Research reportEffects of partial nerve injury on the responses of C-fiber polymodal nociceptors to adrenergic agonists
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.
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Present address: Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin, 2015 Linden Drive West, Madison, WI 53706-1102, USA.