Noradrenergic pain modulation
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 Gi 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 Gs. Alpha-1-adrenoceptors are coupled to phospholipase C through Gq 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.
Section snippets
Peripheral mechanisms of noradrenergic pain modulation
The main sources of peripheral catecholamines are circulation and local release from postganglionic sympathetic nerve fibers. mRNA assessments of the dorsal root ganglion indicate that primary afferent neurons possess several types of alpha-adrenoceptors that potentially mediate peripheral actions of norepinephrine. All three subtypes of alpha-1A, -1B, and -1D have been identified in the dorsal root ganglion (Nicholson et al., 2005, Xie et al., 2001). Of these three subtypes, 1A is the most
Spinal mechanisms of noradrenergic pain modulation
The spinal dorsal horn is a critical link for all ascending pain pathways and the spinal cord receives strong innervation from descending noradrenergic pathways. Therefore, the pain modulatory action of norepinephrine has been more extensively studied in the spinal cord than elsewhere. The source of spinal norepinephrine is descending axons originating in the noradrenergic nuclei of the brainstem (Jones, 1991, Proudfit, 1988), particularly the noradrenergic cell groups A5, A6 (or the locus
Supraspinal mechanisms of noradrenergic pain modulation
Catecholaminergic brainstem nuclei innervate several supraspinal structures that are implicated in mediation and regulation of pain (Lindvall and Björklund, 1974, Moore and Bloom, 1979). The distribution of various adrenoceptor types varies with the supraspinal structure (e.g., Day et al., 1997, Nicholas et al., 1993, Scheinin et al., 1994, Unnerstall et al., 1984, Wang et al., 1996). The finding that intracerebroventricular administration of noradrenergic compounds suppressed pain-related
Postganglionic sympathetic nerve fibers
In healthy subjects the sympathetic nervous system has only little effect on pain, but following a nerve injury it may have a significant and complex role in regulation of pain (Jänig and Häbler, 2000). In nerve injured patients the postganglionic sympathetic nerve fibers may interact with afferent neurons and induce activity in nociceptors. This coupling between primary afferent nociceptive nerve fibers and postganglionic sympathetic nerve fibers may take place at the site of lesion or at a
Interactions of noradrenergic pain modulatory actions with other neurotransmitters
The noradrenergic pain modulatory system interacts with other neurotransmitter systems at various levels of the neuraxis. Since this topic is too large and complex to be described in detail in this review, only a few examples of these interactions are given in this section. Opioidergic and noradrenergic systems have significant interactions at multiple levels.
At the peripheral level, the finding that the antihyperalgesic action of an alpha-2-adrenoceptor agonist was attenuated by a small dose
The role of noradrenergic mechanisms in anesthesia
The role of noradrenergic mechanisms in clinical anesthesia has been reviewed in detail elsewhere (Aantaa and Scheinin, 1993, Eisenach et al., 1996, Maze and Tranquilli, 1991). In the following is only a brief outline of selected aspects on this topic. A decrease in activity of locus coeruleus neurons by activation of alpha-2-adrenoceptors leads to sedation (Aston-Jones and Bloom, 1981, DeSarro et al., 1987). This sedative effect in the locus coeruleus dissociates from the spinal
Norepinephrine in the brain is not only about pain
In addition to regulation of pain, norepinephrine has many other important functions in the nervous system. Norepinephrine is involved in autonomic, particularly sympathetic regulation of cardiovascular, gastrointestinal, and respiratory systems: norepinephrine is a key transmitter released by sympathetic postganglionic nerve fibers (Richerson, 2003) and on the other hand, preganglionic sympathetic neurons in the spinal cord are subject to noradrenergic regulation via alpha-2-adrenoceptors (
Conclusions
In healthy peripheral tissues, norepinephrine has little effect on pain. Following injury, however, peripheral noradrenergic mechanisms are subject to various plastic changes, such as sprouting of postganglionic sympathetic nerve fibers, variable up- or down-regulations of adrenoceptor subtypes, and increased excitability of primary afferent nociceptors. These changes are likely to explain why norepinephrine in an injured peripheral tissue may aggravate pain. Among the peripheral changes
Future implications
The noradrenergic pain inhibitory mechanisms are only little active in baseline conditions, while on demand they may produce a powerful inhibition of pain. Importantly, the noradrenergic pain inhibitory effect, particularly due to action on alpha-2-adrenoceptors in the spinal dorsal horn, is rather selective and its antinociceptive efficacy is increased in inflamed and neuropathic conditions. Synthetic compounds increasing noradrenergic activity or activating directly noradrenergic receptors
Acknowledgements
The author has been supported by grants from the Academy of Finland and from the Sigrid Jusélius Foundation, Helsinki, Finland. Some of the author's original studies on noradrenergic compounds were supported in part by OrionPharma Inc., Turku, Finland. Dr. Denis Artchakov helped in making the illustrations.
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