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Changes of reflexes in vasoconstrictor neurons supplying the cat hindlimb following chronic nerve lesions: a model for studying mechanisms of reflex sympathetic dystrophy?
Journal of the A utonomic Nervous System, 7 (1983) 399-411
399
Elsevier BiomedicalPress
Changes of reflexes in vasoconstrictor neurons supplying the cat hindlimb following chronic nerve lesions: a model for studying mechanisms of reflex sympathetic dystrophy? H. B l u m b e r g i and W. J~inig 2 Physiologisches Institut, Universitiit, Olshausenstr. 40-60, 2300 Kiel, (F.R.G.)
(ReceivedSeptember 1st, 1982) (AcceptedNovember 1st, 1982)
K e y words: reflex sympathetic dystrophy - - hypothesis - - reflex patterns in post-
ganglionic vasoconstrictor neurons
Abstract 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 i Present address: NeurologischeKlinik, Universitat Freiburg, Hansastr. 9, 7800 Freiburg, F.R.G. 2 To whom reprint requests should be addressed. 0165-1838/83/0000-0000/$03.00 © 1983 ElsevierSciencePublishers
400 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.
Introduction Reflex sympathetic dystrophy is an all-inclusive term which describes the clinical symptomatology of etiologically seemingly unrelated disorders such as post-traumatic pain syndrome, minor causatgia [17,30], post-traumatic arthrosis, Sudeck's atrophy (syndrome) [40], shoulder-hand syndrome, chronic traumatic (post-traumatic) edema, reflex dystrophy, algodystrophy [27] and others [7,8]. The term was coined by Evans [12] and has been fully introduced into the literature by Bonica [7]. It describes a syndrome which consists of the following components: (1) pain: burning pain, hyperpathia * and allodynia * occur within the territory concerned. This is obvious for the skin, but also present for deeper tissues, including muscle and bone; (2) dystrophy: the tissues from the region concerned, such as skin, subcutaneous tissue, muscle, bone and joint capsules, may waste. Furthermore, features of abnormal growth, such as ridging of nails, hyperkeratosis and hypertrichiosis, may be observed; (3) sympathetic: abnormal control of blood flow and sweating is observed; (4) reflex: it is believed that pain, trophic changes and abnormal control of blood flow and sweating are produced by activity in the sympathetic fibers supplying the tissues concerned. It should be noticed here that the term "reflex sympathetic dystrophy' expresses a concept in which the sympathetic nervous system plays the major role. The term 'algodystrophy', which was coined by the French school in the Leriche era [27], would be more neutral. The clinical symptomatology of reflex sympathetic, dystrophy is very variable from patient to patient and is sometimes not easily recognized since only one symptom may be dominant. Livingston [30] and Bonica [7,8] have indicated that the classical causalgia [33,35,41] which may occur (but rarely) after partial lesion of median nerve, brachial plexus or sciatic nerve is, from its clinical manifestation, one
* These are the terms recommendedby the International Association for the Study of Pain. Hyperpathia is 'a painful syndrome, characterized by delay, over-reactionand after-sensationto a stimulus especially a repetitive stimulus'. Allodynia is 'pain due to a non-noxious stimulus to normal skin'. This word is now used to describe the state where a very light stimulus, such as touch or stroking with cotton-wool. causes particularly unpleasant pain [34].
401 e x t r e m e of reflex s y m p a t h e t i c d y s t r o p h y . C a u s a l g i a is d o m i n a t e d b y severe s p o n t a n e o u s b u r n i n g p a i n [8,33,35,41]. T h e following p a p e r concentrates: (1) on some clinical features of reflex symp a t h e t i c d y s t r o p h y ; (2) on a h y p o t h e s i s a b o u t the role of the s y m p a t h e t i c s u p p l y to the tissues concerned; a n d (3) on the testing of the h y p o t h e s i s in a n i m a l experiments.
Clinical facts T h e clinical m a n i f e s t a t i o n of reflex s y m p a t h e t i c d y s t r o p h y has been r e p e a t e d l y d e s c r i b e d in the literature [7,8,30,43]. O n l y those d a t a which are i m p o r t a n t for the u n d e r s t a n d i n g of the h y p o t h e s i s o u t l i n e d b e l o w shall be m e n t i o n e d here.
Etiology M o s t causes of reflex s y m p a t h e t i c d y s t r o p h y are t r a u m a t a at the extremities TABLE 1 REFLEX SYMPATHETIC DYSTROPHY Characteristics of fully developed reflex sympathetic dystrophy in its 3 stages when it does not subside spontaneously and is untreated. The division into the 3 stages is rarely as clean as outlined in the table and is therefore an idealization. After refs. 1,7,8,48. For histological changes see refs. 1,43. Stage
Duration
Pain and other sensations
Symptoms due to al- Trophic changes terations of blood flow and sweating
Acute
Several weeks
Skin warm, dry, red (early) Skin cold (cyanotic), sweating (late)
Dystrophic
3-6 months
Spontaneous, restricted to territory of affected nerve; aching, burning; hyperpathia, allodynia, hyperestesia; pain disproportionate to severity of injury Gradual subsidence of pain, pain irradiates, pain on movement
Atrophic
More than 6 months
Rarely pain
spontaneous
Skin cold (cyanotic), pale, sweating
Local edema, increased hair and nail growth
Edema endurates and spreads; hair scant; nails brittle, cracked, grooved; increased thickness of joints, muscle waste; spotty osteoporosis (early), severe diffuse osteoporosis (late) Skin temperature low, Marked, irreversible; skin pale (cyanotic) skin smooth, joints stiff, fixed; contractures; marked bony demineralization and ankylosis
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which are secondary to injuries [7,8,27,30A3]. These injuries include fractures, sprains, dislocations, traumatic amputations of fingers, crush injuries of fingers, hands and wrists, tearing of nerves, iatrogenic complications following surgical and medical therapy such as amputations, tight fitting casts, damage to peripheral nerves due to injections of irritating substances, etc. The common feature of these traumata is that they all lead to damage of peripheral nerves. Sometimes, reflex sympathetic dystrophy may follow visceral diseases (e.g. myocardial infarction), affection of peripheral vessels (e.g. thromboplebitis) musculoskeletal disorders (e.g. shoulder-hand syndrome) or even lesions of the central nervous system [7,8,32].
Stages of reflex sympathetic dystrophy Without treatment reflex sympathetic dystrophy may pass through 3 stages [!,7,8]: acute stage (1), dystrophic stage (2) and atrophic stage (3). The duration and characteristics of these stages are listed in Table I. Treatment
Spontaneous remission very often occurs in the first stage, if the symptoms are relatively mild. Such symptoms are generally treated by physical therapy [8,23]. If the full nature of severe pain with trophic changes, disturbance of local circulation and of sweating develops, a specific and aggressive treatment has been recommended by Bonica [7,8] and others [23,42,48]. This consists initially of temporary blocks of sympathetic activity with transient relief of pain. Very often several temporary blocks of the respective ganglia of the sympathetic chain produce complete relief of pain and remission of trophic changes [8,12,23,42,48]. The same result may be obtained by stopping the release of noradrenaline by injecting guanethidine into the affected limb. The circulation in the limb is occluded and the guanethidine injected intravenously below the occlusion [16,31,34]. Relief from pain and remission of trophic changes after blockade of sympathetic activity, provided it is performed early enough, i.e. if possible, in the first stage, are the only hard facts which convince even the most resistant and conservative physiologist that the sympathetic supply of the affected tissue is involved in the generation and maintenance of reflex sympathetic dystrophy. Furthermore. it may be the starting point in investigating mechanisms of reflex sympathetic dystrophy in animal models.
Hypothesis The observation of vasomotor, sudomotor and trophic disturbances and the alleviation of these disturbances as well as of the pain by blockade of sympathetic activity, led relatively early to the assumption that abnormal impulse patterns in sympathetic fibers to the affected tissues may be responsible for the clinical manifestation of reflex sympathetic dystrophy. In fact, it has been assumed from the first description of the latter, that the cause is in some way of central origin. Mitchel
403
[33], in trying to explain causalgic states said: "Nerve injuries may also cause pain which, owing to inexplicable reflex transfers in the centres, may be felt in remote tissues outside of the region which is tributary of the wounded nerve . . . " . Livingston [30] expressed the idea about the establishment of a vicious circle between abnormal discharges of afferent fibers, a changed processing of the afferent impulse activity in the spinal cord, abnormal impulse patterns in sympathetic fibers and the influence of these sympathetic fibers on the afferent fibers. He stated: "Evidently the part played by the sympathetic nerves is an important one, otherwise an interruption of their activities would not succeed in curing the causalgic state as often as it does. I do not know how the sympathetics contribute to causalgic states, nor how it happens that a periarterial sympathectomy *, a ganglionectomy or even a temporary interruption of their functions by novocaine injection, may act to terminate the syndrome. It is possible, even probable, that the vasomotor activities of the sympathetic nerves play an important role in the maintenance and the cure of the causalgic state. That is to say, the sympathetic nerves may contribute to the development of peripheral tissue changes, which may lead to additional afferent impulses adding themselves to those from the trigger point to assail the spinal cord centers. This is not equivalent to saying that the sympathetic dysfunction causes the causalgic syndrome. It would be more correct to say that the trigger point caused it, but I believe that neither statement is wholly true. Instead, the trigger point starts the central disturbance, the central process in its turn involves the sympathetic nerves and the somatic motor nerves, and the peripheral effects brought about by the motor activity of each, initiate afferent impulses which add themselves to those from the trigger point to sustain and augment the central activity. The sympathetic nerve activity is but one part of this vicious circle". Livingston's concept was quite clear and we cannot add anything essentially new to it. He was aware of the complexities involved and avoided stating that there are simple cause-effect relationships between efferent sympathetic and afferent activity. It is interesting that he believed that the main disturbance is in the activity of vasomotor (vasocontrictor) fibers and that this disturbance is due to a central disturbance. German authors were also convinced that in Sudeck's Syndrome - - as far as the trophic changes are concerned - - the main defect is at the terminal part of the vascular beds and that this defect is induced by neural activity [36-39,43]. Also, Nathan's conception stating that the whole afferent (peripheral and central) pathway is in an abnormal state following its lesion [34] can easily be included in Livingston's general hypothesis. It must be remembered that peripheral nerve lesions, whether partial or complete, do not only lead to abnormal impulse patterns in the lesioned afferent fibers [3,44,45], but also to degenerative and regenerative changes of the afferent neuron [5,28,45], to impairment of synaptic transmission on secondary neurons in the spinal cord [10,11,18,46], and to dramatic biochemical changes of afferent neurons and in the spinal cord [2,21,24]. At present we do not understand the functional implications of these changes.
* A surgical treatment performed by Leriche [27] and other French neurosurg¢ons.
404 REFLEX SYMPATHETIC DYSTROPHY (ALGODYSTROPHY) Trauma with] nerve e8 on I abnormal state of
afferent ~eurones ~ distorted i n f o r m a t i o n ~ processing in s p i n a l ~
°7
dyaregulation of sympathetic activity (vasomotor, sudomotor)
/
Fig. 1. Schematic expression of Livingston's hypothesis about the mechanism of generation of the syndrome of reflex sympathetic dystrophy. Note the vicious circle. For details see text.
Fig. 1 expresses the hypothesis of Livingston, as we believe it today, in simplified form. This hypothesis could explain why blockade of sympathetic activity alleviates pain and trophic changes. It does not explain the processes going on in the spinal cord and the mode of interaction between sympathetic fibers and afferent fibers as well as the peripheral tissues.
Animal experiments Based on the hypothesis explained above we designed an experiment in order to test whether the pattern of activity in postganglionic vasoconstrictor neurons supplying skin and skeletal muscle of the cat hindlimb changes after a nerve lesion of the limb. The idea behind this experiment is that a distorted processing of information in the spinal cord, which may be induced by the nerve lesion, may also entail some changes of activity in vasoconstrictor neurons. We assumed that these changes could be detected by measuring the reaction patterns of postganglionic vasoconstrictor neurons supplying skin and skeletal muscle in standardized experimental conditions. In the following, some preliminary results from experiments of this type will be described. A full description of the quantitative aspects of this type of analysis will be given in a separate paper. Methods
The experiments were performed on chloralose-anesthetized artificially ventilated and immobilized cats [6]. Six to 376 days prior to the experiments the left superficial peroneal nerve was cut, ligated and encapsulated as described recently [4,5]. Another type of nerve lesion was performed by suturing the central stump of the superficial peroneal nerve (skin nerve) to branches of the deep peroneal nerve supplying the m.
405
extensor digitorum longus and the m. tibialis anterior 150-540 days prior to the acute experiments. Multiunit activity was recorded in the acute experiments from 3 nerves supplying the left hindlimb: (1) the nerve with the lesion; (2) the sural nerve as a control skin nerve connected to the periphery; and (3) a muscle nerve. Three parameters of the postganglionic activity were analyzed: cardiac rhythmicity (influence of arterial baroreceptors), reaction to stimulation of arterial chemoreceptors and reaction to stimulation of cutaneous nociceptors. The details of the experimental procedures have already been described [6,13,14].
Results
In artificially ventilated and anesthetized cats muscle vasoconstrictor neurons are excited by stimulation of arterial chemoreceptors, by stimulation of cutaneous nociceptors of the ipsilateral hindpaw and by visceral stimuli, whereas most cutaneous vasoconstrictor neurons are inhibited by these stimuli. This reciprocal behavior reflects aspects of the central organization of the vasoconstrictor systems (see KOmmel, this volume). Arterial baroreceptors have a strong inhibitory influence on muscle vasoconstrictor neurons but no or only weak influence on most cutaneous
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Fig. 2. Normal reflex patterns in cutaneous (CVC) and muscle vasoconstrictor neurons (MVC). A: cardiac rhythmicity of the activity. Histosrams evaluated from 1000 cardiac double cycles with respect to R-wave of ECG (see refs. 6,14). B: reaction to stimulation of arterial chemoreceptors by respiring the animal with a gas mixture of 8% 02 in N 2 (bars). Simultaneous recording from a bundle with one cutaneous vasoconstrictor axon (CVC) and a bundle with one muscle vasoconstrictor axon (MVC). The reaction of these neurons to noxious stimulation of skin of the ipsilateral hindpaw is shown in Fig. 7D of Janig, Sundlbf and Wallin in this volume. (Modified from ref. 6.)
406 cat w i t h nerve l e s i o n stim b a r o r e c e p t o r s
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Fig. 3. Reactions of postganglionic vasoconstrictor neurons supplying skin and skeletal muscle of the cat hindlimb (multiunit activity) to stimulation of arterial baroreceptors and chemoreceptors 43 days after ligating and cutting the superficial peroneal nerve of the same hindlimb. Left side: post-R-wave histograms obtained from superposition of the postganglionic activity in 400 (A), 700 (B) and 800 (C) cardiac double cycles with respect to R-wave of ECG (see refs. 6, 14). Ordinate scale: number of impulses per bin (8 ms). The shift of the peak of the activity in the post-R-wave histogram in B is due to the slower conduction of the postganglionic axons in the neuroma nerve and due to a more distal recording site. Right side: stimulation of arterial chemoreceptors by respiring the animal with a gas mixture of 8ff 02 in N 2 for 2 min (black bar). Ordinate scale: number of impulses per 10 s. A: bundle from nerve to the peroneal muscles. B: bundle from the neuroma nerve (superficial peroneal nerve). C: bundle from sural nerve (intact skin nerve of the same hindlimb!). All bundles contained several postganglionic vasoconstrictor axons. (Modified from ref. 3.) vasoconstrictor neurons. Some cutaneous vasoconstrictor neurons have properties w h i c h are s i m i l a r to t h o s e of m u s c l e v a s o c o n s t r i c t o r n e u r o n s [6.13]. Fig. 2 i l l u s t r a t e s a t y p i c a l e x p e r i m e n t . It s h o w s s i m u l t a n e o u s r e c o r d i n g s f r o m o n e muscle vasoconstrictor neuron and one cutaneous vasoconstrictor neuron. Stimulat i o n of arterial c h e m o r e c e p t o r s b y r e s p i r i n g the a n i m a l w i t h a h y p o x i c gas m i x t u r e e x c i t e d the m u s c l e v a s o c o n s t r i c t o r n e u r o n a n d i n h i b i t e d the c u t a n e o u s v a s o c o n s t r i c tor n e u r o n (Fig. 2B). T h e s a m e r e c i p r o c a l r e a c t i o n was also o b s e r v e d d u r i n g s t i m u l a t i o n o f c u t a n e o u s n o c i c e p t o r s o f the ipsilateral h i n d p a w (this is s h o w n in Fig.
407 7 D of J~inig, Sundl0f and Wallin in this volume). Stimulation of the arterial baroreceptors by the pulse pressure wave led to phasic inhibitions of the muscle vasoconstrictor neuron (Fig. 2A, upper histogram) and had nearly no influence on the cutaneous vasoconstrictor neuron (Fig. 2A, lower histogram). Following the lesions of the cutaneous nerves, the reflex behavior of cutaneous vasoconstrictor neurons changed dramatically. Typical results from one experiment are illustrated in Fig. 3. The vasoconstrictor neurons in the lesioned nerve, in the ipsilateral cutaneous control nerve and in the muscle nerve, are under the strong control of arterial baroreceptors (Fig. 3, left side) and they were excited during stimulation of arterial chemoreceptors (Fig. 3, right side). Mostly, stimulation of cutaneous nociceptors had no effect or else it led to excitations of the vasoconstrictor neurons. These changes of the reflexes in cutaneous vasoconstrictor neurons were observed in the majority of our preparations. The differences from the results obtained from control cats are statistically highly significant.
Conclusions The results of the experiments in which a nerve lesion has been performed some time before the experiment illustrate the fact that the reflex pattern in cutaneous vasoconstrictor neurons changes in m a n y animals. The reciprocity of this reflex pattern between cutaneous and muscle vasoconstrictor neurons [20] m a y disappear
REFLEX PATTERN NORMAL
dominant medulla system oblongata
control
chemo
bar~ci
effector organ
resistance vessels
• inhibition C) excitation
hypothalamus chemo noci ba~warm
shunt vessels (a.v. anastomoses) capacitance vessels
(veins)
j~
REFLEX PATTERN AFTER NERVE LESION
medulla oblongata baro
B
medulla
oblongats
chemo chemo I noci baro / noci
resistance vessels
shunt vessels (a.v. snestomoses) capacitance vessels
(veinsI
Fig. 4. Reflex patterns in postganglionic vasoconstrictor neurons supplying skeletal muscle and skin under normal conditions (A) and after chronic nerve lesions (B). These patterns are simplifications and represent only the (most common) pure cases (see ref. 5). The term 'dominant control system' indicates the brain structure which controls the respective vasoconstrictor system predominantly (but not, of course, exclusively). In B it is proposed that the cutaneous vasoconstrictor system is under predominant control of the medulla oblongata. Note the uniformity of the reflex patterns in B. For details see text.
408
and uniformity of the reactions in the vasoconstrictor neurons may appear. It may be assumed that the muscle vasconstrictor neurons which innervate resistance vessels are normally under control of the medulla oblongata. Cutaneous vasoconstrictor neurons, which innervate shunt and capacitance vessels, are under control of the hypothalamus. The reflex patterns in both types of vasoconstrictor neurons are distinct and are reciprocally organized with respect to many afferent inputs (Fig. 4A) [20]. After acute decerebration this reciprocity is lost, and the reflex pattern in cutaneous vasoconstrictor neurons is then similar to that in muscle vasoconstrictor neurons [13,19]. Investigations of neuronal control of blood flow through skin and muscle and of heart rate show that also the regulation of these parameters tends to become uniform when the hypothalamus is removed (for literature see ref. 26). Thus, it is likely that the descending systems from the hypothalamus are important in generating the reflex pattern of cutaneous vasoconstrictor neurons [t3,26]. This statement does not preclude that the neuronal machinery for expressing the reciprocity is at the spinal cord level (see Ktimmel, this volume). After chronic nerve lesions the cutaneous vasoconstrictor neurons may predominantly be controlled from the medulla oblongata and, therefore, show a reflex pattern which is very similar to that of the muscle vasoconstrictor neurons (Fig. 4B). This type of neuronal control would mean that shunt and capacitance vessels in skin are controlled in the same way as resistance vessels in skeletal muscle. If the same happens in reflex sympathetic dystrophy in patients it could explain the vasomotor disturbances, such as the lack of thermoregulation in the skin of the affected limb. It could probably also explain the trophic changes. Assuming that shunt vessels and capacitance vessels constrict, one can expect an increase of the filtration pressure with consecutive edema. A permissive factor may be ischaemia of the tissue and release of vasoactive and other substances with subsequent increased permeability of the capillary walls. These factors may also lead to enhanced responses in nociceptive afferent fibers [49,50].
General c o m m e n t s
Reflex sympathetic dystrophy (see Table I) is a clinical syndrome which may follow a trauma in an extremity accompanied by nerve lesions. It is generally thought that the disturbance of the sympathetic neuronal supply to the affected tissue is an important component in the generation of this syndrome (Fig. 1). Blocking of sympathetic fibers, which supply the affected tissues~ abolishes or relieves the clinical symptoms. These experiments on the vasoconstrictor supply to the limb of a cat with a chronic nerve lesion show that the reflex pattern changes, compared to the normal (Fig. 3). The change in this pattern could explain part of the pathophysiological changes observed in patients with reflex sympathetic dystrophy. At present we have only very general ideas about the pathophysiological mechanisms of the pain which is one component of this syndrome. Afferent fibers develop abnormal chemosensitivity (see Devor, this volume) and may be excited by
409
noradrenaline released by the postganglionic fibers [3,9,15] (see also Nathan, this volume). An additional component may be the change of the microenvironment of the fine nociceptive afferent fibers which is reflected in the trophic changes (ischaemia, release of vasoactive and algesic substances; see refs. 15,22,29,49,50). In this context, it is worth noting that sympathetic dystrophy can also occur after visceral diseases and even after disorders of the central nervous system [8,32] and that the pain under these conditions can also be abolished or relieved by sympathetic block. Here, the syndrome of reflex sympathetic dystrophy or components of it appear without peripheral trauma. Therefore, without peripheral trauma a disturbance of sympathetic activity, which must be of central origin, is probably enough for generation of the clinical symptoms. This observation can also be reconciled with Livingston's hypothesis (Fig. 1). In order to clarify the pathophysiological mechanisms of reflex sympathetic dystrophy we need, firstly, a deeper insight into the central (particularly spinal) organization of the sympathetic nervous system. Secondly, investigations must concentrate on animal models in which trophic changes can be produced experimentally. These trophic changes must be described histologically and correlated with the discharge patterns in postganglionic sympathetic fibers to and afferent fibers from the trophically altered tissue. Thirdly, afferent fibers and postganglionic sympathetic fibers should be investigated microneurographically in patients with reflex sympathetic dystrophy.
Acknowledgement Supported by the Deutsche Forschungsgemeinschaft.
References 1 Ascherl, R. and Bliimel, G., Zum Krankheitsbild der Sudeck'schen Dystrophie, Fortschr. Med., 99 (1981) 712-720. 2 Barbut, D., Polak, J.M. and Wall, P.D., Substance P in spinal cord dorsal horn decreases following peripheral nerve injury, Brain Res., 205 (1981) 289-298. 3 Blumberg, H. and J~lnig, W., Neurophysiological analysis of efferent sympathetic and afferent fibers in skin nerves with experimentally produced neuromata In J. Siegfried and M. Zimmerman (Eds.), Phantom and Stump Pain, Springer, Berlin, 1981, pp. 15-31. 4 Bhimberg, H. and J~ig, W., Activation of fibers via experimentally produced stump neuromas of skin nerves: ephaptic transmission or retrograde sprouting, Exp. Neurol., 76 (1982) 468-482. 5 Blumberg, H. and Jgmig, W., Changes in unmyelinated fibers including sympathetic postganglionic fibers of a skin nerve after peripheral neuroma formation, J. auton. Nerv. Syst., 6 (1982) 173-183. 6 Blumberg, H., Jiinig, W., Rieckmann, C. and Szulczyk, P., Baroreceptor and chemoreceptor reflexes in postganglionic neurones supplying skeletal muscle and hairy skin, J. auton. Nerv. Syst., 2 (1980) 223-240. 7 Bonica, J.J., The Management of Pain, Lea and Febiger, Philadelphia, 1953, reprinted by Honji Shoji Company, Tokyo, 1980. 8 Bonica, J.J., Causalgia and other reflex sympathetic dystrophies. In J.J. Bonica, J.C. Liebeskind and Albe-Fessard, D.G. (Eds.), Advances in Pain Research and Therapy, Vol. 3, Raven Press, New York, 1979, pp. 141-166.
410 9 Devor, M. and Janig, W., Activation of myelinated afferents ending in a neuroma by stimulation of the sympathetic supply in the rat, Neurosci. Lett. 24 (1981) 43-47. 10 Devor, M. and Wall, P.D., Reorganisation of spinal cord sensory map after peripheral nerve injury, Nature (Lond.), 276 (1978) 75-76. 11 Devor, M. and Wall, P.D., Plasticity in the spinal cord sensory map following peripheral nerve injury in rats, J. Neurosci., 1 (1981) 679-684. 12 Evans, J.A., Reflex sympathetic dystrophy: a report on 57 cases, Ann. Intern. Med, 26 (1947) 417-426. 13 Gregor, M. and Janig, W., Effects of systemic hypoxia and hypercapnia on cutaneous and muscle vasoconstrictor neurones to the cat's hindlimb, Pfli~gers Arch. ges. Physiol., 268 (1977) 71 81. 14 Gregor, M., J~nig, W. and Wiprich, L., Cardiac and respiratory rhythmicities in cutaneous and muscle vasoconstrictor neurones to the cat's hindlimb, Pfltigers Arch. ges. Physiol., 370 (1977) 299-302. 15 Handwerker, H.O., Pain producing substances. In H.W. Kosterlitz, and L.Y. Terenius (Eds.L Pain and Society, Dahlem Konferenzen, Verlag Chemie GmbH, Weinheim, 1980, pp. 325-338. 16 Hannington-Kiff, J.G., Relief of Sudeck's atrophy by regional intravenous guanethidine, Lancet. (1977) 1132-1133. 17 Homans, J., Minor causalgia; a hyperesthetic neurovascular syndrome, New Engl. J. Med.. 222 (1940) 870-874. 18 Horch, K.W. and Lisney, S.J.W., Changes in primary afferent depolarization of sensory neurones during peripheral nerve regeneration in the cat, J. Physiol. (Lond.), 313 (1981 ) 287-299. 19 J~inig, W., Central organization of somatosympathetic reflexes in vasoconstrictor neurones. Brain Res, 87 (1975) 305-312. 20 Janig, W., Reciprocal reaction patterns of sympathetic subsystems with respect to various afferent inputs. In C.McC. Brooks, K. Koizumi and A. Sato (Eds.), Integrative Functions of the Autonomic Nervous System, University of Tokyo Press, Tokyo/Elsevier, North-Holland Biomedical Press, Amsterdam, 1979, pp. 263-274. 21 .lessel, T., Tsunoo, A., Kanazawa, I. and Otsuka, M., Substance P depletion in the dorsal horn of rat spinal cord after section of the peripheral processes of primary sensory neurones, Brain Res.. 168 (1979) 247-259. 22 Keele. C.A. and Armstrong, D., Substances producing pain and itch, Arnold, London, 1964. 23 Kleinert. H.E., Cole, N.M., Wayne, L., Harvey, R., Kutz, J.E. and Atasoy, E., Post-traumatic sympathetic dystrophy, Orth. Clin. N. Amer., 4 (1973) 917-927. 24 Knyihar-Csillik, E. and Csillik, B., FRAP: histochemistry of the primary nociceptive neuron, Progr. Histochem. Cytochem. 14 (1981) 1-137. 25 Korenman, E.M.D. and Devor, M., Ectopic adrenergic sensitivity in damaged peripheral nerve axons in the rat, Exp. Neurol., 72 (1981) 63-81. 26 Korner, P.I., Central nervous control of autonomic cardiovascular function, Handbook of Physiology. Section 2: The Cardiovascular System I. The Heart, American Physiological Society, 1979, pp. 691-739. 27 Leriche, R., La Chirurgie de la Douleur, 3rd Edn., Masson, Paris, 1949. 28 Liebermann, A.R., Some factors affecting retrograde neuronal responses to axonal lesions. In R. Bellairs and E.G. Gray (Eds.), Essays on the Nervous System. A Festschrift for Prof. J.Z. Young, Clarendon Press, Oxford, 1974, pp. 71-105. 29 Lim, R.K.S., Pain, Ann. Rev. Physiol., 32 (1970) 269-288. 30 Livingston, W.K., Pain Mechanisms. A Physiologic Interpretation of Causalgia and its Related States. Macmillan, New York, 1943, unabridged version published by Plenum Press, New York, 1976. 31 Loh, L. and Nathan, P.W., Painful peripheral states and sympathetic blocks, J. Neurol. Neurosurg. Psychiat., 41 (1978) 664-671. 32 Loh, L., Nathan, P.W. and Schott, G.D., Pain due to lesions of central nervous system removed by sympathetic block, Brit. med. J. 282 (1981) 1026-1028. 33 Mitchell, S.W., Injuries of nerves and their consequences, J.P. Lippincott, Philadelphia, 1872. 34 Nathan, P.W., Involvement of the sympathetic nervous system in pain. In H.W. Kosterlitz and L.Y. Terenius (Eds.), Pain and Society. Dahlem Konferenzen, Verlag Chemie GmbH, Weinheim, 1980. pp. 311 324.
411 35 Richards, R.L., Causalsia. A centennial review, Arch. Neurol., 16 (1967) 339-350. 36 Scheibe, G., Die Capillarschadignng bei der Sudeckschen Krankheit, Langenbecks Arch. u. Dtsch. Z. Clair., 283 (1957) 693-707. 37 Scheibe, G. and Karitzky, B., Das funktionelle Hautcapillarbild bei der Sudeckschen Krankheit, Der Chirurg, 25 (1954) 202-206. 38 Sch6nbach, G., Der Einflu$ mechanischer Nervensch~idigungen auf die Permeabilit~it der Gef~isse, Acta neuroveget. Wien, 17 (1957) 18-39. 39 Sch6nbach, G. and Thorban, W., Funktionelle und organische Gef~iBwandver~inderungen nach Sympathektomie und partieller Nervenschadigung, Langenbecks Arch. klin. Chir., 291 (1959) 217-231. 40 Sudeck, P., fiber die akute entziindhche Knochenatrophie, Arch. f. klin. Chir., 62 (1900) 147-156. 41 Sunderland, S., Pain mechanisms in causalgia, J. Neurol. Neurosurg. Psychiat. 39 (1976) 471-480. 42 Thompson, J.., The diagnosis and management of posttraumatic pain syndromes (causalgia), Aust. N.Z. Surg., 49 (1979) 299-304. 43 Thorban, W., Das Sudecksche Syndrom. In A. Sturm and W. Birkmayer (Eds.), Klinische Pathologie des vegetativen Nervensystems, Vol. 2, Gustav Fischer, Stuttgart, 1977, pp. 1186-1206. 44 Wall, P.D., Changes in damaged nerve and their sensory consequences. In J.J. Bonica, J.C. Liebeskind and D.G. Albe-Fessard (Eds.), Advances in Pain Research and Therapy, Vol. 3, Raven Press, New York, 1979, pp. 39-52. 45 Wall, P.D. and Devor, M., Physiology of sensation after peripheral nerve injury, regeneration and neuroma formation. In S.G. Waxman (Ed.), Physiology and Pathobiology of Axons, Raven Press, New York, 1978, pp. 377-388. 46 Wall, P.D. and Devor, M., The effect of peripheral nerve injury on dorsal root potentials and on transmission of afferent signals into the spinal cord, Brain Res., 209 (1981) 95-111. 47 Wirth, F.P. and Rutherford, R.B., A civilian experience with causalgia, Arch. Surg., 100 (1970) 633-638. 48 Wilson, R.L., Management of pain following peripheral nerve injuries, Orth. Clin. N. Amer., 12 (1981) 343-359. 49 Zimmermann, M., Peripheral and central nervous mechanisms of nociception, pain and pain therapy: facts and hypotheses. In J.J. Bonica, J.C. Liebeskind and D.G. Albe-Fessard (Eds.), Advances in Pain Research and Therapy, vol. 3, Raven Press, New York, 1979, pp. 3-32. 50 Zimmerman, M., Physiological mechanisms of chronic pain. In H.W. Kosterlitz and L.Y. Terenius (Eds.), Pain and Society, Dahlem Konferenzen, Verlag Chemic GmbH. Weinheim, 1980, pp. 283-297.
399
Elsevier BiomedicalPress
Changes of reflexes in vasoconstrictor neurons supplying the cat hindlimb following chronic nerve lesions: a model for studying mechanisms of reflex sympathetic dystrophy? H. B l u m b e r g i and W. J~inig 2 Physiologisches Institut, Universitiit, Olshausenstr. 40-60, 2300 Kiel, (F.R.G.)
(ReceivedSeptember 1st, 1982) (AcceptedNovember 1st, 1982)
K e y words: reflex sympathetic dystrophy - - hypothesis - - reflex patterns in post-
ganglionic vasoconstrictor neurons
Abstract 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 i Present address: NeurologischeKlinik, Universitat Freiburg, Hansastr. 9, 7800 Freiburg, F.R.G. 2 To whom reprint requests should be addressed. 0165-1838/83/0000-0000/$03.00 © 1983 ElsevierSciencePublishers
400 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.
Introduction Reflex sympathetic dystrophy is an all-inclusive term which describes the clinical symptomatology of etiologically seemingly unrelated disorders such as post-traumatic pain syndrome, minor causatgia [17,30], post-traumatic arthrosis, Sudeck's atrophy (syndrome) [40], shoulder-hand syndrome, chronic traumatic (post-traumatic) edema, reflex dystrophy, algodystrophy [27] and others [7,8]. The term was coined by Evans [12] and has been fully introduced into the literature by Bonica [7]. It describes a syndrome which consists of the following components: (1) pain: burning pain, hyperpathia * and allodynia * occur within the territory concerned. This is obvious for the skin, but also present for deeper tissues, including muscle and bone; (2) dystrophy: the tissues from the region concerned, such as skin, subcutaneous tissue, muscle, bone and joint capsules, may waste. Furthermore, features of abnormal growth, such as ridging of nails, hyperkeratosis and hypertrichiosis, may be observed; (3) sympathetic: abnormal control of blood flow and sweating is observed; (4) reflex: it is believed that pain, trophic changes and abnormal control of blood flow and sweating are produced by activity in the sympathetic fibers supplying the tissues concerned. It should be noticed here that the term "reflex sympathetic dystrophy' expresses a concept in which the sympathetic nervous system plays the major role. The term 'algodystrophy', which was coined by the French school in the Leriche era [27], would be more neutral. The clinical symptomatology of reflex sympathetic, dystrophy is very variable from patient to patient and is sometimes not easily recognized since only one symptom may be dominant. Livingston [30] and Bonica [7,8] have indicated that the classical causalgia [33,35,41] which may occur (but rarely) after partial lesion of median nerve, brachial plexus or sciatic nerve is, from its clinical manifestation, one
* These are the terms recommendedby the International Association for the Study of Pain. Hyperpathia is 'a painful syndrome, characterized by delay, over-reactionand after-sensationto a stimulus especially a repetitive stimulus'. Allodynia is 'pain due to a non-noxious stimulus to normal skin'. This word is now used to describe the state where a very light stimulus, such as touch or stroking with cotton-wool. causes particularly unpleasant pain [34].
401 e x t r e m e of reflex s y m p a t h e t i c d y s t r o p h y . C a u s a l g i a is d o m i n a t e d b y severe s p o n t a n e o u s b u r n i n g p a i n [8,33,35,41]. T h e following p a p e r concentrates: (1) on some clinical features of reflex symp a t h e t i c d y s t r o p h y ; (2) on a h y p o t h e s i s a b o u t the role of the s y m p a t h e t i c s u p p l y to the tissues concerned; a n d (3) on the testing of the h y p o t h e s i s in a n i m a l experiments.
Clinical facts T h e clinical m a n i f e s t a t i o n of reflex s y m p a t h e t i c d y s t r o p h y has been r e p e a t e d l y d e s c r i b e d in the literature [7,8,30,43]. O n l y those d a t a which are i m p o r t a n t for the u n d e r s t a n d i n g of the h y p o t h e s i s o u t l i n e d b e l o w shall be m e n t i o n e d here.
Etiology M o s t causes of reflex s y m p a t h e t i c d y s t r o p h y are t r a u m a t a at the extremities TABLE 1 REFLEX SYMPATHETIC DYSTROPHY Characteristics of fully developed reflex sympathetic dystrophy in its 3 stages when it does not subside spontaneously and is untreated. The division into the 3 stages is rarely as clean as outlined in the table and is therefore an idealization. After refs. 1,7,8,48. For histological changes see refs. 1,43. Stage
Duration
Pain and other sensations
Symptoms due to al- Trophic changes terations of blood flow and sweating
Acute
Several weeks
Skin warm, dry, red (early) Skin cold (cyanotic), sweating (late)
Dystrophic
3-6 months
Spontaneous, restricted to territory of affected nerve; aching, burning; hyperpathia, allodynia, hyperestesia; pain disproportionate to severity of injury Gradual subsidence of pain, pain irradiates, pain on movement
Atrophic
More than 6 months
Rarely pain
spontaneous
Skin cold (cyanotic), pale, sweating
Local edema, increased hair and nail growth
Edema endurates and spreads; hair scant; nails brittle, cracked, grooved; increased thickness of joints, muscle waste; spotty osteoporosis (early), severe diffuse osteoporosis (late) Skin temperature low, Marked, irreversible; skin pale (cyanotic) skin smooth, joints stiff, fixed; contractures; marked bony demineralization and ankylosis
402
which are secondary to injuries [7,8,27,30A3]. These injuries include fractures, sprains, dislocations, traumatic amputations of fingers, crush injuries of fingers, hands and wrists, tearing of nerves, iatrogenic complications following surgical and medical therapy such as amputations, tight fitting casts, damage to peripheral nerves due to injections of irritating substances, etc. The common feature of these traumata is that they all lead to damage of peripheral nerves. Sometimes, reflex sympathetic dystrophy may follow visceral diseases (e.g. myocardial infarction), affection of peripheral vessels (e.g. thromboplebitis) musculoskeletal disorders (e.g. shoulder-hand syndrome) or even lesions of the central nervous system [7,8,32].
Stages of reflex sympathetic dystrophy Without treatment reflex sympathetic dystrophy may pass through 3 stages [!,7,8]: acute stage (1), dystrophic stage (2) and atrophic stage (3). The duration and characteristics of these stages are listed in Table I. Treatment
Spontaneous remission very often occurs in the first stage, if the symptoms are relatively mild. Such symptoms are generally treated by physical therapy [8,23]. If the full nature of severe pain with trophic changes, disturbance of local circulation and of sweating develops, a specific and aggressive treatment has been recommended by Bonica [7,8] and others [23,42,48]. This consists initially of temporary blocks of sympathetic activity with transient relief of pain. Very often several temporary blocks of the respective ganglia of the sympathetic chain produce complete relief of pain and remission of trophic changes [8,12,23,42,48]. The same result may be obtained by stopping the release of noradrenaline by injecting guanethidine into the affected limb. The circulation in the limb is occluded and the guanethidine injected intravenously below the occlusion [16,31,34]. Relief from pain and remission of trophic changes after blockade of sympathetic activity, provided it is performed early enough, i.e. if possible, in the first stage, are the only hard facts which convince even the most resistant and conservative physiologist that the sympathetic supply of the affected tissue is involved in the generation and maintenance of reflex sympathetic dystrophy. Furthermore. it may be the starting point in investigating mechanisms of reflex sympathetic dystrophy in animal models.
Hypothesis The observation of vasomotor, sudomotor and trophic disturbances and the alleviation of these disturbances as well as of the pain by blockade of sympathetic activity, led relatively early to the assumption that abnormal impulse patterns in sympathetic fibers to the affected tissues may be responsible for the clinical manifestation of reflex sympathetic dystrophy. In fact, it has been assumed from the first description of the latter, that the cause is in some way of central origin. Mitchel
403
[33], in trying to explain causalgic states said: "Nerve injuries may also cause pain which, owing to inexplicable reflex transfers in the centres, may be felt in remote tissues outside of the region which is tributary of the wounded nerve . . . " . Livingston [30] expressed the idea about the establishment of a vicious circle between abnormal discharges of afferent fibers, a changed processing of the afferent impulse activity in the spinal cord, abnormal impulse patterns in sympathetic fibers and the influence of these sympathetic fibers on the afferent fibers. He stated: "Evidently the part played by the sympathetic nerves is an important one, otherwise an interruption of their activities would not succeed in curing the causalgic state as often as it does. I do not know how the sympathetics contribute to causalgic states, nor how it happens that a periarterial sympathectomy *, a ganglionectomy or even a temporary interruption of their functions by novocaine injection, may act to terminate the syndrome. It is possible, even probable, that the vasomotor activities of the sympathetic nerves play an important role in the maintenance and the cure of the causalgic state. That is to say, the sympathetic nerves may contribute to the development of peripheral tissue changes, which may lead to additional afferent impulses adding themselves to those from the trigger point to assail the spinal cord centers. This is not equivalent to saying that the sympathetic dysfunction causes the causalgic syndrome. It would be more correct to say that the trigger point caused it, but I believe that neither statement is wholly true. Instead, the trigger point starts the central disturbance, the central process in its turn involves the sympathetic nerves and the somatic motor nerves, and the peripheral effects brought about by the motor activity of each, initiate afferent impulses which add themselves to those from the trigger point to sustain and augment the central activity. The sympathetic nerve activity is but one part of this vicious circle". Livingston's concept was quite clear and we cannot add anything essentially new to it. He was aware of the complexities involved and avoided stating that there are simple cause-effect relationships between efferent sympathetic and afferent activity. It is interesting that he believed that the main disturbance is in the activity of vasomotor (vasocontrictor) fibers and that this disturbance is due to a central disturbance. German authors were also convinced that in Sudeck's Syndrome - - as far as the trophic changes are concerned - - the main defect is at the terminal part of the vascular beds and that this defect is induced by neural activity [36-39,43]. Also, Nathan's conception stating that the whole afferent (peripheral and central) pathway is in an abnormal state following its lesion [34] can easily be included in Livingston's general hypothesis. It must be remembered that peripheral nerve lesions, whether partial or complete, do not only lead to abnormal impulse patterns in the lesioned afferent fibers [3,44,45], but also to degenerative and regenerative changes of the afferent neuron [5,28,45], to impairment of synaptic transmission on secondary neurons in the spinal cord [10,11,18,46], and to dramatic biochemical changes of afferent neurons and in the spinal cord [2,21,24]. At present we do not understand the functional implications of these changes.
* A surgical treatment performed by Leriche [27] and other French neurosurg¢ons.
404 REFLEX SYMPATHETIC DYSTROPHY (ALGODYSTROPHY) Trauma with] nerve e8 on I abnormal state of
afferent ~eurones ~ distorted i n f o r m a t i o n ~ processing in s p i n a l ~
°7
dyaregulation of sympathetic activity (vasomotor, sudomotor)
/
Fig. 1. Schematic expression of Livingston's hypothesis about the mechanism of generation of the syndrome of reflex sympathetic dystrophy. Note the vicious circle. For details see text.
Fig. 1 expresses the hypothesis of Livingston, as we believe it today, in simplified form. This hypothesis could explain why blockade of sympathetic activity alleviates pain and trophic changes. It does not explain the processes going on in the spinal cord and the mode of interaction between sympathetic fibers and afferent fibers as well as the peripheral tissues.
Animal experiments Based on the hypothesis explained above we designed an experiment in order to test whether the pattern of activity in postganglionic vasoconstrictor neurons supplying skin and skeletal muscle of the cat hindlimb changes after a nerve lesion of the limb. The idea behind this experiment is that a distorted processing of information in the spinal cord, which may be induced by the nerve lesion, may also entail some changes of activity in vasoconstrictor neurons. We assumed that these changes could be detected by measuring the reaction patterns of postganglionic vasoconstrictor neurons supplying skin and skeletal muscle in standardized experimental conditions. In the following, some preliminary results from experiments of this type will be described. A full description of the quantitative aspects of this type of analysis will be given in a separate paper. Methods
The experiments were performed on chloralose-anesthetized artificially ventilated and immobilized cats [6]. Six to 376 days prior to the experiments the left superficial peroneal nerve was cut, ligated and encapsulated as described recently [4,5]. Another type of nerve lesion was performed by suturing the central stump of the superficial peroneal nerve (skin nerve) to branches of the deep peroneal nerve supplying the m.
405
extensor digitorum longus and the m. tibialis anterior 150-540 days prior to the acute experiments. Multiunit activity was recorded in the acute experiments from 3 nerves supplying the left hindlimb: (1) the nerve with the lesion; (2) the sural nerve as a control skin nerve connected to the periphery; and (3) a muscle nerve. Three parameters of the postganglionic activity were analyzed: cardiac rhythmicity (influence of arterial baroreceptors), reaction to stimulation of arterial chemoreceptors and reaction to stimulation of cutaneous nociceptors. The details of the experimental procedures have already been described [6,13,14].
Results
In artificially ventilated and anesthetized cats muscle vasoconstrictor neurons are excited by stimulation of arterial chemoreceptors, by stimulation of cutaneous nociceptors of the ipsilateral hindpaw and by visceral stimuli, whereas most cutaneous vasoconstrictor neurons are inhibited by these stimuli. This reciprocal behavior reflects aspects of the central organization of the vasoconstrictor systems (see KOmmel, this volume). Arterial baroreceptors have a strong inhibitory influence on muscle vasoconstrictor neurons but no or only weak influence on most cutaneous
A
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systemic hypoxia
B n
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CVC
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6
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460
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ms
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Fig. 2. Normal reflex patterns in cutaneous (CVC) and muscle vasoconstrictor neurons (MVC). A: cardiac rhythmicity of the activity. Histosrams evaluated from 1000 cardiac double cycles with respect to R-wave of ECG (see refs. 6,14). B: reaction to stimulation of arterial chemoreceptors by respiring the animal with a gas mixture of 8% 02 in N 2 (bars). Simultaneous recording from a bundle with one cutaneous vasoconstrictor axon (CVC) and a bundle with one muscle vasoconstrictor axon (MVC). The reaction of these neurons to noxious stimulation of skin of the ipsilateral hindpaw is shown in Fig. 7D of Janig, Sundlbf and Wallin in this volume. (Modified from ref. 6.)
406 cat w i t h nerve l e s i o n stim b a r o r e c e p t o r s
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Fig. 3. Reactions of postganglionic vasoconstrictor neurons supplying skin and skeletal muscle of the cat hindlimb (multiunit activity) to stimulation of arterial baroreceptors and chemoreceptors 43 days after ligating and cutting the superficial peroneal nerve of the same hindlimb. Left side: post-R-wave histograms obtained from superposition of the postganglionic activity in 400 (A), 700 (B) and 800 (C) cardiac double cycles with respect to R-wave of ECG (see refs. 6, 14). Ordinate scale: number of impulses per bin (8 ms). The shift of the peak of the activity in the post-R-wave histogram in B is due to the slower conduction of the postganglionic axons in the neuroma nerve and due to a more distal recording site. Right side: stimulation of arterial chemoreceptors by respiring the animal with a gas mixture of 8ff 02 in N 2 for 2 min (black bar). Ordinate scale: number of impulses per 10 s. A: bundle from nerve to the peroneal muscles. B: bundle from the neuroma nerve (superficial peroneal nerve). C: bundle from sural nerve (intact skin nerve of the same hindlimb!). All bundles contained several postganglionic vasoconstrictor axons. (Modified from ref. 3.) vasoconstrictor neurons. Some cutaneous vasoconstrictor neurons have properties w h i c h are s i m i l a r to t h o s e of m u s c l e v a s o c o n s t r i c t o r n e u r o n s [6.13]. Fig. 2 i l l u s t r a t e s a t y p i c a l e x p e r i m e n t . It s h o w s s i m u l t a n e o u s r e c o r d i n g s f r o m o n e muscle vasoconstrictor neuron and one cutaneous vasoconstrictor neuron. Stimulat i o n of arterial c h e m o r e c e p t o r s b y r e s p i r i n g the a n i m a l w i t h a h y p o x i c gas m i x t u r e e x c i t e d the m u s c l e v a s o c o n s t r i c t o r n e u r o n a n d i n h i b i t e d the c u t a n e o u s v a s o c o n s t r i c tor n e u r o n (Fig. 2B). T h e s a m e r e c i p r o c a l r e a c t i o n was also o b s e r v e d d u r i n g s t i m u l a t i o n o f c u t a n e o u s n o c i c e p t o r s o f the ipsilateral h i n d p a w (this is s h o w n in Fig.
407 7 D of J~inig, Sundl0f and Wallin in this volume). Stimulation of the arterial baroreceptors by the pulse pressure wave led to phasic inhibitions of the muscle vasoconstrictor neuron (Fig. 2A, upper histogram) and had nearly no influence on the cutaneous vasoconstrictor neuron (Fig. 2A, lower histogram). Following the lesions of the cutaneous nerves, the reflex behavior of cutaneous vasoconstrictor neurons changed dramatically. Typical results from one experiment are illustrated in Fig. 3. The vasoconstrictor neurons in the lesioned nerve, in the ipsilateral cutaneous control nerve and in the muscle nerve, are under the strong control of arterial baroreceptors (Fig. 3, left side) and they were excited during stimulation of arterial chemoreceptors (Fig. 3, right side). Mostly, stimulation of cutaneous nociceptors had no effect or else it led to excitations of the vasoconstrictor neurons. These changes of the reflexes in cutaneous vasoconstrictor neurons were observed in the majority of our preparations. The differences from the results obtained from control cats are statistically highly significant.
Conclusions The results of the experiments in which a nerve lesion has been performed some time before the experiment illustrate the fact that the reflex pattern in cutaneous vasoconstrictor neurons changes in m a n y animals. The reciprocity of this reflex pattern between cutaneous and muscle vasoconstrictor neurons [20] m a y disappear
REFLEX PATTERN NORMAL
dominant medulla system oblongata
control
chemo
bar~ci
effector organ
resistance vessels
• inhibition C) excitation
hypothalamus chemo noci ba~warm
shunt vessels (a.v. anastomoses) capacitance vessels
(veins)
j~
REFLEX PATTERN AFTER NERVE LESION
medulla oblongata baro
B
medulla
oblongats
chemo chemo I noci baro / noci
resistance vessels
shunt vessels (a.v. snestomoses) capacitance vessels
(veinsI
Fig. 4. Reflex patterns in postganglionic vasoconstrictor neurons supplying skeletal muscle and skin under normal conditions (A) and after chronic nerve lesions (B). These patterns are simplifications and represent only the (most common) pure cases (see ref. 5). The term 'dominant control system' indicates the brain structure which controls the respective vasoconstrictor system predominantly (but not, of course, exclusively). In B it is proposed that the cutaneous vasoconstrictor system is under predominant control of the medulla oblongata. Note the uniformity of the reflex patterns in B. For details see text.
408
and uniformity of the reactions in the vasoconstrictor neurons may appear. It may be assumed that the muscle vasconstrictor neurons which innervate resistance vessels are normally under control of the medulla oblongata. Cutaneous vasoconstrictor neurons, which innervate shunt and capacitance vessels, are under control of the hypothalamus. The reflex patterns in both types of vasoconstrictor neurons are distinct and are reciprocally organized with respect to many afferent inputs (Fig. 4A) [20]. After acute decerebration this reciprocity is lost, and the reflex pattern in cutaneous vasoconstrictor neurons is then similar to that in muscle vasoconstrictor neurons [13,19]. Investigations of neuronal control of blood flow through skin and muscle and of heart rate show that also the regulation of these parameters tends to become uniform when the hypothalamus is removed (for literature see ref. 26). Thus, it is likely that the descending systems from the hypothalamus are important in generating the reflex pattern of cutaneous vasoconstrictor neurons [t3,26]. This statement does not preclude that the neuronal machinery for expressing the reciprocity is at the spinal cord level (see Ktimmel, this volume). After chronic nerve lesions the cutaneous vasoconstrictor neurons may predominantly be controlled from the medulla oblongata and, therefore, show a reflex pattern which is very similar to that of the muscle vasoconstrictor neurons (Fig. 4B). This type of neuronal control would mean that shunt and capacitance vessels in skin are controlled in the same way as resistance vessels in skeletal muscle. If the same happens in reflex sympathetic dystrophy in patients it could explain the vasomotor disturbances, such as the lack of thermoregulation in the skin of the affected limb. It could probably also explain the trophic changes. Assuming that shunt vessels and capacitance vessels constrict, one can expect an increase of the filtration pressure with consecutive edema. A permissive factor may be ischaemia of the tissue and release of vasoactive and other substances with subsequent increased permeability of the capillary walls. These factors may also lead to enhanced responses in nociceptive afferent fibers [49,50].
General c o m m e n t s
Reflex sympathetic dystrophy (see Table I) is a clinical syndrome which may follow a trauma in an extremity accompanied by nerve lesions. It is generally thought that the disturbance of the sympathetic neuronal supply to the affected tissue is an important component in the generation of this syndrome (Fig. 1). Blocking of sympathetic fibers, which supply the affected tissues~ abolishes or relieves the clinical symptoms. These experiments on the vasoconstrictor supply to the limb of a cat with a chronic nerve lesion show that the reflex pattern changes, compared to the normal (Fig. 3). The change in this pattern could explain part of the pathophysiological changes observed in patients with reflex sympathetic dystrophy. At present we have only very general ideas about the pathophysiological mechanisms of the pain which is one component of this syndrome. Afferent fibers develop abnormal chemosensitivity (see Devor, this volume) and may be excited by
409
noradrenaline released by the postganglionic fibers [3,9,15] (see also Nathan, this volume). An additional component may be the change of the microenvironment of the fine nociceptive afferent fibers which is reflected in the trophic changes (ischaemia, release of vasoactive and algesic substances; see refs. 15,22,29,49,50). In this context, it is worth noting that sympathetic dystrophy can also occur after visceral diseases and even after disorders of the central nervous system [8,32] and that the pain under these conditions can also be abolished or relieved by sympathetic block. Here, the syndrome of reflex sympathetic dystrophy or components of it appear without peripheral trauma. Therefore, without peripheral trauma a disturbance of sympathetic activity, which must be of central origin, is probably enough for generation of the clinical symptoms. This observation can also be reconciled with Livingston's hypothesis (Fig. 1). In order to clarify the pathophysiological mechanisms of reflex sympathetic dystrophy we need, firstly, a deeper insight into the central (particularly spinal) organization of the sympathetic nervous system. Secondly, investigations must concentrate on animal models in which trophic changes can be produced experimentally. These trophic changes must be described histologically and correlated with the discharge patterns in postganglionic sympathetic fibers to and afferent fibers from the trophically altered tissue. Thirdly, afferent fibers and postganglionic sympathetic fibers should be investigated microneurographically in patients with reflex sympathetic dystrophy.
Acknowledgement Supported by the Deutsche Forschungsgemeinschaft.
References 1 Ascherl, R. and Bliimel, G., Zum Krankheitsbild der Sudeck'schen Dystrophie, Fortschr. Med., 99 (1981) 712-720. 2 Barbut, D., Polak, J.M. and Wall, P.D., Substance P in spinal cord dorsal horn decreases following peripheral nerve injury, Brain Res., 205 (1981) 289-298. 3 Blumberg, H. and J~lnig, W., Neurophysiological analysis of efferent sympathetic and afferent fibers in skin nerves with experimentally produced neuromata In J. Siegfried and M. Zimmerman (Eds.), Phantom and Stump Pain, Springer, Berlin, 1981, pp. 15-31. 4 Bhimberg, H. and J~ig, W., Activation of fibers via experimentally produced stump neuromas of skin nerves: ephaptic transmission or retrograde sprouting, Exp. Neurol., 76 (1982) 468-482. 5 Blumberg, H. and Jgmig, W., Changes in unmyelinated fibers including sympathetic postganglionic fibers of a skin nerve after peripheral neuroma formation, J. auton. Nerv. Syst., 6 (1982) 173-183. 6 Blumberg, H., Jiinig, W., Rieckmann, C. and Szulczyk, P., Baroreceptor and chemoreceptor reflexes in postganglionic neurones supplying skeletal muscle and hairy skin, J. auton. Nerv. Syst., 2 (1980) 223-240. 7 Bonica, J.J., The Management of Pain, Lea and Febiger, Philadelphia, 1953, reprinted by Honji Shoji Company, Tokyo, 1980. 8 Bonica, J.J., Causalgia and other reflex sympathetic dystrophies. In J.J. Bonica, J.C. Liebeskind and Albe-Fessard, D.G. (Eds.), Advances in Pain Research and Therapy, Vol. 3, Raven Press, New York, 1979, pp. 141-166.
410 9 Devor, M. and Janig, W., Activation of myelinated afferents ending in a neuroma by stimulation of the sympathetic supply in the rat, Neurosci. Lett. 24 (1981) 43-47. 10 Devor, M. and Wall, P.D., Reorganisation of spinal cord sensory map after peripheral nerve injury, Nature (Lond.), 276 (1978) 75-76. 11 Devor, M. and Wall, P.D., Plasticity in the spinal cord sensory map following peripheral nerve injury in rats, J. Neurosci., 1 (1981) 679-684. 12 Evans, J.A., Reflex sympathetic dystrophy: a report on 57 cases, Ann. Intern. Med, 26 (1947) 417-426. 13 Gregor, M. and Janig, W., Effects of systemic hypoxia and hypercapnia on cutaneous and muscle vasoconstrictor neurones to the cat's hindlimb, Pfli~gers Arch. ges. Physiol., 268 (1977) 71 81. 14 Gregor, M., J~nig, W. and Wiprich, L., Cardiac and respiratory rhythmicities in cutaneous and muscle vasoconstrictor neurones to the cat's hindlimb, Pfltigers Arch. ges. Physiol., 370 (1977) 299-302. 15 Handwerker, H.O., Pain producing substances. In H.W. Kosterlitz, and L.Y. Terenius (Eds.L Pain and Society, Dahlem Konferenzen, Verlag Chemie GmbH, Weinheim, 1980, pp. 325-338. 16 Hannington-Kiff, J.G., Relief of Sudeck's atrophy by regional intravenous guanethidine, Lancet. (1977) 1132-1133. 17 Homans, J., Minor causalgia; a hyperesthetic neurovascular syndrome, New Engl. J. Med.. 222 (1940) 870-874. 18 Horch, K.W. and Lisney, S.J.W., Changes in primary afferent depolarization of sensory neurones during peripheral nerve regeneration in the cat, J. Physiol. (Lond.), 313 (1981 ) 287-299. 19 J~inig, W., Central organization of somatosympathetic reflexes in vasoconstrictor neurones. Brain Res, 87 (1975) 305-312. 20 Janig, W., Reciprocal reaction patterns of sympathetic subsystems with respect to various afferent inputs. In C.McC. Brooks, K. Koizumi and A. Sato (Eds.), Integrative Functions of the Autonomic Nervous System, University of Tokyo Press, Tokyo/Elsevier, North-Holland Biomedical Press, Amsterdam, 1979, pp. 263-274. 21 .lessel, T., Tsunoo, A., Kanazawa, I. and Otsuka, M., Substance P depletion in the dorsal horn of rat spinal cord after section of the peripheral processes of primary sensory neurones, Brain Res.. 168 (1979) 247-259. 22 Keele. C.A. and Armstrong, D., Substances producing pain and itch, Arnold, London, 1964. 23 Kleinert. H.E., Cole, N.M., Wayne, L., Harvey, R., Kutz, J.E. and Atasoy, E., Post-traumatic sympathetic dystrophy, Orth. Clin. N. Amer., 4 (1973) 917-927. 24 Knyihar-Csillik, E. and Csillik, B., FRAP: histochemistry of the primary nociceptive neuron, Progr. Histochem. Cytochem. 14 (1981) 1-137. 25 Korenman, E.M.D. and Devor, M., Ectopic adrenergic sensitivity in damaged peripheral nerve axons in the rat, Exp. Neurol., 72 (1981) 63-81. 26 Korner, P.I., Central nervous control of autonomic cardiovascular function, Handbook of Physiology. Section 2: The Cardiovascular System I. The Heart, American Physiological Society, 1979, pp. 691-739. 27 Leriche, R., La Chirurgie de la Douleur, 3rd Edn., Masson, Paris, 1949. 28 Liebermann, A.R., Some factors affecting retrograde neuronal responses to axonal lesions. In R. Bellairs and E.G. Gray (Eds.), Essays on the Nervous System. A Festschrift for Prof. J.Z. Young, Clarendon Press, Oxford, 1974, pp. 71-105. 29 Lim, R.K.S., Pain, Ann. Rev. Physiol., 32 (1970) 269-288. 30 Livingston, W.K., Pain Mechanisms. A Physiologic Interpretation of Causalgia and its Related States. Macmillan, New York, 1943, unabridged version published by Plenum Press, New York, 1976. 31 Loh, L. and Nathan, P.W., Painful peripheral states and sympathetic blocks, J. Neurol. Neurosurg. Psychiat., 41 (1978) 664-671. 32 Loh, L., Nathan, P.W. and Schott, G.D., Pain due to lesions of central nervous system removed by sympathetic block, Brit. med. J. 282 (1981) 1026-1028. 33 Mitchell, S.W., Injuries of nerves and their consequences, J.P. Lippincott, Philadelphia, 1872. 34 Nathan, P.W., Involvement of the sympathetic nervous system in pain. In H.W. Kosterlitz and L.Y. Terenius (Eds.), Pain and Society. Dahlem Konferenzen, Verlag Chemie GmbH, Weinheim, 1980. pp. 311 324.
411 35 Richards, R.L., Causalsia. A centennial review, Arch. Neurol., 16 (1967) 339-350. 36 Scheibe, G., Die Capillarschadignng bei der Sudeckschen Krankheit, Langenbecks Arch. u. Dtsch. Z. Clair., 283 (1957) 693-707. 37 Scheibe, G. and Karitzky, B., Das funktionelle Hautcapillarbild bei der Sudeckschen Krankheit, Der Chirurg, 25 (1954) 202-206. 38 Sch6nbach, G., Der Einflu$ mechanischer Nervensch~idigungen auf die Permeabilit~it der Gef~isse, Acta neuroveget. Wien, 17 (1957) 18-39. 39 Sch6nbach, G. and Thorban, W., Funktionelle und organische Gef~iBwandver~inderungen nach Sympathektomie und partieller Nervenschadigung, Langenbecks Arch. klin. Chir., 291 (1959) 217-231. 40 Sudeck, P., fiber die akute entziindhche Knochenatrophie, Arch. f. klin. Chir., 62 (1900) 147-156. 41 Sunderland, S., Pain mechanisms in causalgia, J. Neurol. Neurosurg. Psychiat. 39 (1976) 471-480. 42 Thompson, J.., The diagnosis and management of posttraumatic pain syndromes (causalgia), Aust. N.Z. Surg., 49 (1979) 299-304. 43 Thorban, W., Das Sudecksche Syndrom. In A. Sturm and W. Birkmayer (Eds.), Klinische Pathologie des vegetativen Nervensystems, Vol. 2, Gustav Fischer, Stuttgart, 1977, pp. 1186-1206. 44 Wall, P.D., Changes in damaged nerve and their sensory consequences. In J.J. Bonica, J.C. Liebeskind and D.G. Albe-Fessard (Eds.), Advances in Pain Research and Therapy, Vol. 3, Raven Press, New York, 1979, pp. 39-52. 45 Wall, P.D. and Devor, M., Physiology of sensation after peripheral nerve injury, regeneration and neuroma formation. In S.G. Waxman (Ed.), Physiology and Pathobiology of Axons, Raven Press, New York, 1978, pp. 377-388. 46 Wall, P.D. and Devor, M., The effect of peripheral nerve injury on dorsal root potentials and on transmission of afferent signals into the spinal cord, Brain Res., 209 (1981) 95-111. 47 Wirth, F.P. and Rutherford, R.B., A civilian experience with causalgia, Arch. Surg., 100 (1970) 633-638. 48 Wilson, R.L., Management of pain following peripheral nerve injuries, Orth. Clin. N. Amer., 12 (1981) 343-359. 49 Zimmermann, M., Peripheral and central nervous mechanisms of nociception, pain and pain therapy: facts and hypotheses. In J.J. Bonica, J.C. Liebeskind and D.G. Albe-Fessard (Eds.), Advances in Pain Research and Therapy, vol. 3, Raven Press, New York, 1979, pp. 3-32. 50 Zimmerman, M., Physiological mechanisms of chronic pain. In H.W. Kosterlitz and L.Y. Terenius (Eds.), Pain and Society, Dahlem Konferenzen, Verlag Chemic GmbH. Weinheim, 1980, pp. 283-297.