Descending noradrenergic influences on pain

doi:10.1016/S0079-6123(08)63824-8

Progress in Brain Research

Volume 88, 1991, Pages 381-394

https://doi.org/10.1016/S0079-6123(08)63824-8 Get rights and content

Multiple separate and distinct supraspinally organized descending inhibitory systems have been identified which are capable of powerfully modulating spinal nociceptive transmission. Until recently, brainstem sites known to be involved in the centrifugal modulation of spinal nociceptive transmission were few in number, being limited to midline structures in the midbrain and medulla (e.g., periaqueductal gray and nucleus raphe magnus). However, with continued investigation, that number has increased and brainstem sites previously thought to be primarily involved in cardiovascular function and autonomic regulation (e.g., nucleus tractus solitarius; locus coeruleus/subcoeruleus (LC/SC); A5 cell group; lateral reticular nucleus) also have been demonstrated to play a role in the modulation of spinal nociceptive transmission. Spinal monoamines (norepinephrine (NE) and serotonin) have been shown to mediate stimulation-produced descending inhibition of nociceptive transmission from these brainstem sites.

The majority of NE-containing fibers and terminations in the spinal cord arise from supraspinal sources; thus, the LC/SC, the parabrachial nuclei, the Kölliker-Fuse nucleus and the A5 cell group have all been suggested as possible sources of the spinal noradrenergic (NA) innervation involved in the centrifugal modulation of spinal nociceptive transmission. Several lines of evidence suggest that the LC/SC plays a significant role in a functionally important descending inhibitory NA system. Focal electrical stimulation in the LC produces an antinociception and increases significantly the spinal content of NA metabolites. The inhibition of the nociceptive tail-flick withdrawal reflex produced by electrical stimulation in the LC/SC has been demonstrated to be mediated by postsynaptic α₂-adrenoceptors in the lumbar spinal cord. Similarly, electrical or chemical stimulation given in the LC/SC inhibits noxious-evoked dorsal horn neuronal activity. Thus, results reported in electrophysiological experiments confirm those reported in functional studies and the NA coeruleospinal system appears to play a significant role in spinal nociceptive processing.

Introduction

Multiple separate and distinct supraspinally organized descending inhibitory systems have been identified which, when activated either by electrical stimulation or by the microinjection of drugs (e.g., morphine or glutamate) into selected regions of the brain (see Yaksh and Rudy, 1978; Gebhart, 1982 and Hammond, 1986 for reviews), powerfully modulate spinal nociceptive transmission (Besson et al., 1975; Handwerker et al., 1975; Duggan et al., 1977 and Soja and Sinclair, 1983). The relevance of these descending inhibitory systems to antinociception and analgesia became clear with the demonstration that both spinal nociceptive reflexes and complex behaviors elicited by nociceptive stimuli are inhibited in rats, cats and monkeys (e.g., see Mayer, 1979 for review) and analgesia is produced in man (e.g., Hosobuchi et al., 1977) by stimulation or opioids given into these same brain regions.

Until recently, brainstem sites known to be involved in the centrifugal modulation of spinal nociceptive transmission were few in number, being limited to midline structures in the midbrain and medulla (e.g., the periaqueductal gray and nucleus raphe magnus (NRM)). However, with continued investigation, that number has increased and brainstem sites previously thought to be primarily involved in cardiovascular function and autonomic regulation, (e.g., nucleus tractus solitarius; locus coeruleus (LC); A5 cell group; lateral reticular nucleus) also have been shown to play a role in the modulation of spinal nociceptive transmission. Spinal monoamines (norepinephrine (NE) and serotonin) have been demonstrated to mediate stimulation-produced descending inhibition of nociceptive transmission from these brainstem sites (see Proudfit, 1988 for review). This chapter will review the role that monoamines play in spinal nociceptive processing and will focus on the descending coeruleospinal system.

Section snippets

Adrenoceptor agonists and antinociception

It has been known since the 1940s that monoamines are involved in the modulation of pain and analgesia when it was demonstrated that systemically administered sympathomimetic agents (e.g., amphetamine) produced an analgesia in man (Burill et al., 1944). It became clear, however, that not all sympathomimetic agents produce an antinociception (e.g., oxymetazoline) when administered systemically. It was soon recognized that the failure of such agents to produce antinociceptive effects was due to

Modulation of spinal nociceptive transmission by α-adrenoceptor agonists

Behavioral studies suggest that intrathecally administered NE is selective with regard to its antinociceptive effects; doses of NE required for maximal antinociceptive effects produce no significant signs of motor dysfunction (e.g., Reddy et al., 1980; Howe et al., 1983; Yaksh, 1985). NE also has been demonstrated to modulate sensory transmission in the dorsal horn; however, the effects of NE on evoked dorsal horn neuronal activity, and the selectivity of those effects for spinal nociceptive

The coeruleospinal projection

Transection studies have revealed that spinal cord NE and serotonin content are depleted significantly caudal, but not rostral, to the level of a complete transection of the spinal cord, indicating that the source of spinal cord monoaminergic innervation is organized supraspinally (e.g., Carlsson et al., 1963; Magnusson and Rosengren, 1963). In the rat, pontine NA cell groups have been demonstrated to be the primary source of NA nerve terminals in the spinal cord (Nygren and Olson, 1977; Moore

Termination patterns in the spinal cord

High densities of DβH-labeled fibers have been identified in the superficial laminae of the dorsal horn, in the ventral horn around large motoneurons, around the central gray and in the intermediolateral spinal gray matter in the thoracic and sacral spinal cord (e.g., Westlund et al., 1983). Both α₁- and α₂-adrenoceptors are present in the spinal gray matter of the rat spinal cord (Seybold and Elde, 1984; Unnerstall et al., 1984). Autoradiographic studies have revealed dense distributions of p-[

Modulation of spinal nociceptive transmission by coeruleospinal efferents

As discussed above, NE has been shown to be involved in both antinociception and inhibition of spinal nociceptive transmission. Since the majority of NE-containing fibers and terminations arise from supraspinal sources, the LC/SC, the parabrachial nuclei, the Kölliker-Fuse nucleus and the A5 cell group have all been suggested as possible sources of the spinal NA nerve terminals involved in the centrifugal modulation of spinal nociceptive transmission. Several lines of evidence suggest that the

Physiological conclusions of LC / SC

Clearly, an abundance of evidence indicates that endogenous descending inhibitory systems exist which, when activated by electrical stimulation or drugs, can modulate spinal nociceptive transmission. What peripheral stimuli activate these descending systems “naturally,” and whether they play an important physiological role in the modulation of nociceptive transmission, however, is not known. It is hypothesized that ascending nociceptive projection neurons (i.e., spinothalamic, spinoreticular

Acknowledgements

Special thanks is extended to G.F. Gebhart for his comments regarding the manuscript. The author's data reported here were supported by USPHS awards DA02879 and NS19912.

References (68)

D.G. Amaral et al.
The locus coeruleus: Neurobiology of a central noradrenergic nucleus
Prog. Neurobiol.
(1977)
G. Belcher et al.
The differential effects of 5-hydroxytryptamine, noradrenaline, and raphe stimulation on nociceptive and non-nociceptive dorsal horn interneurons in the cat
Brain Res.
(1978)
F. Cervero et al.
A positive feedback loop between spinal cord nociceptive pathways and antinociceptive areas of the cat's brain stem
Pain
(1984)
J.W. Commissiong et al.
A new projection from the locus coeruleus to the spinal ventral columns: Histochemical and biochemical evidence
Brain Res.
(1978)
J.N. Crawley et al.
Locus coeruleus stimulation increases noradrenergic metabolite levels in rat spinal cord
Brain Res.
(1979)
A.W. Duggan et al.
The effect of naloxone on the excitation of dorsal horn neurones of the cat by noxious and non-noxious cutaneous stimuli
Brain Res.
(1977)
M. Fillenz et al.
Selective uptake and retrograde axonal transport of dopamine-β-hydroxylase antibodies in peripheral adrenergic neurons
Brain Res.
(1976)
S.M. Fleetwood-Walker et al.
An α₂-receptor mediates the selective inhibition by noradrenaline of nociceptive responses of identified dorsal horn neurons
Brain Res.
(1985)
J-M. Fritschy et al.
Distribution of locus coeruleus axons in the rat spinal cord: Combined anterograde transport and immunohistochemical study
Brain Res.
(1987)
G.F. Gebhart
Opiate and opioid peptide effects on brain stem neurons: Relevance to nociception and antinociceptive mechanisms
Pain
(1982)

P.G. Guyenet

The coeruleospinal noradrenergic neurons: An anatomical and electrophysiological study in the rat

Brain Res.

(1980)

H.O. Handwerker et al.

Segmental and supraspinal actions on dorsal horn neurons responding to noxious and non-noxious skin stimuli

Pain

(1975)

P.M. Headley et al.

Selective reduction by noradrenaline and 5-hydroxy-tryptamine of nociceptive responses of cat dorsal horn neurons

Brain Res.

(1978)

C.J. Hodge et al.

Locus coeruleus modulation of dorsal horn unit responses to cutaneous stimulation

Brain Res.

(1981)

A.J. Janss et al.

Effect of spinal norepinephrine depletion on descending inhibition of the tail-flick reflex from the locus coeruleus and lateral reticular nucleus in the rat

Brain Res.

(1987)

S.L. Jones et al.

Characterization of coeruleospinal inhibition of the nociceptive tail-flick reflex in the rat: Mediation by spinal α₂-adrenoceptors

Brain Res.

(1986)

Y. Kuraishi et al.

Noradrenaline regulation of pain-transmission in the spinal cord is mediated by α-adrenoceptors

Brain Res.

(1979)

H.G.J.M. Kuypers et al.

Retrograde axonal transport of horseradish peroxidase from spinal cord to brainstem cell groups in the cat

Neurosci. Lett.

(1975)

Y-Y. Lai et al.

A spinal projection of serotonergic neurons of the locus coeruleus in the cat

Neurosci. Lett.

(1985)

S.E. Loughlin et al.

Efferent projections of nucleus locus coeruleus: Topographic organization of cells of origin demonstrated by three-dimensional reconstruction

Neuroscience

(1986)

S.E. Loughlin et al.

Efferent projections of nucleus locus coeruleus: Morphologic subpopulations have different efferent targets

Neuroscience

(1986)

L.G. Nygren et al.

A new major projection from locus coeruleus: The main source of noradrenergic nerve terminals in the ventral and dorsal columns of the spinal cord

Brain Res.

(1977)

L. Olson et al.

Further mapping out of central noradrenaline neuron systems: Projections of the “subcoeruleus” area

Brain Res.

(1972)

H.K. Proudfit

Pharmacologic evidence for the modulation of nociception by noradrenergic neurons

M. Segal et al.

Analgesia produced by electrical stimulation of catecholamine nuclei in the rat brain

Brain Res.

(1977)

R.T. Stevens et al.

Kölliker-Fuse nucleus: The principal source of pontine catecholaminergic cells projecting to the lumbar spinal cord of the cat

Brain Res.

(1982)

R.T. Stevens et al.

Funicular course of catecholamine fibers innervating the lumbar spinal cord of the cat

Brain Res.

(1985)

A.J. Todd et al.

Receptive fields and responses to iontophoretically applied noradrenaline and 5-hydroxytryptamine of units recorded in laminae I–III of cat dorsal horn

Brain Res.

(1983)

J.R. Unnerstall et al.

Distribution of α₂ agonist binding sites in the rat and human central nervous system: Analysis of some functional anatomic correlates of the pharmacologic effects of clonidine and related adrenergic agonists

Brain Res. Rev.

(1984)

K.N. Westlund et al.

Descending projections of the locus coeruleus and subcoeruleus/medial parabrachial nuclei in monkey: Axonal transport studies and dopamine-β-hydroxylase immunocytochemistry

Brain Res. Rev.

(1980)

K.N. Westlund et al.

Noradrenergic projections to the spinal cord of the rat

Brain Res.

(1983)

T.L. Yaksh

Pharmacology of spinal adrenergic systems which modulate spinal nociceptive processing

Pharmacol. Biochem. Behav.

(1985)

T.L. Yaksh et al.

Narcotic analgetics: CNS sites and mechanisms of action as revealed by intracerebral injection techniques

Pain

(1978)

M.G. Ziegler et al.

Retrograde axonal transport of antibody to dopamine-β-hydroxylase

Brain Res.

(1976)

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Chapter 29 - Descending noradrenergic influences on pain

Introduction

Section snippets

Adrenoceptor agonists and antinociception

Modulation of spinal nociceptive transmission by α-adrenoceptor agonists

The coeruleospinal projection

Termination patterns in the spinal cord

Modulation of spinal nociceptive transmission by coeruleospinal efferents

Physiological conclusions of LC / SC

Acknowledgements

Prog. Neurobiol.

Brain Res.

Pain

Brain Res.

Brain Res.

Brain Res.

Brain Res.

Brain Res.

Brain Res.

Pain

Brain Res.

Pain

Brain Res.

Brain Res.

Brain Res.

Brain Res.

Brain Res.

Neurosci. Lett.

Neurosci. Lett.

Neuroscience

Neuroscience

Brain Res.

Brain Res.

Brain Res.

Brain Res.

Brain Res.

Brain Res.

Brain Res. Rev.

Brain Res. Rev.

Brain Res.

Pharmacol. Biochem. Behav.

Pain

Brain Res.