Descending Monoaminergic Pain Modulation

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CLINICAL IMPLICATIONS OF NEUROSCIENCE Descending monoaminergic pain RESEARCH modulation Section Editor Eduardo E. Benarroch, MD Bidirectional control and clinical relevance

Eduardo E. Benarroch, Pain is a complex sensation that has sensory- rons; and a distributed supraspinal network that MD discriminative, cognitive-evaluative, and affective- modulates relay and processing of nociceptive inputs emotional dimensions.1 Several areas distributed in the dorsal horn. Primary nociceptive afferents pro-

Address correspondence and throughout the neuraxis exert a top-down modula- vide excitatory glutamatergic inputs to several lami- reprint requests to Dr. Eduardo tion of pain sensation according to the nature of the nae of the spinal dorsal horn, including lamina I E. Benarroch, Mayo Clinic, painful stimulus and the behavioral state of the indi- (superficial dorsal horn), lamina II (substantia gelati- Department of Neurology, 200 First Street SW, West 8A Mayo vidual, both in normal and pathologic conditions. nosa), and lamina V (deep dorsal horn). Some noci- Bldg, Rochester, MN 55905 This modulation is largely mediated by descending ceptive afferents also release neuropeptides, such as [email protected] monoaminergic pathways that either inhibit or facil- substance P, which has an important role in mecha- itate transmission of nociceptive information at the nisms of sensitization of dorsal horn neurons in con- level of the dorsal horn.2-7 Monoamines, including ditions such as neuropathic pain.2-5 Lamina I and serotonin, norepinephrine, and dopamine, act via lamina V project via the spinothalamic tract to the different receptor subtypes to exert a complex modu- thalamus and via spinobulbar pathways to subcorti- lation of neurotransmitter release from nociceptive cal structures, including the parabrachial nucleus afferents and excitability of dorsal horn neurons. (which conveys these inputs to the hypothalamus and These monoaminergic systems have an important amygdala), periaqueductal gray (PAG), and rostral ven- role in mechanisms of inflammatory and neuropathic tromedial medulla (RVMM). Lamina II contains in- pain4 and are a target for pharmacologic manage- hibitory interneurons that utilize ␥-aminobutyric ment of these conditions. A large number of experi- acid (GABA), glycine, or opioids such as enkepha- mental studies and the recent development of lins, and provide both feedforward and feedback in- knockout mice models8 provide insights into the hibition to the spinothalamic and spinobulbar complex role of monoamines in the normal and ab- projection neurons.2,5 normal pain processing in the spinal cord. This infor- There are several areas of the CNS that, directly or mation helps to elucidate the pathophysiology of indirectly, are activated by nociceptive inputs, are tar- different pain disorders and the mechanism of action gets of opioids, and participate in the central modula- of drugs used for their treatment. Although hista- tion of pain1-3 (figure 1). They include the prefrontal, minergic pathways may also contribute to descend- anterior cingulate, and insular cortices; amygdala; ing modulation of pain transmission in the dorsal periventricular and posterolateral hypothalamus; PAG; horn,5 this brief review focus on the serotonergic, dorsolateral pons; and RVMM. These brain areas exert noradrenergic, and dopaminergic systems, given bidirectional influences on pain sensation as they may their potential clinical implications. either inhibit or facilitate transmission of nociceptive inputs at the level of the dorsal horn.1-4 These modula- PAIN MODULATION NETWORK The pain system tory effects are largely mediated by descending encompasses the small diameter nociceptive afferents monoaminergic pathways that utilize serotonin, norepi- from dorsal root ganglion neurons; relay neurons of nephrine, or dopamine.5-7 the dorsal horn projecting via the spinothalamic and The effects of descending monoaminergic systems spinobulbar pathways; local circuit dorsal horn neu- on nociceptive processing in the dorsal horn are com-

GLOSSARY CGRP ϭ calcitonin gene-related peptide; DAT ϭ dopamine transporter; GABA ϭ ␥-aminobutyric acid; NET ϭ norepinephrine transporter; NRM ϭ nucleus raphe magnus; PAG ϭ periaqueductal gray; RLS ϭ restless legs syndrome; RVMM ϭ rostral ventromedial medulla; SERT ϭ serotonin transporter; SNRI ϭ serotonin and norepinephrine reuptake inhibitor; SSRI ϭ selective serotonin reuptake inhibitor; STT ϭ spinothalamic tract.

From the Mayo Clinic, Department of Neurology, Rochester, MN. Disclosure: The author reports nodisclosures.

Target Neurotransmitter

Primary nociceptive Glutamate, substance P, afferents CGRP

Spinothalamic neurons Glutamate, CGRP

Excitatory interneurons Glutamate

Inhibitory interneurons GABA, enkephalin

CGRP ϭ calcitonin gene-related peptide; GABA ϭ ␥-aminobutyric acid.

presynaptic inhibitory autoreceptors regulate the local concentration of monoamines and thus their effects on the targets in the dorsal horn.5

MONOAMINERGIC MODULATION OF PAIN TRANSMISSION IN THE DORSAL HORN Seroto- nin. Serotonergic inputs to the dorsal horn originate in neurons of the RVMM, including the nucleus raphe magnus and the nucleus reticularis magnocellu- laris.5 These neurons project to the superficial, and to a lesser extent deep dorsal horn. The RVMM receives a strong projection from the PAG; this PAG-RVMM serotonergic pathway has been classically considered the primary endogenous pain modulatory system and target of supraspinal opioid analgesia.7 However, the RVMM contains functionally heterogeneous groups of serotonergic and nonserotonergic neurons that are not only involved in pain modulation but also in control of autonomic and other homeostatic functions.11 The RVMM contains two types of cells: OFF cells that are inhibited by noxious stimulation and excited by opioids, and ON cells that have an opposite pattern of response. The OFF cells have a net inhibitory effect on ascending nociceptive transmission, whereas ON cells facilitate nociception through activation of a descending pathway to the The central pain modulatory network includes the cingulate gyrus, periaqueductal gray, spinal cord.2,11 dorsolateral pontine tegmentum, and ventromedial medulla. These areas exert either an- Serotonin, acting via different receptor subtypes, ex- tinociceptive or pronociceptive effects via descending pathways that utilize serotonin, norepinephrine, or dopamine as their primary neurotransmitters. (Copyright held by Mayo erts complex modulatory effects on nociceptive trans- 5 Foundation for Medical Education and Research. All rights reserved. Reproduced with per- mission in the dorsal horn. Activation of 5-HT1 mission.) receptors exerts an antinociceptive effect; postsynaptic

5-HT1A receptors inhibit excitability of spinothalamic plex (figure 2). Monoamines may act via different neurons and excitatory interneurons, whereas presynap-

subtypes of receptors located at the primary nocicep- tic 5-HT1B/D receptors inhibit neurotransmitter release tive afferents, dorsal horn projection neurons, local from primary afferents. The descending serotonergic excitatory or inhibitory interneurons, and glial pathways also have pronociceptive effects that appear to 5,6,9 cells (table 1). Serotonin, norepinephrine, and be mediated by 5-HT2 and particularly 5-HT3 recep- 3,12 dopamine may exert either antinociceptive or prono- tors. The 5-HT3 receptors are cation channels that

ciceptive effects according to the type of receptor in- elicit depolarization; presynaptic 5-HT3 receptors involved, site of action in the dorsal horn, and crosstalk crease neurotransmitter release from primary nocicep-

between descending and local neurochemical signals, tive afferents, whereas postsynaptic 5-HT3 receptors including adenosine, endogenous opioids, and nitric increase excitability of STT neurons. oxide5,6 (table 2). In addition, presynaptic reuptake Studies on Lmx gene knockout mice, which lack via selective transporters and control of release via brainstem serotonergic neurons, provide insights

218 Neurology 71 July 15, 2008 Table 2 Source and effects of monoaminergic inputs to the dorsal horn

Neurotransmitter Source Antinociceptive receptors (target) Pronociceptive receptors (target)

␣ Norepinephrine Locus ceruleus-subceruleus 2 (presynaptic) ? ␣ A5 region 1 (inhibitory interneurons)

Serotonin RVMM (NRM) 5-HT1B (presynaptic and STT neuron) 5-HT3 (presynaptic and STT neuron)

5-HT2 (STT neuron)

Dopamine A11 D2,D3 (presynaptic, possible STT neuron) D1 (STT neuron)

RVMM ϭ rostral ventromedial medulla; NRM ϭ nucleus raphe magnus; STT ϭ spinothalamic tract. into the involvement of central serotonergic system the behavioral responses to noxious stimulation, and 8 in pain and analgesia. These mutant mice are less this effect is mediated by D2-type receptors. These re- sensitive to noxious mechanical stimuli but exhibit ceptors elicit presynaptic inhibition of neurotransmitter more inflammatory pain compared to control mice. release from primary nociceptive afferents. D2 agonists This indicates that central serotonergic neurons have a may also elicit antinociception by potentiating the ef- dual role in pain processing; they facilitate nociceptive fects of endogenous opioids.5 In contrast, D1 receptor transmission in response to mechanical stimuli but sup- stimulation elicits pronociceptive effects both directly press the initial response to chemical activation of pri- and by antagonizing the actions of D2 agonists or opi- mary afferents and neurogenic inflammation. oids. The effects of dopamine on spinal nociception Norepinephrine. The noradrenergic innervation of may depend on its local concentration, as low levels the dorsal horn originates from several cell groups in may activate the antinociceptive D2 type receptors, the pontine tegmentum, including the A5, A6 (locus whereas high levels activate the pro-nociceptive D1 10 ceruleus), and A7 groups.5,6 Whereas noradrenergic receptors. axon terminals innervate the cell bodies of both pro- Spinal monoamines and descending pain modulation. jection neurons and interneurons, volume transmis- Many brain areas involved in control of motivation, sion appears to be an important mechanism for anxiety, fear, and mood strongly influence pain sen- noradrenergic modulation of neurotransmitter re- sation.1 The prefrontal, anterior cingulate, and insu- lease from primary afferents. Norepinephrine pri- lar cortices, amygdala, and hypothalamus, project to marily inhibits nociceptive transmission in the dorsal the brainstem pain modulatory network, including ␣ ␣ horn via presynaptic 2 (particularly 2A) receptors the PAG, RVMM, and pontine noradrenergic cell in primary nociceptive terminals. These receptors groups. In addition, inputs from nociceptive dorsal may also mediate postsynaptic inhibition of spino- horn neurons to the PAG, RVMM, and cat- ␣ thalamic neurons. The analgesic effects of 2 recep- echolaminergic cell groups provide for excitatory or tor agonists, such as clonidine, also involve complex inhibitory spino-bulbo-spinal feedback loops that are interactions with other antinociceptive neurotrans- affected by these forebrain influences and may am- mitter systems, including opioids and adenosine in plify the pain state.12 The overall balance between the dorsal horn.5,6 Activation of postsynaptic ␣ re- 1 inhibitory and excitatory supraspinal signals medi- ceptors may contribute to antinociception that in- ated by monoamines provides the basis for top-down creases release of GABA or glycine by local inhibitory modulation of pain sensation according to motiva- neurons.5,6 tion, emotion, and other behavioral variables13 and Dopamine. The main source of descending dopaminer- has an important role in mechanisms of inflamma- gic innervation of the dorsal horn is the A11 neurons of tory and neuropathic pain.4 the periventricular posterior hypothalamus.10,13 Primary afferents and dorsal horn neurons in lamina I express CLINICAL CORRELATIONS Neuropathic pain. There is experimental evidence that there is upregu- both D1 (D1 and D5)- and D2 (D2 and D3)-type recep- 14 lation of central pain inhibitory control in cases of tors. Although D1 receptors are expressed at much higher concentration than D2 or D3 receptors, the inflammatory pain, as a possible compensatory

D2/D3 receptors have higher affinities and are activated mechanism for central sensitization that occurs in by lower concentrations of dopamine than D1 recep- this setting. In contrast, descending pain facilitation tors.10 Both acute and sustained noxious stimuli in- may promote a chronic pain state following nerve or crease dopamine turnover in the dorsal horn, suggesting spinal cord injury.4,15 This pronociceptive modula- an enhancement of the activity of the descending dopa- tion may involve an excitatory spino-bulbo-spinal minergic pathway.5 Activation of A11 neurons reduces loop initiated from projections from the superficial

Neurology 71 July 15, 2008 219 Figure 2 Potential targets and receptor mechanism mediating the pain modulatory effects of monoamines in the dorsal horn

In the dorsal horn, serotonin, norepinephrine, and dopamine exert an antinociceptive action primarily by reducing neuro- ␣ transmitter release from primary afferents; these affects are mediated by presynaptic 5-HT1B, 2, and D2/D3 receptors, respectively. These receptors also contribute to postsynaptic inhibition of spinothalamic tract neurons. In contrast, seroto-

nin acting via postsynaptic 5-HT2 and both pre-and postsynaptic 5-HT3 receptors, and dopamine, acting via D1 receptors, may have a pronociceptive effect. Interneurons may also mediate the modulatory effects of monoamines. For example, ␣ ␥ norepinephrine may elicit antinociception via excitatory 1 receptors in local -aminobutyric acid (GABA)ergic neurons. Presynaptic reuptake and control of release by presynaptic inhibitory autoreceptors determine the local levels of monoamines and thus their effects on their different targets in the dorsal horn. DAT ϭ dopamine transporter; NET ϭ norepinephrine transporter; SERT ϭ serotonin transporter.

dorsal horn to the RVMM and mediated by descend- knockout mice indicate that the involvement of sero-

ing serotonergic pain facilitation via 5-HT3 receptors tonin in the mechanism of action of antidepressant 12,16 8 in the deep dorsal horn. Ondansetron, a 5-HT3 an- drugs varies with the type of pain. The analgesic tagonist, inhibits pain in response to mechanical punc- effect of both SSRI and SNRI during an acute ther- tate stimuli in rats with peripheral nerve injury.16 A mal pain test was greatly reduced or absent in these randomized double-blind study has recently shown that animals lacking brainstem serotonergic neurons, sug- a single IV bolus of ondansetron alleviates mechanical gesting that blockade of serotonin reuptake is the pri- allodynia in patients with neuropathic pain.17 mary mechanism of the acute analgesic effects of Mechanism of action of analgesic drugs. Antidepres- antidepressants. In contrast, the analgesic effect of sant drugs that block reuptake of monoamines, li- duloxetine in models of persistent pain was not af- gands of the ␣2/␦ subunit of presynaptic voltage- fected by the loss of serotonergic neurons, indicating gated calcium channels, and opioids constitute the a critical role of norepinephrine for antidepressant- mainstay of treatment of neuropathic pain. The anal- induced analgesia in chronic pain states.8 gesic effect of antidepressant has been classically at- Gabapentin and pregabalin are ligands of the tributed primarily to inhibition of reuptake of ␣2/␦ subunit of presynaptic voltage-gated calcium norepinephrine rather than serotonin, since the channels that inhibit neurotransmitter release from efficacy of selective serotonin reuptake inhibitors primary afferents. These drugs may also interact with (SSRIs) is lower than that of serotonin and norepi- the monoaminergic systems at both spinal and su- nephrine reuptake inhibitors (SNRIs) such as dulox- praspinal levels. In rats with experimentally induced etine and venlafaxine. However, studies in Lmx neuropathic pain, the inhibitory effect of gabapentin

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