A search for activation of C nociceptors by sympathetic fibers in complex regional pain syndrome
Introduction
Historically it has been assumed that the sympathetic nervous system plays a pathogenic role in some chronic pain conditions, variously labeled RSD (reflex sympathetic dystrophy), SMP (sympathetically maintained pain) or CRPS (complex regional pain syndrome) (Ochoa and Verdugo, 1993), largely on the grounds of physical signs commonly regarded as autonomic, and of subjective symptom relief following sympatholysis (Loh and Nathan, 1978). The presumptive site of interaction between the sympathetic efferent fibers and the afferent system has shifted over time, from the nerve trunk (Nathan, 1947), to the nociceptor terminal (Hannington-Kiff, 1974, Loh and Nathan, 1978, Sato and Perl, 1991, Gibbs et al., 2008), to low threshold mechanoreceptors (Roberts, 1986), and to the dorsal root ganglion (Michaelis et al., 1996). An abnormal state of excitability in the dorsal horn, triggered or maintained by sympathetic activity, has also been postulated (Evans, 1946).
In animals, several studies have investigated possible sympathetic–nociceptor interactions following experimental nerve damage. Roberts and Elardo (1985) reported that electrical stimulation of the sympathetic chain in cats might activate Aδ nociceptor afferents after experimental inflammation. Also, following nerve injury in animals, nociceptor terminals may develop sensitivity to catecholamines, and become excitable during sympathetic stimulation (Häbler et al., 1987, Sato and Perl, 1991, Jänig et al., 1996, O’Halloran and Perl, 1997, Birder and Perl, 1999). According to Ren et al. (2005) sensitization of cutaneous Aδ and C nociceptors by capsaicin was prevented by sympathectomy and rekindled by adrenergic agonists. In a previous report, however, sympathectomy did not prevent discharge of chemically sensitized afferents (Koltzenburg et al., 1992).
In behavioral studies in human volunteers, the capsaicin-evoked pain and mechanical hyperalgesia remained unchanged during full body warming or cooling, maneuvers known to decrease and increase maximally the sympathetic vasoconstrictor tone (Baron et al., 1999). Moreover, in volunteers, mechano-insensitive C nociceptors, sensitized by capsaicin and tested through microneurography, were not responsive to sympathetic reflex maneuvers (Serra et al., 2004). Furthermore, the putative abnormal interaction between sympathetic efferent activity and afferent activity in human polymodal nociceptors sensitized with mustard oil has also been addressed through microneurography with negative results (Elam et al., 1999).
In chronic pain patients with or without demonstrable nerve damage, psychophysical studies led to the assumption that sympathetic efferent activity is a significant determinant of the pains. Indeed, diagnostic and therapeutic sympathetic blocks are often followed by transient symptom relief, although this effect has been attributed directly to placebo (Verdugo and Ochoa, 1994, Verdugo et al., 1994, Jadad et al., 1995, Ramamurthy and Hoffman, 1995). Conversely, there are examples where exogenous norepinephrine might trigger a pain complaint. An injection of norepinephrine near a stump neuroma in amputees reportedly evoked significant pain (Chabal et al., 1992). Further, norepinephrine injected in previously symptomatic skin of patients diagnosed with SMP, neuralgia or causalgia, was reported to rekindle the symptom (Wallin et al., 1976, Torebjörk et al., 1995). Ali et al. (2000) reported that norepinephrine injections produced pain in SMP patients at doses that were just at the threshold for producing vasoconstriction. Mailis-Gagnon and Bennett (2004) describe enhanced pain responses to intradermal norepinephrine in asymptomatic skin in patients with SMP and suggest a central rather than a peripheral mechanism for this phenomenon. All these claims are based upon subjective self-reports.
In fact, no pathologically increased sympathetic neuro-secretion to symptomatic areas has been documented in patients labeled with RSD (Goldstein et al., 2000) and sympathetic efferent neural activity is not abnormally increased in patients assessed with SMP (Elam, 1998). However, a recent case report (Jørum et al., 2007) described a patient with a chronic pain condition in whom spontaneous activity recorded by microneurography from skin nociceptor units was enhanced by maneuvers that normally increase sympathetic outflow. Further direct neurophysiological studies in patients therefore seemed warranted.
Here, we present a series of 24 patients with complex regional pain syndromes type I and II (CRPS I and II, without and with nerve injury, respectively) in whom we searched, through the use of microneurography, for potential interactions between natural sympathetic activity documented for individual efferent fibers and afferent activity in subtype-identified nociceptors innervating symptomatic areas. No evidence of interaction was found for either polymodal or mechanically-insensitive C fiber nociceptors in these patients.
Section snippets
Subjects
All subjects (24 patients and 1 healthy volunteer) gave informed written consent to be studied; the consent form was approved by the Legacy System and Universidad del Desarrollo local ethics committees.
Thirteen consecutive patients fulfilling diagnostic criteria for CRPS I (Merskey and Bogduk, 1994) (see Section 4) were included, as well as 11 patients with CRPS II, of which 10 had painful neuropathy and 1 a traumatic nerve injury. Patients reporting chronic pain associated with motor and
Clinical aspects
Twenty-four patients (Table 1) that fulfilled the diagnosis of CRPS (13 CRPS I and 11 CRPS II) underwent successfully one or more microneurography recordings. Mean age of CRPS I patients (8 females, 5 males) was 40.2 years, slightly younger than the CRPS II patients (4 females, 7 males) (mean age 44.5 years). All patients communicated spontaneous pain and various degrees of static or dynamic mechanical hyperalgesias. Their main clinical features are summarized in Table 1. The sensory symptoms of
Discussion
Our search for abnormal excitation of single identified CMH and mechano-insensitive nociceptor afferents, induced by documented sympathetic efferent activation in symptomatic painful limbs of 24 patients fitting the descriptive categories CRPS I and CRPS II (Merskey and Bogduk, 1994), has been negative. The present results differ from those in a single case study that also used microneurography (Jørum et al., 2007, Ochoa, 2007). In all 24 CRPS patients we have failed to detect any evidence of
Conclusions
In 13 CRPS I and 11 CRPS II patients we could find no electrophysiological single nerve fiber evidence for activation of C nociceptors related to efferent activity in sympathetic efferent fibers. Therefore an a priori supposition of sympathetic involvement in pain generation at the C nociceptor level in either CRPS I or CRPS II is likely to be unfounded and may distract attention away from potentially treatable mechanisms.
Acknowledgment
This work was supported by NIH Grant R01-NS48932. The authors do not have conflicts of financial interests, and there are no sponsors from the industry.
References (43)
- et al.
Intradermal injection of norepinephrine evokes pain in patients with sympathetically maintained pain
Pain
(2000) - et al.
Pain response to perineuromal injection of normal saline, epinephrine, and lidocaine in humans
Pain
(1992) - et al.
Activation of unmyelinated afferents in chronically lesioned nerves by adrenaline and excitation of sympathetic efferents in the cat
Neurosci Lett
(1987) Intravenous regional sympathetic block with guanethidine
Lancet
(1974)- et al.
Intravenous regional sympathetic blockade for pain relief in reflex sympathetic dystrophy: a systematic review and a randomized, double-blind crossover study
J Pain Symptom Manage
(1995) - et al.
Interactions of sympathetic and primary afferent neurons following nerve injury and tissue trauma
Prog Brain Res
(1996) - et al.
Catecholamine-induced excitation of nociceptors in sympathetically maintained pain
Pain
(2007) - et al.
The nociceptor sensitization by bradykinin does not depend on sympathetic neurons
Neuroscience
(1992) - et al.
Abnormal contralateral pain responses from an intradermal injection of phenylephrine in a subset of patients with complex regional pain syndrome (CRPS)
Pain
(2004) - et al.
Effects of partial nerve injury on the responses of C-fiber polymodal nociceptors to adrenergic agonists
Brain Res
(1997)
A hypothesis on the physiological basis for causalgia and related pains
Pain
Noradrenaline-evoked pain in neuralgia
Pain
Activity from skin mechanoreceptors recorded percutaneously in awake human subjects
Exp Neurol
Preliminary observations on the patho-physiology of hyperalgesia in the causalgic pain syndrome
Effect of sympathetic activity on capsaicin-evoked pain, hyperalgesia, and vasodilatation
Neurology
Expression of alpha2-adrenergic receptors in rat primary afferent neurones after peripheral nerve injury or inflammation
J Physiol
Partial reversal of conduction slowing during repetitive stimulation of single sympathetic efferents in human skin
Acta Physiol Scand
The relation between sympathetically maintained pain, regional vasomotor disturbances and sympathetic nerve activity: a remaining enigma
Schmerz
Does sympathetic nerve discharge affect the firing of polymodal C-fibre afferents in humans?
Brain
Reflex sympathetic dystrophy
Surg Clin North Am
Unravelling the pathophysiology of complex regional pain syndrome: focus on sympathetically maintained pain
Clin Exp Pharmacol Physiol
Cited by (39)
Review of techniques useful for the assessment of sensory small fiber neuropathies: Report from an IFCN expert group
2022, Clinical NeurophysiologyCitation Excerpt :Vasomotor and sudomotor sympathetic efferent fibers have been largely studied through MNG (Carter, 2019). Although this technique provides evidence to understand numerous physiological processes no relation to potential activation of C nociceptors nor interaction with large diameter tactile afferents have been identified (Campero et al., 2010; Elam, 1998; Elam, 2001). Namer et al (2009) analyzed the distribution of types of C-fibers in young adults, compared to aged healthy subjects.
How is chronic pain related to sympathetic dysfunction and autonomic dysreflexia following spinal cord injury?
2018, Autonomic Neuroscience: Basic and ClinicalNew Concepts in Complex Regional Pain Syndrome
2016, Hand ClinicsMicroneurographic recording from unmyelinated nerve fibers in neurological disorders: An update
2015, Clinical NeurophysiologyThe complex regional pain syndrome
2015, Handbook of Clinical Neurology