Cutaneous Vasoconstrictor Neurones Research Articles

Cardiorespiratory coupling of sympathetic outflow in humans: a comparison of respiratory and cardiac modulation of sympathetic nerve activity to skin and muscle

What is the central question of this study?Muscle sympathetic nerve activity (MSNA) is well known to be modulated by the arterial baroreceptors and respiration, but what are the magnitudes of cardiac and respiratory modulation of skin sympathetic nerve activity (SSNA), which primarily subserves thermoregulation?What is the main finding and what is its importance?Using direct microelectrode recordings of MSNA and SSNA in awake humans, we show that the magnitude of respiratory modulation of SSNA is identical to that of MSNA, the primary difference between the two sources of sympathetic outflow being the greater cardiac modulation of MSNA. This emphasises the role of the baroreceptors in entraining sympathetic outflow to muscle. It is well known that microelectrode recordings of skin sympathetic nerve activity (SSNA) in awake human subjects reveal spontaneous bursts of activity with no overt modulation by changes in blood pressure or respiration, in contrast to the clear cardiac and respiratory modulation of muscle sympathetic nerve activity (MSNA). However, cross-correlation analysis has revealed that, like individual muscle vasoconstrictor neurones, the firing of individual cutaneous vasoconstrictor neurones is temporally coupled to both the cardiac and respiratory rhythms during cold-induced cutaneous vasoconstriction, and the same is true of single sudomotor neurones during heat-induced sweating. Here, we used cross-correlation analysis to determine whether SSNA exhibits cardiac and respiratory modulation in thermoneutral conditions and to compare respiratory and cardiac modulation of SSNA with that of MSNA. Oligounitary recordings of spontaneous SSNA (n = 20) and MSNA (n = 18) were obtained during quiet, unrestrained breathing. Respiration was recorded by a strain-gauge transducer around the chest and ECG recorded by surface electrodes. Respiratory and cardiac modulation of SSNA and MSNA were quantified by fitting polynomial equations to the cross-correlation histograms constructed between the sympathetic spikes and respiration or ECG. The amplitude of the respiratory modulation (52.5 ± 3.4%) of SSNA was not significantly different from the amplitude of the cardiac modulation (46.6 ± 3.2%). Both were comparable to the respiratory modulation of MSNA (47.7 ± 4.2%), while cardiac modulation of MSNA was significantly higher (89.8 ± 1.5%). We conclude that SSNA and MSNA share similar levels of respiratory modulation, the primary difference between the two sources of sympathetic outflow being the marked cardiac modulation of MSNA provided by the baroreceptors.

Firing properties of sudomotor neurones in hyperhidrosis and thermal sweating

Idiopathic palmar-plantar hyperhidrosis is characterized by excessive sweating of the palms and feet, and is commonly treated by transthoracic regional sympathicotomy. As the condition is believed to be due to a high sudomotor drive, we wanted to assess the firing properties of individual sudomotor neurones in this state of sympathoexcitation, extending our recent work on other pathologies associated with high sympathetic nerve activity. Single-unit recordings were made from eight sudomotor neurones supplying the fingers via tungsten microelectrodes inserted percutaneously into the median nerve at the wrist or upper arm. Typical of sudomotor, muscle vasoconstrictor and cutaneous vasoconstrictor neurones recorded in healthy individuals in states of high sympathetic drive, all units had low firing probabilities (active in only 30.0 +/- 6.7 (SE) % of cardiac intervals) and primarily fired only once per heart beat. The percentage of cardiac intervals in which the neurones generated 1, 2, 3 or 4 spikes was 60.4 +/- 6.3, 22.9 +/- 3.9, 9.7 +/- 2.1 and 3.4 +/- 1.3%, respectively. For comparison, these values were 77.6 +/- 7.7, 15.0 +/- 4.1, 4.6 +/- 2.3 and 1.8 +/- 1.3% for eight sudomotor neurones innervating the hairy skin of the foot during thermally-induced sweating in normal subjects. We conclude that the firing properties of spontaneously active sudomotor neurones in subjects with hyperhidrosis are similar to those of sudomotor neurones active during thermal sweating, reflecting an increase in central sympathetic drive to the sweat glands in hyperhidrosis.

Central pathway for spontaneous and prostaglandin E2-evoked cutaneous vasoconstriction

A reduction of heat loss to the environment through increased cutaneous vasoconstrictor (CVC) sympathetic outflow contributes to elevated body temperature during fever. We determined the role of neurons in the dorsomedial hypothalamus (DMH) in increases in CVC sympathetic tone evoked by PGE2 into the preoptic area (POA) in chloralose/urethane-anesthetized rats. The frequency of axonal action potentials of CVC sympathetic ganglion cells recorded from the surface of the tail artery was increased by 1.8 Hz following nanoinjections of bicuculline (50 pmol) into the DMH. PGE2 nanoinjection into the POA elicited a similar excitation of tail CVC neurons (+2.1 Hz). Subsequent to PGE2 into the POA, muscimol (400 pmol/side) into the DMH did not alter the activity of tail CVC neurons. Inhibition of neurons in the rostral raphé pallidus (rRPa) eliminated the spontaneous discharge of tail CVC neurons but only reduced the PGE2-evoked activity. Residual activity was abolished by subsequent muscimol into the rostral ventrolateral medulla. Transections through the neuraxis caudal to the POA increased the activity of tail CVC neurons, which were sustained through transections caudal to DMH. We conclude that while activation of neurons in the DMH is sufficient to activate tail CVC neurons, it is not necessary for their PGE2-evoked activity. These results support a CVC component of increased core temperature elicited by PGE2 in POA that arises from relief of a tonic inhibition from neurons in POA of CVC sympathetic premotor neurons in rRPa and is dependent on the excitation of CVC premotor neurons from a site caudal to DMH.

Non‐nicotinic transmission in autonomic ganglia revisited – an important physiological function?

Autonomic ganglia, in particular sympathetic ones, have fascinated investigators since ancient times. It was believed that these structures are ‘little brains’ that integrate, carry and distribute the ‘animal spirits’ from the brain to the periphery leading to coordinated actions of the peripheral target organs (the ‘sympathies’) in association with the activity of the brain (McLachlan, 1995). However, their primary function is to distribute messages to the periphery from relatively small pools of preganglionic neurones to large pools of postganglionic neurones. Integration occurs in some sympathetic pathways of prevertebral ganglia (Janig, 1995). The primary transmitter in all ganglia is acetylcholine (ACh) acting on nicotinic receptors. ACh released by preganglionic fibres also acts on muscarinic receptors and preganglionic fibres may release neuropeptides, both generating slow excitatory synaptic potentials (EPSPs) in some types of postganglionic neurone by decrease of potassium conductance (M currents). What is the function of these slow EPSPs in postganglionic neurones? The paper by Morris et al. (2005) in this issue of The Journal of Physiology describes experiments on an in vitro preparation of the anterior pelvic (paracervical) ganglia with attached uterine artery and nerves that contain the preganglionic sympathetic or parasympathetic axons innervating the postganglionic vasodilator (VD) neurones to the uterine artery. Repetitive electrical stimulation of the preganglionic axons dilates the artery. This preganglionically induced VD is generated by release of NO and VIP, outlasts the train of stimuli by more then 10 min, and is only slightly reduced in amplitude and delayed after complete block of nicotinic transmission in the paracervical ganglia. It is generated by continuous discharge of the postganglionic VD neurones produced by a slow EPSP. The transmitter involved is unknown (but unlikely to be substance P, ATP, 5-HT, glutamate or ACh (muscarinic action)). The continuous discharge of the postganglionic neurones cannot be due to a long-term potentiation of cholinergic nicotinic transmission since VD neurones in the paracervical ganglia receive synaptic inputs from two preganglionic fibres, one being strong (i.e. always suprathreshold). The results of Morris et al. (2005) compare with those obtained more than 20 years ago in vivo in the cat. Repetitive electrical stimulation of preganglionic axons in the lumbar sympathetic trunk (LST; 50 stimuli at 25 Hz) elicits, in a decentralized preparation, early high frequency discharges and late cholinergic mucarinic and/or non-cholinergic long-lasting afterdischarges in many postganglionic neurones supplying the cat hindlimb (Fig. 1B). These afterdischarges can only be elicited when small-diameter (largely unmyelinated) preganglionic axons are stimulated (Janig et al. 1984); they require trains of 50 stimuli of at least 3–4 Hz or 3–10 stimuli at 25 Hz, and only occur in vasoconstrictor (VC) neurones (most muscle (MVC) and some 30% cutaneous VC neurones) but not in sudomotor or pilomotor neurones (Hoffmeister et al. 1978). In a preparation with intact LST the rate of ongoing activity in VC neurones is enhanced for 4–40 min or longer following repetitive stimulation of the small-diameter preganglionic axons (Fig. 1C). This enhancement can also be elicited heterosynaptically and is associated with a long-lasting decrease of blood flow (Blumberg & Janig, 1983; Janig & Koltzenburg, 1991). Stimulation of arterial chemoreceptors by hypoxia (8% O2 in N2) excites MVC neurones. This reflex excitation is also present in many MVC neurones after blockade of nicotinic transmission or of both nicotinic and muscarinic transmission (Fig. 1D) (Janig et al. 1983). Figure 1 Muscarinic and non-cholinergic responses elicited in postganglionic vasoconstrictor neurones (skin (CVC), muscle (MVC)) projecting to the cat hindlimb by activation of preganglionic neurones In conclusion, non-nicotinic (muscarinic and/or peptidergic) synaptic transmission in postganglionic VC neurones may be important under certain functional conditions (Fig. 1E). Infrequent bursts of impulses in preganglionic neurones with slowly conducting axons that converge on postganglionic VC neurones are necessary to generate a long-term increase in ongoing activity in postganglionic VC neurones. This may also apply to the VD and secretomotor pathways supplying the internal reproductive organs in females, leading via a non-cholinergic mechanism in paracervical ganglia to long-lasting effector responses (vasodilatation, secretion) as shown by Morris et al. (2005). These results tie up with observations in the cat that preganglionic non-VC neurones projecting in lumbar splanchnic nerves can be activated reflexly for 1–12 min after mechanical stimulation of sacral afferents for 20 s (e.g. from the anal canal; Bahr et al. 1986). The mechanism underlying this unique reflex activation that outlasts the afferent stimulus by many minutes is most likely to lie within the spinal pathways. Thus, it may be hypothesized that a centrally potentiated reflex in preganglionic neurones, that probably have VD and secretomotor function, is further amplified by non-cholinergic synaptic transmission in paracervical ganglia. This sequential cascade of amplification of a central signal might turn out to be of considerable importance in the regulation of the reproductive organs.

Influence of Deep Brain Stimulation on the Autonomic Nervous System in Patients Suffering from Parkinson's Disease

Introduction: Deep brain stimulation of the subthalamic nucleus (STN) is one of the most effective options of therapy in Parkinson's disease. On the other hand dysfunctions of the autonomic nervous system are very common in Parkinson's disease. How STN stimulation influences the autonomic nervous system, and therefore autonomic disorders, is not known yet. The aim of this study is to examine the coherences between autonomic dysfunctions and deep brain stimulation. Methods: So far 5 patients suffering from Parkinson's disease being treated with bilateral STN stimulation were examined. For this purpose blood pressure and heart rate during rest were taken and a heart rate variability test was performed. For investigations of the functions of sympathetic cutaneous vasoconstrictor neurons, a laser-Doppler was used for measuring vasoconstriction after deep inspiration. All examinations were randomized and performed on oral medication during „On“ as well as „Off“ states of the stimulator. Results: There was a trend to higher systolic and diastolic blood pressure in the supine position and an increased vasoconstriction due to increased activation of sympathetic cutaneous vasoconstrictor neurons during STN stimulation. Blood pressure during rest and heart rate variability were not influenced by deep brain stimulation. Conclusions: The results suggest an influence of STN stimulation on the sympathetic nervous system whereas tests examining mainly parasympathetic innervation have not been influenced. Further studies are needed to prove these preliminary data. Supported by the Deutsche Forschungsgemeinschaft (DFG Ba 1921/1–3).

Sympathetic nerve activity to amputated lower leg in humans: Evidence of altered skin vasoconstrictor discharge

Transection of a peripheral nerve in the cat is known to cause a regional change in sympathetic impulse pattern. Our aim was to determine whether microneurography can be used to study sympathetic activity in the transected nerve of human amputees, and whether any such activity shows an abnormal pattern similar to that observed in the cat. Seven successful sympathetic recording sessions were performed in the peroneal nerve of four subjects with posttraumatic transtibial leg amputation; one of them was studied on four occasions. Muscle nerve sympathetic activity (MSA) was detected in all four subjects. Skin nerve sympathetic activity (SSA) was found in one patient only, but on three occasions. It was more difficult to obtain high quality sympathetic recordings than for intact nerves, particularly in patients amputated many years before our studies. MSA showed a qualitatively normal pattern at rest and during various manoeuvres. In three recordings from skin nerve fascicles without innervation zone, SSA displayed normal characteristics at room temperature and qualitatively normal responses to arousal stimuli and various manoeuvres. During body cooling there was an abnormal shift in SSA pattern with a reduction in burst duration instead of the increase occurring normally. Cardiac rhythmicity of SSA was more pronounced during body cooling than during body heating. This is also a reversal of the normal pattern. The abnormal SSA pattern during body cooling suggests increased baroreflex regulation of cutaneous vasoconstrictor neurones, similar to the change after nerve transection in the cat. This is the first time that human nerve recordings support the hypothesis of a regional alteration in sympathetic impulse pattern following a nerve lesion. The implications of this phenomenon for pain conditions remains to be explored; our patients did not suffer from phantom or stump pain.

Relation between sympathetic vasoconstrictor activity and pain and hyperalgesia in complex regional pain syndromes: a case-control study

Complex regional pain syndromes can be relieved by sympathetic blockage. The mechanisms of sympathetically maintained pain (SMP) are unclear. We aimed to establish the effect of physiological sympathetic cutaneous vasoconstrictor activity on pain and hyperalgesia in patients with complex regional pain syndromes. High and low cutaneous vasoconstrictor activity was produced by whole-body cooling and warming (thermal suit) in 13 patients with type I disease and in ten controls. The degree of cutaneous vasoconstrictor discharge was monitored by measurement of skin blood flow and temperature at the arm and leg. Local skin temperature at the affected region was fixed at 35 degrees C. Pain was quantified during high and low cutaneous vasoconstrictor activity (intensity of spontaneous pain, area of mechanical hyperalgesias, heat-pain thresholds). Furthermore, pain was measured before and after diagnostic sympathetic blockage to identify patients with SMP and sympathetically independent pain. In patients with SMP, intensity of spontaneous pain significantly increased, by 22%, and spatial distribution of mechanical dynamic and punctate hyperalgesia increased by 42% and 27%, respectively, during high sympathetic activity compared with low activity. Heat-pain thresholds did not differ during high and low cutaneous vasoconstrictor activity (cold and warm state, 43.6 degrees C vs 44.6 degrees C). Pain relief after sympathetic blockage correlated with augmentation of spontaneous pain after experimental stimulation of cutaneous vasoconstrictor activity (r=0.6, p=0.0244). We have shown that in complex regional pain syndromes with SMP, physiological activation of cutaneous vasoconstrictor neurons projecting to the painful arm or leg enhances spontaneous pain and hyperalgesia. We postulate that there is a pathological interaction between sympathetic and afferent neurons within the skin.

Vascular Abnormalities in Acute Reflex Sympathetic Dystrophy (CRPS I)

Reflex sympathetic dystrophy/complex regional pain syndrome type I (RSD/CRPS I) is a painful neuropathic disorder that may develop as a disproportionate consequence of a trauma affecting the limbs without overt nerve injury. Clinical features are spontaneous pain, hyperalgesia, impairment of motor function, swelling, changes in sweating, and vascular abnormalities. To investigate pathophysiological mechanisms of vascular abnormalities in RSD/CRPS I. Case study. Autonomic test laboratory at a university hospital. A patient with an early stage of RSD/ CRPS I of the upper limb and 2 healthy control subjects. Cutaneous sympathetic vasoconstrictor innervation was assessed by measuring cutaneous blood flow (laser Doppler flowmetry) and skin temperature (infrared thermometry). To quantify sympathetic vasoconstrictor function, phasic (induced by deep inspiration) and tonic (induced by controlled thermoregulation) sympathetic reflexes were analyzed. Venous norepinephrine levels were determined bilaterally. The same tests were performed in the controls after induction of cutaneous antidromic vasodilation produced by histamine dihydrochloride application. Sympathetic cutaneous vasoconstrictor function in RSD/CRPS 1. Two weeks after the onset of RSD/CRPS I, skin temperature on the affected side was higher (close to core body temperature) than on the contralateral side at room temperature and during controlled thermoregulation, indicating maximal vasodilation. Phasic and tonic stimulation of cutaneous vasoconstrictor neurons did not induce a decrease of skin blood flow or temperature on the affected side but were normal on the contralateral side. Venous norepinephrine levels were lower on the affected side. Parallel to clinical improvement, loss of vasoconstrictor function completely recovered within weeks. Results of investigations in healthy subjects ruled out the possibility that antidromic vasodilation caused by activation of nociceptive afferents is responsible for the complete depression of sympathetic vasoconstrictor reflexes. Demonstrated for the first time is a complete functional loss of cutaneous sympathetic vasoconstrictor activity in an early stage of RSD/CRPS I with recovery. The origin of this autonomic dysfunction is in the central nervous system.

Vesico-sympathetic reflexes in cat vasoconstrictor neurones supplying skin and skeletal muscle depend on the integrity of the sacral bladder afferents

In anesthetized cats, distension of the urinary bladder induces powerful reflexes in postganglionic sympathetic neurones projecting to the hindlimb: muscle vasoconstrictor neurones (MVC) are excited and cutaneous vasoconstrictor neurones (CVC) are inhibited. We investigated these reflexes quantitatively before and after sacral rhizotomy. The reflex responses in MVC and CVC neurones were completely abolished after elimination of the pelvic afferent input demonstrating that these reflexes are generated exclusively by excitation of sacral bladder afferents. The activation of lumbar bladder afferents which are supposed to be able to elicit painful sensations did not contribute to vesico-sympathetic reflexes in MVC and CVC neurones.

Sympathetic vasoconstrictor neurons projecting from the guinea-pig superior cervical ganglion to cutaneous or skeletal muscle vascular beds can be distinguished by soma size

We have used a combination of retrograde axonal tracing and intracellular dye injections to determine the soma size of sympathetic vasoconstrictor neurons projecting from the superior cervical ganglion to the cutaneous vascular bed of the eartips, or to the vascular beds of the masseter muscle, of guinea-pigs. Neurons projecting to vasculature of the masseter muscle had a cross-sectional area of 956 ± 295 μm 2 (mean ± SD; n = 45 cells) and were significantly larger than neurons projecting to the vasculature of the eartip skin (mean cross-sectional area ± SD, 604 ± 251 μm 2; n = 39 cells). These results are consistent with physiological observations showing that muscle vasoconstrictor neurons have faster conduction velocities than cutaneous vasoconstrictor neurons. Furthermore, they suggest that muscle vasoconstrictor neurons may innervate a larger volume of vasculature compared with cutaneous vasoconstrictor neurons.

Effects of hypothalamic thermal stimuli on sympathetic neurones innervating skin and skeletal muscle of the cat hindlimb.

1. Postganglionic neurones supplying hairless and hairy skin of the cat hindlimb were analysed for their responses to thermal stimuli applied to the anterior hypothalamus and spinal cord in anaesthetized and artificially ventilated cats. Activity was recorded from multi- and single-unit bundles which were isolated from peripheral nerves. The neurones were functionally identified as cutaneous vasoconstrictor (CVC) and muscle vasoconstrictor (MVC) neurones. Activity in sudomotor (SM) neurones was either monitored indirectly by recording the phasic negative deflections of the skin potential from the surface of the hairless skin, or in some experiments additionally by recording activity directly from the SM axons. 2. The activity in forty-one out of forty-four multi-unit and six out of six single-unit CVC bundles was inhibited, in a graded manner, by hypothalamic warming. An increase in the temperature of the surface of hairless skin followed the decrease in activity of the CVC neurones supplying it. Large changes in skin temperature only followed decreases in CVC activity of more than 40%. Cooling of the hypothalamus had only weak transient effects on CVC neurones. 3. Simultaneous warming of hypothalamus and spinal cord had multiplicative effects on the activity in CVC neurones. Subthreshold warming of one structure increased the response to warming of the other one and reduced the threshold temperature. 4. SM neurones were not affected by hypothalamic warming, but activated during hypothalamic cooling. 5. MVC neurones were weakly activated during hypothalamic warming only if arterial blood pressure decreased, otherwise they were unaffected. It is likely that this activation was due to secondary unloading of arterial baroreceptors. 6. Two silent postganglionic neurones projecting to skin were activated during hypothalamic warming. These neurones may have had a vasodilatory function. 7. Rhythmicity of the activity in CVC neurones, related to the cycle of artificial ventilation, increased during hypothalamic warming whereas that of MVC neurones was unchanged. 8. The functionally highly specific responses to hypothalamic warming in CVC neurones indicate a pathway from the hypothalamus that is specific for CVC neurones, in contrast to MVC and SM neurones. This central pathway is integrated with other spinal and supraspinal reflex pathways that determine the characteristic reflex pattern of CVC neurones to somatic and visceral stimuli and possibly with pathways that generate other physiological changes during hypothalamic warming (e.g. increase in respiratory drive).

Coordination of sympathetic and respiratory systems: neurophysiological experiments.

Many sympathetic neurons exhibit respiratory rhythmicity in their activity which is due to a central coupling between respiratory neurons and neurons of autonomic pathways. The presence or absence and the pattern of this respiratory modulation depend on the function of sympathetic neurons and on the way by which both systems are coupled. In the cat, neurons supplying resistance vessels such as muscle vasoconstrictor and visceral vasoconstrictor neurons are activated during inspiration and suppressed during postinspiration. In contrast, most cutaneous vasoconstrictor neurons show no respiratory modulation in their activity, some are inhibited during inspiration and activated during expiration, and others exhibit a weak peak during inspiration. Sudomotor neurons are preferentially active during postinspiration and "inspiratory-type" neurons only during inspiration. In addition to the central coupling between presympathetic and respiratory neurons, cardiovascular afferents, notably the arterial baroreceptors, contribute an important peripheral reflex component of respiratory modulation, but only in neurons of muscle and visceral vasoconstrictor pathways.

Effects of preoptic warming on subretrofacial and cutaneous vasoconstrictor neurons in anaesthetized cats.

1. Sympathetic and subretrofacial neuron responses to preoptic warming were studied in chloralose- or Saffan-anaesthetized, paralysed cats. 2. Warming a thermode in the preoptic region inhibited the activity of cutaneous vasoconstrictor fibres supplying hairy skin. Muscle vasoconstrictor fibre activity recorded at the same time was either unaffected or raised. 3. Small injections of sodium glutamate (5 nl, 0.1 M) were made into the region of the subretrofacial nucleus in the ventrolateral medulla. The part of that region where glutamate injections evoked brisk increases in cutaneous vasoconstrictor fibre activity was chosen for further study. 4. Extracellular single unit recordings were made in that area from seventy-seven subretrofacial neurons, which were identified by their barosensitivity (inhibition by carotid blind sac inflation). Forty-seven of them were antidromically activated by stimulation in the spinal cord. 5. The activity of twenty subretrofacial neurons (twelve proven bulbospinal) was significantly reduced by periods of preoptic warming. Cutaneous vasoconstrictor activity recorded at the same time also fell. Forty-nine subretrofacial neurons (thirty-five proven bulbospinal) were unaffected or excited by periods of preoptic warming that inhibited cutaneous vasoconstrictor fibres. The response of eight neurons was unclear. 6. No difference in either mean firing rate or axonal conduction velocity was found between neurons inhibited by preoptic warming and other subretrofacial neurons. 7. The subretrofacial neurons inhibited by warming were found intermingled with those unaffected or excited. Marked recording sites of warm-inhibited neurons were clustered around the ventromedial border of the subretrofacial nucleus. 8. In two cats, bilateral inhibition of subretrofacial neurons by surface application of 1 M glycine reduced cutaneous vasoconstrictor fibre activity to 32 and 44% of control levels. 9. The results suggest that specific cutaneous vasoconstrictor premotor neurons exist in the subretrofacial nucleus. These apparently provide most of the background excitatory drive to cutaneous vasomotor neurons. Central warming stimuli may act, at least in part, by withdrawing that drive.

Reflex patterns in postganglionic neurons supplying skin and skeletal muscle of the rat hindlimb.

1. Reflex patterns were analyzed in spontaneously active postganglionic vasoconstrictor neurons supplying skeletal muscle [muscle vasoconstrictor (MVC) neurons] and hairy skin [cutaneous vasoconstrictor (CVC) neurons] of the rat hindlimb. Postganglionic activity was recorded from single units and from filaments containing the axons of several spontaneously active neurons (multiunit preparations). The animals were freely breathing or artificially ventilated and maintained, in different experiments, under three different types of anesthesia (pentobarbital, chloralose, urethan). Reflexes were elicited by stimulation of arterial baroreceptors, chemoreceptors, cutaneous nociceptors, and cold receptors and visceral receptors from urinary bladder and colon. 2. Spontaneous activity of single postganglionic neurons ranged from 0.3 to 3.6 imp/s (median 1.15 imp/s and 1.0 imp/s in MVC and CVC neurons, respectively). Postganglionic axons conducted at 0.56 +/- 0.15 m/s (mean +/- SD, MVC neurons) and 0.53 +/- 0.11 m/s (CVC neurons). There was almost no difference in the rate of spontaneous activity under the three anesthetics used and whether the animals were artificially ventilated or breathing freely. 3. Stimulation of arterial baroreceptors by increasing arterial blood pressure by > 30 mmHg with intravenous injections of phenylephrine or angiotensin led to a depression of the activity in almost all vasoconstrictor neurons. In simultaneous recordings, with an identical increase of blood pressure, the magnitude of inhibition was greater in MVC neurons than in CVC neurons. Phasic stimulation of the arterial baroreceptors by the pulse pressure wave evoked a pronounced cardiac rhythmicity in the activity of the majority of MVC neurons (78%), but in only a small fraction of CVC neurons (18%). In most CVC neurons the cardiac rhythmicity was weak (33%) or absent (49%). When quantified the difference in the degree of cardiac rhythmicity between simultaneously recorded MVC and CVC neurons was highly significant (P < 0.001). 4. Noxious mechanical stimulation of skin of the ipsilateral hindpaw activated 20/35 MVC preparations (57%) and inhibited 25/47 CVC preparations (53%). Some CVC neurons (19%) were also activated, whereas the remainder of neurons were not affected. The quality of responses to noxious stimulation was correlated with the degree of cardiac rhythmicity that the sympathetic neurons displayed in their activity. A similar reciprocal response pattern in CVC and MVC neurons, albeit less pronounced, was observed to intense cold stimuli (chlor-ethyl spray) applied to the hindlimb. 5. This reciprocal pattern of the responses of MVC and CVC neurons was not observed when nociceptors from the contralateral hindlimb were stimulated and when cold stimuli were applied to the abdominal skin.(ABSTRACT TRUNCATED AT 400 WORDS)

Viscero-sympathetic reflex responses to mechanical stimulation of pelvic viscera in the cat

Viscero-sympathetic reflex responses to mechanical stimulation of urinary bladder and colon were studied in cutaneous vasoconstrictor (CVC) neurones supplying hairy skin, in muscle vasoconstrictor (MVC) neurones supplying skeletal muscle and in sudomotor (SM) neurones supplying the sweat glands of the central paw pad of the cat hindlimb. The cats were anaesthetized, paralysed and artificially ventilated. The vasoconstrictor activity was recorded from the axons of the postganglionic fibres that were isolated in filaments from the respective peripheral hindlimb nerves. The activity in the sudomotor neurones was monitored by recording the fast skin potential changes occurring on the surface of the central paw pad. Afferents from the urinary bladder and from the colon were stimulated by isotonic distension and isovolumetric contraction of the organs. Most CVC neurones with ongoing activity were inhibited by these stimuli; only a few CVC neurones were excited. The MVC and SM neurones were generally excited by the visceral stimuli, yet the size of the evoked skin potential changes was variable. The reflex responses elicited in the sympathetic outflow to the cat hindlimb by stimulation of visceral afferents from the pelvic organs are uniform with respect to the different types of afferent input system but differentiated with respect to the efferent output systems. Graded stimulation of the visceral afferents from the urinary bladder by isotonic pressure steps elicited graded reflex responses in CVC (threshold < 30 mmHg) and MVC neurones (threshold < 20 mmHg) and a graded increase of the arterial blood pressure (threshold < 20 mmHg). These graded reflex responses are closely related to the quantitative activation of sacral afferent neurones with thin myelinated axons innervating the urinary bladder that are also responsible for eliciting the micturition reflex, but not to the quantitative activation of sacral afferent neurones with unmyelinated axons. The latter have thresholds of 40–50 mmHg intravesical pressure at which the size of the vesico-sympathetic reflexes in the vasoconstrictor neurones was about 50% of maximal size. This does not exclude the fact that activation of unmyelinated vesical afferents contributes to the vesico-sympathetic reflexes.

Respiratory modulation of the activity in sympathetic neurones supplying muscle, skin and pelvic organs in the cat.

1. The respiratory-related modulation of activity in neurones of the lumbar sympathetic outflow to skeletal muscle, skin and pelvic organs was investigated in anaesthetized, paralysed and artificially ventilated cats, using single- and multi-unit recordings. The activity of the neurones was analysed with respect to the phrenic nerve discharge under various experimental conditions. 2. Neurones tentatively classified as muscle vasoconstrictor and visceral vasoconstrictor neurones exhibited two activity peaks, one caused by baroreceptor unloading during the declining phase of the second order blood pressure waves and a respiratory drive-dependent peak in parallel with inspiration. The two peaks were separated by depressions of activity in early inspiration and post-inspiration. After cutting vagus and buffer nerves the activity peak during inspiration remained and was followed and sometimes preceded by a depression of activity. 3. The majority of the neurones tentatively classified as cutaneous vasoconstrictor neurones exhibited no respiratory modulation in their activity. Others exhibited an activity peak in expiration, an activity peak in inspiration, or a respiratory profile similar to that in muscle vasoconstrictor neurones. During increased respiratory drive (induced by hypercapnia) some neurones with unmodulated activity changed to an inspiratory or an expiratory pattern. Neurones discharging predominantly in inspiration projected preferentially to hairless skin. 4. Neurones which were tentatively classified as sudomotor neurones discharged predominantly in early expiration. 5. Some preganglionic neurones which were tentatively classified as motility-regulating neurones discharged during expiration. The majority of these neurones disclosed no respiratory modulation of their activity. 6. The study shows that different types of neurone of the lumbar sympathetic system exhibit distinct patterns of respiratory modulation in their activity. We conclude that the type and degree of central coupling between respiratory system and sympathetic nervous system may vary according to the destination of the sympathetic neurones.

Changes of reflexes in vasoconstrictor neurons supplying the cat hindlimb following chronic nerve lesions: a model for studying mechanisms of reflex sympathetic dystrophy?

The generic term ·reflex sympathetic dystrophy’ describes a clinical syndrome which sometimes develops after traumata at the extremities with lesions of nerves or — more rarely — after other events. The syndrome consists of the following components: pain (hyperpathia, allodynia), trophic changes of skin and deep tissues, dysregulation of sweating and cutaneous blood flow of the extremity concerned. It is assumed that all symptoms are produced by abnormal sympathetic activity. Interruption of the sympathetic activity to the affected extremity abolishes most of the pain and may lead to remission of the trophic changes. The hypothesis is that the trauma with lesion of the primary afferent axons leads subsequently to an abnormal state of the primary afferent neurons and to distorted processing of information in the spinal cord. As a consequence of this abnormal central state the activity in the sympathetic (vasomotor and sudomotor) supply to the affected extremity is distorted. The results are pain, trophic changes and dysregulations of autonomic effector organs. In some yet unknown way a vicious circle between periphery and spinal cord is established (afferent → spinal cord → sympathetic → afferent). This hypothesis was the starting point for analysis of the reflex pattern in postganglionic vasoconstrictor neurons supplying the cat hindlimb after chronic nerve lesions performed in the same limb (cutting and ligating a skin nerve; suturing the central stump of a skin nerve to the peripheral stump of a muscle nerve). The results obtained show that the reciprocity of the reflex pattern which is normally observed between cutaneous and muscle vasoconstrictor neurons is lost in many animals. Cutaneous vasoconstrictor neurons are very similar to muscle vasoconstrictor neurons in their reactions to stimulation of arterial baroreceptors and chemoreceptors. If the same sequence of events also occurs in patients with reflex sympathetic dystrophy, it could explain the dysregulation of blood flow through skin and also the occurrence of trophic changes in the limb.

Discharge patterns of sympathetic neurons supplying skeletal muscle and skin in man and cat

Skeletal muscle and skin of humans and cats are supplied by various sympathetic systems: vasoconstrictor neurons, sudomotor neurons, vasodilator neurons and pilomotor neurons. Only vasoconstrictor and sudomotor neurons have resting activity in both species. Discharge patterns of spontaneous activity in postganglionic neurons with resting activity as well as their reflex responses to various stimuli have been compared for both species: (1) muscle vasoconstrictor neurons react similarly in both species; they are under dominant control of arterial baroreceptors; (2) in both species cutaneous vasoconstrictor neurons are under no or weak control of arterial baroreceptors and they are influenced in similar ways by thermal stimuli. In contrast, other (somatic and visceral) stimuli elicit largely inhibition in these neurons in cats but excitation in humans. This may be due to the different experimental situations (anesthesia, etc.); (3) sudomotor neurons in humans are involved in thermoregulation, in cats they are not. The differences in the reflexes may also be due to the different experimental situations and to species differences; (4) the implications of studies on sympathetic neurons in humans and animals for the progress of research in this field have been discussed.

Reflex activation of postganglionic vasoconstrictor neurones supplying skeletal muscle by stimulation of arterial chemoreceptors via non-nicotinic synaptic mechanisms in sympathetic ganglia.

Postganglionic sympathetic neurones supplying skeletal muscle and skin can be activated from the preganglionic site via cholinergic nicotinic, muscarinic and noncholinergic synaptic mechanisms. The experiments described in this paper were designed in order to show that postganglionic vasoconstrictor neurones supplying skeletal muscle can be activated by the naturally occurring discharge pattern in preganglionic axons when the nicotinic transmission is blocked. For this purpose, the activity was recorded simultaneously from postganglionic vasoconstrictor axons supplying skeletal muscle and vasoconstrictor axons supplying hairy skin. The preganglionic neurones were driven reflexly by stimulation of the arterial chemoreceptors. 1) During blockade of nicotinic transmission muscle vasoconstrictor neurones were activated via the CNS during stimulation of arterial chemoreceptors. This activation is either generated by muscarinic action of released acetylcholine or by a noncholinergic synaptic mechanism. 2) Postganglionic cutaneous vasoconstrictor neurones were inhibited during stimulation of arterial chemoreceptors. During blockade of cholinergic nicotinic transmission these neurones were not activated reflexly by stimulation of arterial chemoreceptors although they received inputs via cholinergic muscarinic and noncholinergic synaptic mechanisms. 3) The results illustrate that postganglionic vasoconstrictor neurones supplying skeletal muscle can not only be activated via non-nicotinic synaptic mechanisms through synchronous repetitive electrical stimulation of preganglionic axons but also by the discharge pattern produced in preganglionic neurones during stimulation of arterial chemoreceptors.

Effects of sytemic hypoxia and hypercapnia on cutaneous and muscle vasoconstrictor neurones to the cat's hindlimb.

1. Reactions of cutaneous and muscle vasoconstrictor neurones to the hindlimb on systemic hypoxia and systemic hypercapnia were investigated in chloralose anaesthetized cats. Mainly four types of preparations were used: brain intact and decrebrate (pontomedullary) animals with and without carotid sinus (CSN) and vagal nerves (VN). 2. In brain intact animals with intact CSN and VN most cutaneous vasoconstrictor neurones were depressed and most muscle vasoconstrictor neurones were excited during systemic hypoxia and hypercapnia. The responses to hypercapnia were smaller than those to hypoxia. 3. In brain intact deafferented animals and in decerebrate animals with and without intact CSN and VN systemic hypoxia and hypercapnia induced excitation in both cutaneous and muscle vasoconstrictor neurones. The responses to hypoxia were significantly smaller in deafferented preparations when compared to those in preparations with intact CSN and VN. Furthermore in muscle vasoconstrictor neurones the size of the responses was not significantly different in decerebrate preparations from that in brain intact preparations. 4. These results indicate a distinct neuronal organization of the chemoreceptor reflexes in the vasoconstrictor systems in the brain stem. Suprapontine brain structures are most important for producing the inhibition of the cutaneous vasoconstrictor neurones during hypoxia and hypercapnia.