Noradrenergic pain modulation

Abstract

Norepinephrine is involved in intrinsic control of pain. Main sources of norepinephrine are sympathetic nerves peripherally and noradrenergic brainstem nuclei A1–A7 centrally. Peripheral norepinephrine has little influence on pain in healthy tissues, whereas in injured tissues it has variable effects, including aggravation of pain. Its peripheral pronociceptive effect has been associated with injury-induced expression of novel noradrenergic receptors, sprouting of sympathetic nerve fibers, and pronociceptive changes in the ionic channel properties of primary afferent nociceptors, while an interaction with the immune system may contribute in part to peripheral antinociception induced by norepinephrine. In the spinal cord, norepinephrine released from descending pathways suppresses pain by inhibitory action on alpha-2A-adrenoceptors on central terminals of primary afferent nociceptors (presynaptic inhibition), by direct alpha-2-adrenergic action on pain-relay neurons (postsynaptic inhibition), and by alpha-1-adrenoceptor-mediated activation of inhibitory interneurons. Additionally, alpha-2C-adrenoceptors on axon terminals of excitatory interneurons of the spinal dorsal horn possibly contribute to spinal control of pain. At supraspinal levels, the pain modulatory effect by norepinephrine and noradrenergic receptors has varied depending on many factors such as the supraspinal site, the type of the adrenoceptor, the duration of the pain and pathophysiological condition. While in baseline conditions the noradrenergic system may have little effect, sustained pain induces noradrenergic feedback inhibition of pain. Noradrenergic systems may also contribute to top-down control of pain, such as induced by a change in the behavioral state. Following injury or inflammation, the central as well as peripheral noradrenergic system is subject to various plastic changes that influence its antinociceptive efficacy.

Introduction

More than a century ago, Weber (1904) applied epinephrine to the spinal cord of the cat and showed that catecholamines modulate pain-related withdrawal responses. A more extensive study of catecholaminergic, particularly noradrenergic pain modulatory mechanisms did not start, however, until the development of selective noradrenergic compounds several decades later. Previous reviews on noradrenergic pain control systems have dealt with spinal noradrenergic pain modulation (Yaksh, 1985), descending noradrenergic pain modulatory pathways (Jones, 1991, Proudfit, 1988), molecular mechanisms of noradrenergic antinociception (Kingery et al., 1997) or pain-related actions of some specific noradrenergic compounds (Pertovaara, 1993, Pertovaara, 2004). Additionally, general characteristics of noradrenergic pain regulation have been briefly dealt with in a number of reviews on descending control of pain in general (e.g., Millan, 2002, Pertovaara and Almeida, 2006) or pharmacology and physiology of pain transmission in particular (e.g., Fields et al., 2006, Yaksh, 2006). During the last decade, gene knockouts of various types of adrenoceptors or enzymes involved in metabolism of norepinephrine have provided new possibilities for addressing the role of noradrenergic pain modulatory mechanisms at the system level. Additionally, novel techniques, such as patch clamp and in situ hybridization have allowed determining the actions of noradrenergic compounds at a higher precision than before. Furthermore, development of various types of pathophysiological pain models in experimental animals has allowed investigating noradrenergic pain modulation not only in physiological but also in pathophysiological conditions. The application of these methodological developments has significantly extended our understanding of noradrenergic pain modulatory mechanisms. The purpose of this review is to give an up-to-date description of noradrenergic pain regulatory mechanisms both in health and disease. Since the perception of pain requires a complex neural circuitry, the main focus of this review is on the integrative level.

Norepinephrine, as other catecholamines dopamine and epinephrine, possesses two hydroxyl groups and one amine group bound to a benzene ring. It is biosynthesized from tyrosine. Tyrosine is first converted to dihydroxyphenylalanine (DOPA) by tyrosine hydroxylase, which is converted to dopamine by aromatic amino acid decarboxylase. In noradrenergic cells dopamine is further converted to norepinephrine by dopamine-beta-hydroxylase. In the brain, noradrenergic cell groups are classified as A1–A7 (Dahlström and Fuxe, 1964). The A1 cell group is located at the level of the area postrema (Fig. 1), A2 is distributed throughout the dorsal vagal complex, A3 is in the medullary reticular formation, and A4 surrounds the fourth ventricle. The A5 cell group is in the ventrolateral pons, A6 or the locus coeruleus is dorsally in the pons and A7 is in the lateral part of the pons, close to the lateral lemniscus (Fig. 2). The main ascending noradrenergic projection pathways in the central nervous system are the dorsal and ventral bundles and the periventricular bundle (Cooper et al., 2003). Additionally, cell groups A5–A7 have significant descending noradrenergic projections to the spinal cord (Kwiat and Basbaum, 1992, Proudfit, 1988). In the periphery, the sympathetic nervous system is the main neuronal source of norepinephrine.

Catecholamine receptors are classically divided into two main categories, alpha- and beta-adrenoceptors. Alpha-adrenoceptors are classified into subtypes 1A, 1B, 1D, 2A, 2B, and 2C, and beta-adrenoceptors into subtypes 1–3 (Aantaa et al., 1995, Bylund, 1995, Ruffolo and Hieble, 1994). In general, guanine nucleotide-binding regulatory proteins (G proteins) mediate the actions of adrenoceptors. Alpha-2-adrenoceptors decrease intracellular adenylcyclase activity through G_i or directly modify activity of ion channels such as the Na⁺/H⁺ antiport, Ca²⁺ channels, or K⁺ channels (Summers and McMartin, 1993). Beta-adrenoceptors increase adenylcyclase activity through G_s. Alpha-1-adrenoceptors are coupled to phospholipase C through G_q or they are coupled directly to Ca²⁺ influx (Summers and McMartin, 1993). Adrenoceptors located on the noradrenergic neurons are considered autoreceptors (Cooper et al., 2003). In general, noradrenergic autoreceptors located in the somatodendritic area inhibit impulse discharge of neurons and those on noradrenergic axon terminals inhibit the release of norepinephrine. Adrenoceptors located on non-noradrenergic neurons are considered heteroreceptors. Heteroreceptors located on non-adrenergic target cells are activated by norepinephrine released from noradrenergic neurons. In addition to classic synaptic transmission across the synaptic cleft (“wiring”), noradrenergic receptors are activated by “volume transmission” from distant sites of norepinephrine release (Zoli and Agnati, 1996). Alpha-adrenoceptors have a key role in mediating pain regulatory effects of norepinephrine as described in the following sections, whereas beta-adrenoceptors may predominantly mediate epinephrine-induced modulation of pain.