Introduction

As early as a century ago, Weber showed that adrenaline applied to the spinal cord of the cat attenuates a thermally evoked withdrawal response. A more extensive study of mechanisms underlying norepinephrine-induced pain suppression did not really start until the 1970s, following the development of several novel adrenergic compounds with a potential for clinical use. The role of various aspects of adrenergic mechanisms in pain control has been reviewed previously by a number of authors. This chapter attempts to present what is currently known on pain modulatory actions of norepinephrine at various levels of the nervous system in physiological and pathophysiological conditions.

Peripheral mechanisms of noradrenergic pain modulation

Peripheral norepinephrine has only a minor role in modulation of pain in physiological conditions. Administration of norepinephrine in the skin of healthy subjects does not evoke pain, although it may induce a selective hyperalgesia to thermal stimulation. However, in pathophysiological conditions, peripheral norepinephrine has a significant influence on nerve endings mediating pain. This is shown by the finding that administration of norepinephrine in inflamed or neuropathic skin in humans aggravates pain and hyperalgesia.

Plasticity in peripheral noradrenergic systems following injury or inflammation

In line with psychophysical observations, neurophysiological studies in experimental animals indicate that under physiological conditions nociceptive primary afferent fibers are little, if at all, influenced by norepinephrine, sympathetic stimulation, or synthetic noradrenergic compounds. However, following nerve injury particularly nociceptive C fibers, and to a lesser extent nociceptive A-delta fibers, are excited by norepinephrine and sympathetic stimulation.