End-stage reflex sympathetic dystrophy

Reflex sympathetic dystrophy is an automatic dysfunction that occasionally complicates healing after trauma or surgery. The syndrome is characterized by pain, swelling, stiffness, and discoloration often out of proportion to the original injury. Early diagnosis and appropriate treatment are the most important factors in the successful outcome of this disabling condition. A case of longstanding, previously untreated reflex sympathetic dystrophy secondary to a minor injury is presented.     

Fever-inducing sympathetic neural pathways

1. Fever is the widely known hallmark of disease and induced by the action of the nervous system. 2. It is generally accepted that the action of prostaglandin E₂ in the preoptic area (POA) triggers the stimulation of the sympathetic nervous system, and this results in the production of fever. 3. Recent findings have demonstrated that the rostral medullary raphe regions are essential for the pyrogenic signal transmission from the POA to sympathetic output neurons. 4. Here, I review the functional role of these raphe regions in febrile responses and also discuss the pyrogenic transmission from the POA to the raphe regions.     

Effect of cervical sympathetic trunk transection on renal sympathetic nerve activity in rats

Stellate ganglion blockade (SGB) with a local anesthetic increases muscle sympathetic nerve activity in the tibial nerve in humans. However, whether this sympathetic excitation in the tibial nerve is due to a sympathetic blockade in the neck itself, or due to infiltration of a local anesthetic to adjacent nerves including the vagus nerve remains unknown. To rule out one mechanism, we examined the effects of cervical sympathetic trunk transection on renal sympathetic nerve activity (RSNA) in anesthetized rats. Seven rats were anesthetized with intraperitoneal urethane. RSNA together with arterial blood pressure and heart rate were recorded for 15 min before and 30 min after left cervical sympathetic trunk transection. The baroreceptor unloading RSNA obtained by decreasing arterial blood pressure with administration of sodium nitroprusside was also measured. Left cervical sympathetic trunk transection did not have any significant effects on RSNA, baroreceptor unloading RSNA, arterial blood pressure, and heart rate. These data suggest that there was no compensatory increase in RSNA when cervical sympathetic trunk was transected and that the increase in sympathetic nerve activity in the tibial nerve during SGB in humans may result from infiltration of a local anesthetic to adjacent nerves rather than a sympathetic blockade in the neck itself.     

Cardiac sympathetic afferent stimulation impairs baroreflex control of renal sympathetic nerve activity in rats

It is well known that cardiac sympathetic afferent reflexes contribute to increases in sympathetic outflow and that sympathetic activity can antagonize arterial baroreflex function. In this study, we tested the hypothesis that in normal rats, chemical and electrical stimulation of cardiac sympathetic afferents results in a decrease in the arterial baroreflex function by increasing sympathetic nerve activity. Under alpha-chloralose (40 mg/kg) and urethane (800 mg/kg i.p.) anesthesia, renal sympathetic nerve activity, mean arterial pressure, and heart rate were recorded. The arterial baroreceptor reflex was evaluated by infusion of nitroglycerin (25 microg i.v.) and phenylephrine (10 microg i.v.). Left ventricular epicardial application of capsaicin (0.4 microg in 2 microl) blunted arterial baroreflex function by 46% (maximum slope 3.5 +/- 0.3 to 1.9 +/- 0.2%/mmHg, P < 0.01). When the central end of the left cardiac sympathetic nerve was electrically stimulated (7 V, 1 ms, 20 Hz), the sensitivity of the arterial baroreflex was similarly decreased by 42% (maximum slope 3.2 +/- 0.3 to 1.9 +/- 0.4%/mmHg; P < 0.05). Pretreatment with intracerebroventricular injection of losartan (500 nmol in 1 microl of artificial cerebrospinal fluid) completely prevented the impairment of arterial baroreflex function induced by electrical stimulation of the central end of the left cardiac sympathetic nerve (maximum slope 3.6 +/- 0.4 to 3.1 +/- 0.5%/mmHg). These results suggest that the both chemical and electrical stimulation of the cardiac sympathetic afferents reduces arterial baroreflex sensitivity and the impairment of arterial baroreflex function induced by cardiac sympathetic afferent stimulation is mediated by central angiotensin type 1 receptors.     

Localization of heart-innervating sympathetic neurons

Localization, amount, form of the bodies and maximal diameter of horseradish peroxidase (HP)-labelled neurons in the right stellate ganglion (SG) in the cat spinal cord have been investigated. HP application has been performed on the central parts of the SG connective branch with vagus nerve, or with the caudal cardiac nerve. In the neurons HP has been revealed after Straus or Mesulam method. In the SG, regardless the HP application place, the labelled neurons arrange in the zone, adjoining the place, where the caudal cardiac nerve and the connective branch get to the vagus nerve. In the spinal cord, when HP is applied on the connective branch, the labelled neurons are revealed in the lateral horns of the TI-TVI segments. The amount of the labelled neurons decreases in the rostro-caudal direction. Their greatest amount is revealed in the TI-TIII segments. When HP is applied on the central part of the caudal cardiac nerve, a small amount of the labelled neurons has been found in TI-TIII segments of the spinal cord only in one experiment. Thus, in the connective branch of the SG with the vagus nerve much more amount of the preganglionar fibers run than in the caudal cardiac nerve.     

Differential control of sympathetic outflow

With advances in experimental techniques, the early views of the sympathetic nervous system as a monolithic effector activated globally in situations requiring a rapid and aggressive response to life-threatening danger have been eclipsed by an organizational model featuring an extensive array of functionally specific output channels that can be simultaneously activated or inhibited in combinations that result in the patterns of autonomic activity supporting behavior and mediating homeostatic reflexes. With this perspective, the defense response is but one of the many activational states of the central autonomic network. This review summarizes evidence for the existence of tissue-specific sympathetic output pathways, which are likely to include distinct populations of premotor neurons whose target specificity could be assessed using the functional fingerprints developed from characterizations of postganglionic efferents to known targets. The differential responses in sympathetic outflows to stimulation of reflex inputs suggest that the circuits regulating the activity of sympathetic premotor neurons must have parallel access to groups of premotor neurons controlling different functions but that these connections vary in their ability to influence different sympathetic outputs. Understanding the structural and physiological substrates antecedent to premotor neurons that mediate the differential control of sympathetic outflows, including those to noncardiovascular targets, represents a challenge to our current technical and analytic approaches.     

Physiological properties of newly formed synapses between sympathetic preganglionic neurons and sympathetic ganglion neurons

We have examined the physiological properties of transmission at newly formed synapses between sympathetic preganglionic neurons and sympathetic ganglion neurons in vitro. Chick neurons were labeled with fluorescent carbocyanine dyes before they were placed into culture (Honig and Hume, 1986), and were studied by making intracellular recordings during the first 2 weeks of coculture. Evoked monosynaptic excitatory postsynaptic potentials (EPSPs) were not observed until 48 h of coculture. Beyond this time, the frequency with which connected pairs could be found did not vary greatly with time. With repetitive stimulation, the evoked monosynaptic EPSPs fluctuated in amplitude from trial to trial and showed depression at frequencies as low as 1 Hz. To gain further information about the quantitative properties of transmission at newly formed synapses, we analyzed the pattern of fluctuations of delayed release EPSPs. In mature systems, delayed release EPSPs are known to represent responses to single quanta, or to the synchronous release of a small number of quanta. For more than half of the connections we studied, the histograms of delayed release EPSPs were extremely broad. This result suggested that either quantal reponses are drawn from a continuous distribution that has a large coefficient of variation or that there are several distinct size classes of quantal responses. The pattern of fluctuation of monosynaptic EPSPs was consistent with both of these possibilities, and was inconsistent with the possibility that monosynaptic EPSPs are composed of quantal subunits with very little intrinsic variation. Although variation in the size of responses to single quanta might arise in a number of ways, one attractive explanation for our results is that the density and type of acetylcholine receptors varies among the different synaptic sites on the surface of developing sympathetic ganglion neurons.     

VEGF promotes vascular sympathetic innervation

The sympathetic nervous system, via postganglionic innervation of blood vessels and the heart, is an important determinant of cardiovascular function. The mechanisms underlying sympathetic innervation of targets are not fully understood. This study tests the hypothesis that target-derived vascular endothelial growth factor (VEGF) promotes sympathetic innervation of blood vessels. Western blot and immunohistochemical analyses indicate that VEGF is produced by vascular cells in arteries and that VEGF receptors are expressed on sympathetic nerve fibers innervating arteries. In vitro, exogenously added VEGF and VEGF produced by vascular smooth muscle cells (VSMCs) in sympathetic neurovascular cocultures inhibited semaphorin 3A (Sema3A)-induced collapse of sympathetic growth cones. In the absence of Sema3A, VEGF and VSMCs also increased growth cone area. These effects were mediated via VEGF receptor 1. In vivo, the neutralization of VEGF inhibited the reinnervation of denervated femoral arteries. These data demonstrate that target-derived VEGF plays a previously unrecognized role in promoting the growth of sympathetic axons.     

A demonstration of sympathetic cotransmission

Currently, most undergraduate textbooks that cover the autonomic nervous system retain the concept that autonomic nerves release either acetylcholine or norepinephrine. However, in recent years, a large volume of research has superseded this concept with one in which autonomic nerves normally release at least one cotransmitter along with a dominant transmitter that may or may not be acetylcholine or norepinephrine. Cotransmission involving the simultaneous release of norepinephrine, ATP, and neuropeptide Y can easily be demonstrated in an isometric ring preparation of the rat tail artery, which is described here. The experiment clearly demonstrates the principle of cotransmission but allows more advanced concepts in autonomic cotransmission to be addressed.     

Central Tempol alters basal sympathetic nerve discharge and attenuates sympathetic excitation to central ANG II

In the present study, we established dose-response relationships between central administration of 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl (Tempol, a superoxide dismutase mimetic) and the level of renal sympathetic nerve discharge (SND) and tested the hypothesis that intracerebroventricular (icv) Tempol pretreatment would attenuate centrally mediated changes in SND produced by icv ANG II administration. Urethane-chloralose-anesthetized, baroreceptor-denervated, normotensive rats were used. We found that icv Tempol administration produced dose-dependent sympathoinhibitory, hypotensive, and bradycardic responses. Mean arterial pressure and SND values were significantly increased after icv ANG II (150 ng/kg) administration, and these responses were abrogated after icv pretreatment with Tempol (75 micromol/kg) or losartan. Brain superoxide levels tended to be higher in ANG II-treated rats compared with rats treated with Tempol and ANG II. Tempol pretreatment did not prevent increases in SND level that were produced by acute heat stress, which indicates specificity in the effect of Tempol in reducing sympathoexcitation. These results demonstrate that icv Tempol administration influences central sympathetic neural circuits in a dose-dependent manner and attenuates SND responses to central ANG II infusion.