Elsevier

Joint Bone Spine

Volume 70, Issue 1, 1 February 2003, Pages 12-17
Joint Bone Spine

Review
Reflex sympathetic dystrophy syndrome and neuromediators

https://doi.org/10.1016/S1297-319X(02)00006-4Get rights and content

Abstract

Concepts related to the pathophysiology of reflex sympathetic dystrophy syndrome (RSDS) are changing. Although sympathetic influences are still viewed as the most likely mechanism underlying the development and/or perpetuation of RSDS, these influences are no longer ascribed to an increase in sympathetic tone. Rather, the most likely mechanism may be increased sensitivity to catecholamines due to sympathetic denervation with an increase in the number and/or sensitivity of peripheral axonal adrenoceptors. Several other pathophysiological mechanisms have been suggested, including neurogenic inflammation with the release of neuropeptides by primary nociceptive afferents and sympathetic efferents. These neuromediators, particularly substance P, calcitonin gene-related peptide, and neuropeptide Y (NPY), may play a pivotal role in the genesis of pain in RSDS. They induce an inflammatory response (cutaneous erythema and edema) and lower the pain threshold. Neurogenic inflammation at the site of the lesion with neuromediator accumulation or depletion probably contributes to the pathophysiology of RSDS. However, no single neuromediator has been proved responsible, and other hypotheses continue to arouse interest.

Introduction

Despite an abundance of studies [1], the pathophysiology of reflex sympathetic dystrophy syndrome (RSDS) remains obscure [2]. The clinical abnormalities characteristic of RSDS have been ascribed to dysfunction of the sympathetic nervous system since Leriche [3] first put forward this theory in 1916. The increase in local sympathetic outflow in response to heightened afferent activity from the damaged area was thought to cause the symptoms (pain, redness, heat, and edema) [4], [5]. This hypothesis is consistent with the ability of surgical or chemical sympathectomy to alleviate the symptoms in some patients [6], [7]. However, current hypotheses for sympathetic system involvement in the pathogenesis of RSDS differ markedly from this classic theory, and other mechanisms have also been incriminated, most notably neurogenic inflammation.

Section snippets

Abnormalities in sympathetic activity in reflex sympathetic dystrophy syndrome

Several lines of evidence point to a decrease in sympathetic outflow from the affected limb. Thus, local cutaneous blood flow, which indirectly reflects sympathetic activity [8], is decreased in the affected limb [9] or even in both limbs [10], and skin temperature is identical to that in controls [11]. These findings suggest a decrease in sympathetic vasomotor tone at rest in the affected limb [12], [13], [14].

The blood flow difference between the healthy limb and the affected limb is dynamic

Local catecholamine levels are not elevated

One way of evaluating sympathetic function is to assay sympathetic neurotransmitters, i.e., catecholamines, in the bloodstream. Many studies have shown that disorders or procedures associated with a decrease in sympathetic activity are associated with a reduction in plasma catecholamine levels [19], [20], [21] and that these levels are correlated with sympathetic outflow [22].

No animal model for RSDS is available. The model that best replicates the many symptoms and behaviors found in RSDS is

Mechanisms of sensitization

The discovery that sympathetic outflow had decreased or was even normal in the affected limb prompted a search for explanations regarding the abnormal interaction between the sensory and sympathetic nervous systems. Sympathetic denervation increases blood vessel sensitivity to catecholamines [33]. Consequently, the blood vessels of the affected limb should show increased sensitivity to catecholamines. This was confirmed by Arnold et al. [34] for venous α-adrenoceptors. This increased vascular

Why does sympathectomy alleviate the symptoms?

Several studies reported clinical improvements after sympathectomy in patients with RSDS [37], [38], [39]. This effect is difficult to reconcile with the concept of catecholamine sensitization induced by denervation.

The most likely explanation is that sympathetic denervation is incomplete. This may explain the increase in cutaneous blood flow at the early stage of RSDS [9]. Chemical or surgical sympathectomy may reduce the concentrations of noradrenaline released in the synaptic cleft and, in

Neurogenic inflammation

Several neuromediators have been identified within nociceptive afferents, including substance P and calcitonin gene-related peptide (CGRP) [47], [48], [49], [50]. Substance P (SP) can induce vasodilation and plasma extravasation [51]. CGRP, also a potent vasodilator, causes lasting erythema [52], [53].

In 1920, Lewis hypothesized that the inflammatory symptoms seen in RSDS may be related to the release of algogenic vasodilating substances by sensory fiber nerve endings in response to axonal

Substance P

Substance P, a peptide composed of 11 amino acids, is found throughout the central nervous system. Substance P has many functions, and its distribution suggests a neurocrine or paracrine role [57]. Substance P is one of the main neurotransmitters in pain [58]. Its role in joint inflammation [59] and chronic neuropathies [60] is better understood. Substance P also causes vasodilation via direct interaction with endothelial cells. Similar to vasoactive intestinal polypeptide (VIP), neurotensin,

Sympathetic neuromediators may contribute to RSDS

Sympathetic mediators other than catecholamines may contribute to the pathophysiology of RSDS.

Conclusion

Abnormal sympathetic responses cannot explain all the symptoms of RSDS [6], [42], [84]. It has been established that RSDS is not due to sympathetic hyperactivity, and there is evidence suggesting increased adrenergic sensitivity. Neurogenic inflammation at the lesion site with neuromediator accumulation or depletion probably contributes to precipitate and/or perpetuate RSDS [36]. However, other mechanisms are being examined, particularly central mechanisms such as loss of descending inhibition

References (86)

  • W.J. Roberts

    A hypothesis on the physiological basis for causalgia and related pain

    Pain

    (1986)
  • S.D. Brain et al.

    Potent vasodilator activity of calcitonin gene-related peptide in human skin

    J Invest Dermatol

    (1986)
  • P. Kenins

    Identification of the unmyelinated sensory nerves which evoke plasma extravasation in response to antidromic stimulation

    Neurosci Lett

    (1981)
  • D.G. Snijdelaar et al.

    Eur J Pain

    (2000)
  • J.L. Vaught

    Substance P, antagonists and analgesia: a review of hypotheses

    Life Sci

    (1988)
  • Z. Khalil et al.

    Serotonin modulates substance P-induced plasma extravasation and vasodilatation in rat skin by an action through capsaicin-sensitive primary afferent nerves

    Brain Res

    (1990)
  • A. Szallasi et al.

    Vanilloid receptors: new insights enhance potential as a therapeutic target

    Pain

    (1996)
  • J. Winter et al.

    Capsaicin and pain mechanisms

    Br J Anaesth

    (1995)
  • G.N. Onuoha et al.

    Calcitonin gene-related peptide and others neuropeptides in the plasma of patients with soft tissue injury

    Life Sci

    (1999)
  • R. Oku et al.

    Calcitonin gene-related peptide promotes mechanical nociception by potentiating release of substance P from the spinal dorsal horn in rats

    Brain Res

    (1987)
  • S.B. McMahon et al.

    Visceral pain

    Br J Anaesth

    (1995)
  • C.J. Woolf

    Somatic pain-pathogenesis and prevention

    Br J Anaesth

    (1995)
  • A. Vaalasti et al.

    Vasoactive intestinal polypeptide (VIP)-like immunoreactivity in the nerves of human axillary sweat gland

    J Invest Dermatol

    (1985)
  • E. Ekblad et al.

    Neuropeptide Y co-exists and co-operate with noradrenaline in perivascular nerve fibres

    Regul Pept

    (1984)
  • A. Balasubramaniam

    Neuropeptide Y family of hormones: receptor subtypes and antagonists

    Peptides

    (1997)
  • R.P. Pawl

    Controversies surrounding reflex sympathetic dystrophy: a review article

    Curr Rev Pain

    (2000)
  • A.T. Marshall et al.

    Reflex sympathetic dystrophy

    Rheumatology

    (2000)
  • R. Leriche

    De la causalgie envisagée comme une névrite du sympathique et de son traitement par la dénudation et de l'excision des plexus nerveux péri-artériels

    Presse Méd

    (1916)
  • A.J.M. Kurvers

    Reflex sympathetic dystrophy: facts and hypotheses

    Vascular Medicine

    (1998)
  • R. Leriche

    Oedème dur post-traumatique de la main avec impotence fonctionnelle complète. Transformation soudaine 5 heures après sympathectomie humérale

    Lyon Chir

    (1923)
  • H.A. Kurvers et al.

    The spinal component to skin blood flow abnormalities in reflex sympathetic dystrophy

    Arch Neurol

    (1996)
  • L. Rosen et al.

    Skin microvascular circulation in the sympathetic dystrophies evaluated by video photometric capillaroscopy and laser Doppler fluxmetry

    Eur J Clin Invest

    (1988)
  • K. Christensen et al.

    The reflex sympathetic dystrophy syndrome. An experimental study of sympathetic reflex control of subcutaneous blood flow in the hand

    Scand J Rheumatol

    (1983)
  • H.A. Kurvers et al.

    Reflex sympathetic dystrophy: result of autonomic denervation?

    Clin Sci (Colch)

    (1994)
  • A.A.K. Hassan et al.

    Mechanism of the postural vasoconstrictor response in the human foot

    Clin Sci

    (1998)
  • R. Casale et al.

    Normal sympathetic nerve activity in a reflex sympathetic dystrophy with marked skin vasoconstriction

    J Auton Nerv Syst

    (1992)
  • D.M. Clinchot et al.

    Sympathetic skin response in patients with reflex sympathetic dystrophy

    Am J Phys Med Rehabil

    (1996)
  • L. Van der Laan et al.

    Complex regional pain syndrome type 1: pathology of skeletal muscle and peripheral nerve

    Neurology

    (1998)
  • C.J. Mathias et al.

    Plasma catecholamines during paroxysmal neurogenic hypertension in quadriplegic man

    Circ Res

    (1976)
  • R.J. Polinsky et al.

    Pharmacologic distinction of different orthostatic hypotensive syndromes

    Neurology

    (1981)
  • B.G. Wallin et al.

    Plasma noradrenaline correlates to sympathetic muscle nerve activity in normotensive man

    Acta Physiol Scand

    (1981)
  • G.J. Bennet

    An animal model of neuropathic pain

    Muscle Nerve

    (1993)
  • G.J. Bennet et al.

    A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man

    Pain

    (1988)
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