Vascular and nociceptive effects of localized prolonged sympathetic blockade in human skin

doi:10.1016/S1566-0702(01)00215-6

Autonomic Neuroscience

Volume 88, Issues 1–2, 12 April 2001, Pages 86-93

https://doi.org/10.1016/S1566-0702(01)00215-6 Get rights and content

Abstract

Supersensitivity to noradrenaline contributes to certain vascular disorders (e.g., hypertension) and chronic neuropathic pain conditions (e.g., complex regional pain syndrome). We aimed to develop a procedure for inducing adrenergic supersensitivity that could be used to investigate the role of catecholamines in these clinical conditions. In the first study, three doses of guanethidine were administered by iontophoresis to separate small patches of skin in the forearm of healthy human volunteers. Four to five hours later, the vasoconstrictor response to the adrenergic releasing agent tyramine was inhibited in a dose-dependent manner by iontophoretic pretreatment with guanethidine, indicating that guanethidine had depleted endogenous adrenergic stores. In a second study, guanethidine and saline were administered by iontophoresis four times over approximately 2 weeks at separate sites in the forearm. One to two days after the final pretreatment, vasoconstriction to the iontophoresis of a weak dose of noradrenaline was enhanced at sites pretreated with guanethidine. To investigate the effect of guanethidine pretreatment on thermal hyperalgesia, the experimental sites were sensitized to heat by the topical application of 0.6% capsaicin. Both before and after the application of capsaicin, the heat-pain threshold and heat-pain ratings to suprathreshold stimulation were similar at sites pretreated for 2 weeks with guanethidine or saline. However, after the iontophoresis of noradrenaline, thermal hyperalgesia was greater at the guanethidine-pretreated site than the saline pretreated site. These observations indicate that prolonged depletion of adrenergic stores by guanethidine induces adrenergic supersensitivity in cutaneous vessels, and that adrenergic supersensitivity enhances thermal hyperalgesia in the presence of noradrenaline.

Introduction

The sensitivity to adrenergic agonists of tissue expressing adrenoceptors is inversely related to prior levels of agonist exposure. For example, vascular smooth muscle becomes desensitized to the constrictive effect of adrenergic agonists after repeated administrations of high concentrations of noradrenaline (Insel and Motulsky, 1987). Conversely, physiologically low levels of noradrenaline induce the development of adrenergic supersensitivity, characterized by an enhanced tissue response to adrenergic agonists Cannon and Rosenblueth, 1949, Fleming and Westfall, 1988.

The experimental induction of adrenergic supersensitivity has clarified the physiological mechanism of medical conditions that exhibit exaggerated responses to adrenoceptor agonists. For example, adrenergic supersensitivity appears to contribute to essential hypertension (de Champlain, 1990) and heightens autonomic reflexes in patients with spinal cord injury, multiple system atrophy or pure autonomic failure Polinsky et al., 1981, Davies et al., 1982, Arnold et al., 1995. Adrenergic supersensitivity is also implicated in the symptoms experienced by some patients with chronic neuropathic pain. In such patients, sympathetic activity and administration of adrenoceptor agonists may produce or exacerbate spontaneous burning and abnormal painful responses to cutaneous stimuli Wallin et al., 1976, Torebjörk et al., 1995.

Adrenergic supersensitivity can be induced pharmacologically by drugs such as reserpine and guanethidine, which interfere with adrenergic storage and thus mimic the effects of sympathectomy. Guanethidine is transported into sympathetic neurones by the amine transport system and once within adrenergic varicosities depletes and reoccupies noradrenaline storage vesicles. Since guanethidine prevents normal sympathetic neurone function, it has been used therapeutically to treat hypertension (Oates, 1996). Hogikyan and Supiano, 1993, Hogikyan and Supiano, 1994 used the guanethidine analogue guanadrel to induce adrenergic supersensitivity in healthy humans. Noradrenaline produced a greater decrease in forearm blood flow after 3 weeks of pretreatment with guanedral than pretreatment with placebo, consistent with the development of adrenergic supersensitivity.

We aimed to induce adrenergic supersensitivity in small regions of skin by local administration of guanethidine. Local administration allows intra-individual measurements to be obtained from both supersensitive and normal skin, thus enhancing the efficiency and power of experimentation. An additional advantage of local administration is that systemic effects are minimized. High local drug concentrations can be achieved with transcutaneous iontophoresis (Morris and Shore, 1996), defined as ‘the facilitated movement of ions of soluble salts across a membrane under an externally applied potential difference’ (Singh and Maibach, 1994, p. 161).

The first aim of this study was to identify the iontophoretic dose of guanethidine that depleted adrenergic stores at the site of administration. The presence of noradrenaline in sympathetic varicosities was investigated with tyramine, a drug that releases noradrenaline from neuronal vesicles and cytoplasm (Smith, 1973). The optimal dose of guanethidine was then administered periodically to a new group of subjects over a 2-week interval. It was anticipated that vasoconstrictive responses to noradrenaline would increase after prolonged sympathetic blockade with guanethidine, administered periodically by iontophoresis.

Sensory consequences of prolonged sympathetic blockade were also investigated. Since noradrenaline increases thermal hyperalgesia in capsaicin-inflamed skin (Drummond, 1995), it was hypothesized that pretreatment with guanethidine would enhance the sensitizing effect of noradrenaline due to the development of adrenergic supersensitivity.

Section snippets

Subjects

The study sample consisted of four males and 23 females aged between 18 and 45 years (mean age 23 years). Some subjects participated in more than one experiment. Subjects provided informed consent for the procedures, which were approved by the Murdoch University Human Research Ethics Committee.

Procedures

Blood flow and sensory data were obtained in a temperature controlled laboratory, maintained at 22±1°C (±S.D.).

Study 1: effect of guanethidine on tyramine-induced vasoconstriction

The response to tyramine was expressed as a percentage of blood flow at untreated sites. As seen in Fig. 1, the vasoconstrictive response to tyramine diminished with increasing doses of guanethidine pretreatment [F(5,36)=5.33, p<0.001]. Since there was no vasoconstriction after tyramine was administered to sites pretreated with 180 mC of guanethidine, the 180-mC dose was chosen for use in Study 2 to produce sympathetic blockade. Pretreatment with saline did not influence the vasoconstrictive

Discussion

Vasoconstriction to noradrenaline was enhanced after the skin had been pretreated with guanethidine for approximately 2 weeks, consistent with the development of adrenergic supersensitivity. In addition, sensitivity to painful heat was enhanced in the guanethidine pretreated and inflamed skin after the administration of noradrenaline.

Conclusions

Our findings indicate that the iontophoresis of guanethidine four times over a 2-week period induces local adrenergic supersensitivity in blood vessels and possibly other cutaneous tissue. Since adrenergic supersensitivity is limited to a small patch of skin, the technique avoids the side-effects and complications of systemic administration (i.e., the necessity for separate experimental and control groups or a washout period between drug and placebo administrations in the same subjects). The

Acknowledgements

This project was supported by the Australian Research Council and Medtronic Australasia.

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Guanethidine displaces noradrenaline from storage vesicles in sympathetic varicosities, thus evoking prolonged sympathetic blockade. To investigate effects of this treatment on sensitivity to heat, guanethidine was administered by iontophoresis to a 2 cm patch of skin four times over a 2 week period (Lipnicki and Drummond, 2001). The guanethidine treatment induced vascular signs of adrenergic supersensitivity and intensified sensitivity to noxious heat in inflamed skin in the presence of noradrenaline.
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In certain animal models of neuropathic pain, stimulation of preganglionic sympathetic fibres facilitates the discharge of sensitized nociceptive afferents (e.g., Chen et al., 1996; Nam et al., 2000). In humans, prolonged local sympathetic blockade increases vasoconstrictor responses to noradrenaline, and also augments thermal hyperalgesia at a dose of noradrenaline that normally does not influence sensitivity to heat (Lipnicki and Drummond, 2001). It would be interesting to determine whether normal sympathetic neural discharge or electrically-evoked release of noradrenaline induces hyperalgesia in inflamed skin at sites of adrenergic supersensitivity.
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Vascular and nociceptive effects of localized prolonged sympathetic blockade in human skin

Abstract

Introduction

Section snippets

Subjects

Procedures

Study 1: effect of guanethidine on tyramine-induced vasoconstriction

Discussion

Conclusions

Acknowledgements

Pain

Pain

Pain

Pain

Pain

Trends Neurosci.

Am. J. Surg.

Pain

Prog. Brain Res.

Lancet

Pain

Lancet

Exp. Cell Res.

Uninjured C-fiber nociceptors develop spontaneous activity and α-adrenergic sensitivity following L6 spinal nerve ligation in monkey

J. Neurophysiol.

Increased venous alpha-adrenoceptor responsiveness in patients with reflex sympathetic dystrophy

Ann. Intern. Med.

Autonomic dysreflexia in tetraplegic patients: evidence for α-adrenoceptor hyper-responsiveness

Clin. Auton. Res.

Effect of sympathetic activity on capsaicin-evoked pain, hyperalgesia, and vasodilatation

Neurology

Noradrenergic and neuropeptide Y mechanisms in guanethidine-sympathectomized rats

Am. J. Physiol.

Expression of α2-adrenergic receptors in rat primary afferent neurones after peripheral nerve injury or inflammation

J. Physiol.

Sympathectomy induces adrenergic excitability of cutaneous C-fiber nociceptors

J. Neurophysiol.

The Supersensitivity of Denervated Structures: A Law of Denervation

Regulation of the postsynaptic α-adrenergic receptor in rat mesenteric artery: effects of chemical sympathectomy and epinephrine treatment

Circ. Res.

Chemical sympathectomy decreases alveolar hypoxic vasoconstriction in lambs but not in sheep

J. Appl. Physiol.

Increased numbers of alpha receptors in sympathetic denervation supersensitivity in man

J. Clin. Invest.

Uninjured C-fiber nociceptors develop spontaneous activity and α-adrenergic sensitivity following L₆ spinal nerve ligation in monkey

Expression of α₂-adrenergic receptors in rat primary afferent neurones after peripheral nerve injury or inflammation