After cutting the dorsolateral funiculus (DLF) contralateral to the stimulated hindpaw (segmental level C5/C6 and T8/T9), depression of BK-induced PE was weak or absent both in rats with intact vagus nerves and in vagotomised rats, suggesting that an ascending excitatory pathway was interrupted. After cutting the DLF ipsilateral to the stimulated hindpaw, depression of BK-induced PE was already markedly enhanced, even in the absence of vagotomy. Ipsilateral DLF lesion (L2/L3) below the level of the spinal output to the adrenal medullae produced the same effect, suggesting interruption of a descending inhibitory pathway that relays the effect of vagal activity to the level of the capsaicin-induced nociceptive input. Contralateral and ipsilateral hemisection of the spinal cord (C5/C6) produced the same changes as the corresponding DLF lesions. Ipsi- or contralateral lesion of the dorsal funiculus at the spinal level T8/T9 had no effect on depression of BK-induced PE generated by cutaneous noxious stimulation of the forepaw. We suggest that noxious stimulation activates an ascending pathway of the spino-bulbo-spinal excitatory circuit which projects through the DLF contralateral to the nociceptive input, and that the inhibitory pathway which is activated by vagal afferent activity projects through the DLF ipsilateral to the nociceptive input.

Reflex patterns in preganglionic sympathetic neurons projecting to the superior cervical ganglion in the rat.

Reflex patterns in preganglionic neurons projecting in the cervical sympathetic trunk (CST) were analyzed in response to stimulation of various afferent systems. We focused on the question whether these preganglionic neurons can be classified into functionally distinct subpopulations. Reflex responses were elicited by stimulation of trigeminal and spinal nociceptive, thermoreceptive as well as baroreceptor and chemoreceptor afferents. Multi- and single fiber preparations were studied in baroreceptor intact and sino-aortically denervated animals. Spontaneous activity of 36 preganglionic single neurons ranged from 0.2 to 3.5 imp/s (median= 1.11 imp/s). The degree of cardiac rhythmicity (CR) in the activity of sympathetic neurons was 69.5+/-13% (mean+/-S.D.; N=52; range=39-95%). Noxious stimulation of acral skin activated the majority (67%) of sympathetic preparations by 37+/-25% (N=35) above pre-stimulus activity; 15% were inhibited. In these neurons the response to noxious stimulation of acral skin was significantly correlated with the degree of CR (P<0.001, N=52) in that neurons showing the strongest excitation to noxious stimulation displayed the strongest CR. Noxious mechanical stimulation of body trunk skin (N=60) inhibited the majority (80%) of fiber preparations tested (by 34+/-18% of pre-stimulus activity, N=48); an activation was not observed. Cold stimulation of acral (N=9) and body trunk skin (N=42) activated most fiber preparations. Trigeminal stimulation evoked a uniform reflex activation of preganglionic neurons (+79+/-73% of pre-stimulus activity, N=32). Chemoreceptor stimulation by systemic hypercapnia elicited inhibitory (-31+/-19%, N=8) as well as excitatory (+59+/-5%, N=4) responses. These results show that preganglionic sympathetic neurons projecting to target organs in the head exhibit distinct reflex patterns to stimulation of various afferent systems; however, a clear classification into different functional subgroups did not emerge. Furthermore, reflex patterns showed a segmental organization to noxious cutaneous stimulation of acral parts and body trunk reflecting a differential central integration of spinal afferent input. Compared with the cat the reflex organization of sympathetic neurons projecting to the head seems to be less differentiated in the anesthetized rat.

Respiratory rhythmicity in the activity of postganglionic neurones supplying the rat tail during hyperthermia.

It has been suggested that thermoregulatory stimulation changes respiration-related rhythmicity in the activity of postganglionic sympathetic neurones supplying the rat tail to a distinct modulation independent of respiration. To study this possibility, single and few fibre recordings were made from ten filaments split from the ventral collector nerves of the rat during whole body warming. Sympathetic activity was analysed by autocorrelation and phrenic-triggered summation. All neurones except one were gradually inhibited and lost their on-going activity above a core temperature of 39-39.5 degrees C while the frequency of the phrenic bursts increased significantly. During hyperthermia, all neurones tested exhibited a prominent respiratory modulation in their activity which, compared to normothermia, was significantly increased in strength, or even newly acquired. No other rhythm emerged. These results speak against the hypothesis that in the rat sympathetic pathways controlling the tail vasculature and thus involved in thermoregulation, during hyperthermia become controlled by central oscillators distinct from the respiratory rhythm generator. Rather, respiratory modulation appears to remain the dominant rhythm as is common for sympathetic neurones supplying other cardiovascular targets.

Nociceptive neuroendocrine negative feedback control of neurogenic inflammation activated by capsaicin in the rat paw: role of the adrenal medulla.

Recently we have found that inhibition of bradykinin-induced synovial plasma extravasation by transcutaneous electrical stimulation at strengths which excite unmyelinated afferent axons is mediated by the hypothalamo-pituitary-adrenal axis. Here we tested whether stimulation of nociceptors in the rat paw by intradermally injected capsaicin inhibits bradykinin-induced synovial plasma extravasation and whether this inhibition is mediated by the hypothalamo-pituitary-adrenal or sympatho-adrenal axis. Furthermore, we tested whether inhibition of bradykinin-induced plasma extravasation generated by intraperitoneally injected capsaicin, which preferentially excites visceral afferents, is mediated by the hypothalamo-pituitary-adrenal or sympatho-adrenal axis. We used normal rats, subdiaphragmatically vagotomized rats, rats with denervated adrenal medullae and rats with acutely transected spinal cords at the segmental levels T1/T2 or T12/L1. Injection of capsaicin into the plantar or palmar surface of the paws produced a depression of bradykinin-induced plasma extravasation. The inhibition elicited from the forepaw was larger than that from the hindpaw. The inhibition of bradykinin-induced plasma extravasation elicited from both paws was potentiated by subdiaphragmatic vagotomy. Denervation of the adrenal medullae abolished the inhibitory effect of intradermal capsaicin in vagus-intact and in vagotomized animals. After spinalization at the segmental level T1/T2, capsaicin injected into the forepaw did not depress bradykinin-induced plasma extravasation either in vagus-intact or in vagotomized animals. Capsaicin injected into the hindpaw in these spinalized animals produced a small depression. After spinalization at the segmental level T12/L1 no depression was produced by capsaicin injected into the hindpaw. Depression of bradykinin-induced plasma extravasation generated by intraperitoneal injection of capsaicin in vagus-intact and in vagotomized animals was also abolished or attenuated after denervation of the adrenal medullae. This shows that this depression was also largely dependent on the activation of the sympatho-adrenal system. We conclude that depression of bradykinin-induced plasma extravasation during stimulation of nociceptors by capsaicin is mediated predominantly by the sympathoadrenal pathway. This finding differs from the inhibitory mechanism of depression of bradykinin-induced plasma extravasation generated by cutaneous electrical stimulation, which is mediated by the hypothalamo-pituitary-adrenal axis.