Elsevier

Brain Research

Volume 759, Issue 2, 6 June 1997, Pages 233-240
Brain Research

Research report
Effects of partial nerve injury on the responses of C-fiber polymodal nociceptors to adrenergic agonists

https://doi.org/10.1016/S0006-8993(97)00261-8Get rights and content

Abstract

The effects of partial division of the great auricular nerve of adult rabbits were evaluated on the responsiveness of cutaneous C-fiber polymodal nociceptors (CPMs) to sympathetic stimulation (SS), close-arterial injections of epinephrine (EPI) and other α-adrenergic agonists. In normal unanesthetized rabbits, the two ears were usually at the same temperature. Two to 4 weeks after partial nerve lesions, however, the operated ear was cooler by 1–3°C in the majority of animals, suggestive of increased vasoconstriction and possible denervation supersensitivity. Neither SS nor EPI (50 ng) excited CPM units (n=23) from intact anesthetized animals. In contrast, 14–27 days after partial nerve lesions, SS (8 out of 38 units) and EPI (12 out of 38 units) were excitatory for a class of CPMs. There was notable variability in the response of different units and of a given unit between first and second trials. Responses consisted of 1–22 impulses for SS and 1–23 impulses for EPI in the 60 s following a trial. Arterial occlusion did not activate responsive units, suggesting that the excitation was not caused by vascular or temperature changes. Selective α2-adrenoceptor blockade with yohimbine (0.6–1.0 mg/kg i.v.) or rauwolscine (1.0 mg/kg i.v.) reversibly antagonized the effects of SS and EPI. EPI-responsive units were also excited by norepinephrine (50 ng) and guanabenz (10 μg) but not by clonidine (3 μg) or B-HT 933 (3 μg). The results suggest that circulating EPI, acting via an α-adrenoceptor subtype, can play a part in the development and/or maintenance of aberrant pain syndromes such as causalgia and other sympathetically related dystrophies.© 1997 Elsevier Science B.V. All rights reserved.

Introduction

The sympathetic nervous system has been implicated for many years in certain human conditions with pain as a dominant symptom, notably causalgia and other related pathophysiological states. Many of these painful states are accompanied by clinical features often associated with sympathetic dysfunction: vasomotor, sudomotor, thermal disturbances and trophic changes. The painful burning sensation, allodynia and hyperpathia characteristic of these disorders often can be alleviated by sympathectomy or sympathetic block 3, 4, 25, 27, 30, 31, 34, 45, 52, 62and aggravated by sympathomimetic conditions 14, 15, 59, 61. On the other hand, they are not always susceptible to such treatment 19, 39, 40, 41, 42, 53, 57, 58. A role for adrenergic substances in the development of human pain states is also supported by the report that norepinephrine (NE) injected into the skin of patients whose causalgic pain was relieved by sympathectomy or sympathetic block can reproduce the former causalgic pain [61], but does not cause pain or hyperalgesia either on a normal side or in normal patients 10, 61. This suggests that causalgic pain results from an interaction between NE and sensory nerve terminals or fibers in the skin. There also is recent evidence that these pain syndromes are not linked to enhanced sympathetic efferent discharge since levels of the sympathetic efferent mediators NE, neuropeptide Y and the intracellular metabolite, 3,4-dihydroxyphenylethyleneglycol (DHPG), of NE in venous blood from affected limbs are less than that of contralateral asymptomatic limbs 17, 18.

Activation of cutaneous C-fiber polymodal nociceptors (CPMs) has been related to pain with a burning quality in man 43, 55, 56. Neither sympathetic stimulation (SS) nor physiological concentrations of adrenergic substances excite normal cutaneous nociceptors 1, 47, 48, 54. On the other hand, partial injury of a peripheral nerve induces excitatory responses to SS and NE in a significant proportion of uninjured nociceptors in the nerve 5, 49. These excitatory effects are observed within days after nerve lesions and persist for months, with maximal effects 2–3 weeks after nerve injury. It has been suggested that such induced changes of responsiveness in sense organs related to pain may be responsible for the development of sympathetically-related pain syndromes such as causalgia 44, 49.

The role of the sympathetic nervous system in the development of causalgic-like pain syndromes has been reconsidered largely on the basis of unpredictability of relief of pain following sympathetic block (see 42, 53). Surgical sympathectomy rarely provides a cure 39, 41, 42and sympathetic blockade is reported to sometimes worsen pain [40]. One suggestion is that much of the beneficial effect of sympathetic blockade (by whatever means) is due to a placebo effect 19, 57, 58. Indeed, recent randomized controlled studies report the effects of regional sympathetic blockade with guanethidine to be no better than placebo 7, 22, 46.

The endogenous catecholamine, epinephrine (EPI), exerts similar physiological actions to NE. We hypothesized that circulating EPI could be a factor in the development and maintenance of aberrant pain syndromes following partial nerve injury and/or in the maintenance or recurrence of symptoms in patients treated by sympathectomies or sympathetic block for causalgia or related neuropathic states. We therefore undertook experiments to examine the effects of EPI and other α2-adrenergic agonists on CPMs left functioning after partial nerve injury.

Section snippets

Materials and methods

Forty-two commercially bred, adult, New Zealand white rabbits (2.5–3.3 kg) of both sexes were anesthetized with urethane (2 g/kg i.p.) and the trachea cannulated. Anesthesia was supplemented as needed to maintain areflexia through a cannula in the right jugular vein and systemic arterial pressure was monitored from the right carotid artery. The left cervical sympathetic trunk was freed from surrounding tissue, transected proximal to the superior cervical ganglion and its rostral stump threaded

Results

Surface skin temperatures of the ears differed by ≤0.5°C in 14 of 15 intact, restrained unanesthetized, rabbits. In contrast, an average of 21 days (range 14–27) after partial nerve injury the ear skin temperatures typically differed by 1–3°C; 17 of 27 had the left (operated) ear cooler than the right ear, in 4 the operated side was the warmer, and in 6 both were the same.

CPM units rarely exhibit activity prior to skin stimulation. The absence of neural activity in the 60 s prior to each trial

Discussion

The main finding of this study is that following partial nerve injury, unilateral SS and close-arterial injections of EPI are excitatory for a class of CPMs. SS evoked responses in ∼20% of lesioned units while EPI was excitatory for about one-third of the CPMs tested in operated animals. Under equivalent experimental conditions, none of a comparable sample of units from intact animals were excited. The latter result confirms other reports on the failure of SS to excite or enhance the activity

Acknowledgements

This work was supported by Grant NS 10321 from the NINDS of the NIH. We gratefully acknowledge Dr. Virginia K. Shea for helpful comments during the course of this work.

References (62)

  • W.J Roberts et al.

    Sympathetic activation of unmyelinated mechanoreceptors in cat skin

    Brain Res.

    (1985)
  • J Sato et al.

    Adrenergic excitation of cutaneous nociceptors in chronically inflamed rats

    Neurosci. Lett.

    (1993)
  • J Scadding

    Development of ongoing activity, mechanosensitivity and adrenaline sensitivity in severed peripheral nerve axons

    Exp. Neurol.

    (1981)
  • P.D Wall et al.

    Ongoing activity in peripheral nerves: The physiology and pharmacology of impulses originating from a neuroma

    Exp. Neurol.

    (1974)
  • P Bessou et al.

    Response of cutaneous sensory units with unmyelinated fibers to noxious stimuli

    J. Neurophysiol.

    (1969)
  • J.J Bonica

    Causalgia and other reflex sympathetic dystrophies

    Adv. Pain Res. Ther.

    (1979)
  • J.J. Bonica (Ed.), Causalgia and other reflex sympathetic dystrophies, in: The Management of Pain, Lea and Febinger,...
  • D.F Bossut et al.

    Effects of nerve injury on sympathetic excitation of Aδ mechanical nociceptors

    J. Neurophysiol.

    (1995)
  • D.F Bossut et al.

    Sympathectomy induces adrenergic excitability of cutaneous C-fiber nociceptors

    J. Neurophysiol.

    (1996)
  • J.N. Campbell, S.N. Raja, R.A. Meyer, Painful sequelae of nerve injury, in: R. Dubrier, G.F. Gebhart, M.R. Bond (Eds.),...
  • J.N. Campbell, S.N. Raja, R.A. Meyer, How should sympathetically maintained pain be diagnosed?: A case study, in: J.M....
  • W.B. Cannon, A. Rosenbleuth, The Supersensitivity of Denervated Structures: A Law of Denervation, McMillan, New York,...
  • M. Devor, W. Jänig, Activation of myelinated afferents ending in a neuroma by stimulation of the sympathetic supply in...
  • P.D Drummond et al.

    Plasma neuropeptide Y in the symptomatic limb of patients with causalgic pain

    Clin. Autonom. Res.

    (1994)
  • P.D Drummond et al.

    Reflex sympathetic dystrophy: The significance of differing plasma catecholamine concentrations in affected and unaffected limbs

    Brain

    (1991)
  • F.J Evans

    The placebo response in pain reduction

    Adv. Neurol.

    (1974)
  • W Feldberg

    The peripheral innervation of the vessels of the external ear of the rabbit

    J. Physiol.

    (1926)
  • M Fitzgerald et al.

    The sensitization of high threshold mechanoreceptors with myelinated axons by repeated heating

    J. Physiol.

    (1977)
  • C.J. Glynn, P.C. Jones, An investigation of the role of clonidine in the treatment of reflex sympathetic dystrophy, in:...
  • J.S Gutkind et al.

    Noradrenaline uptake inhibitors counteract the cardiovascular effects of clonidine but not those of guanabenz

    Comun. Biol.

    (1983)
  • J.S Gutkind et al.

    Cardiovascular effects of alpha-adrenergic drugs: Differences between clonidine and guanabenz

    Naunyn-Schmiedeberg's Arch. Pharmacol.

    (1986)
  • Cited by (52)

    • Prostaglandin levels, vaginal innervation, and cyst innervation as peripheral contributors to endometriosis-associated vaginal hyperalgesia in rodents

      2016, Molecular and Cellular Endocrinology
      Citation Excerpt :

      It is also possible that “direct coupling” between the cyst's sensory and sympathetic fibers, in which the fibers are physically close enough in proximity to influence one another, is involved in endometriosis-associated pain. After peripheral nerve injury it has been shown that sensory C-fibers can begin expressing adrenoceptors that can directly be stimulated by NE released from sympathetic nerve terminals (O'Halloran and Perl, 1997; Sato and Perl, 1991). Further, during inflammation, C-fibers can become more sensitive to NE (Banik et al., 2001).

    • A search for activation of C nociceptors by sympathetic fibers in complex regional pain syndrome

      2010, Clinical Neurophysiology
      Citation Excerpt :

      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.

    • Norepinephrine-induced nociception and vasoconstrictor hypersensitivity in rats with chronic post-ischemia pain

      2008, Pain
      Citation Excerpt :

      Importantly, exaggerated painful responses to NE are exhibited in CRPS-I and II patients whose pain is relieved by sympathetic blocks (i.e., SMP), but not in those whose pain is not relieved by sympathetic blocks or phentolamine (sympathetically-independent pain, SIP) [2,36a,58]. While experimental evidence has suggested that SMP may depend on sympathetic efferent–primary afferent coupling [12] that causes de novo adrenergic sensitivity in damaged afferents [18,60], dorsal root ganglion cells [19,39] or nociceptors [43,49], clinical evidence further suggests that SMP may depend on sympathetic-dependent vasoconstriction that produces pain by reducing blood flow in the affected tissue [1,5,30,64]. Indeed, NE-induced pain in CRPS patients occurs at doses which produce vasoconstriction [2], and CRPS-I patients show a hyper-responsiveness of vascular responses to NE [3,8,55].

    View all citing articles on Scopus
    1

    Present address: Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin, 2015 Linden Drive West, Madison, WI 53706-1102, USA.

    View full text