Serotonin in Pain and Pain Control

CHAPTER 3.11

Serotonin in Pain and Pain Control Claudia Sommer* Department of Neurology, University of Würzburg, Germany

Abstract: In pain processing and modulation, serotonin (5-hydroxtryptamine, 5-HT) has excitatory (hyperalgesic) and inhibitory (analgesic) actions, depending on the site of action, the cell type and the type of receptor. In the periphery, 5-HT sensitizes afferent nerve fibers, thus contributing to inflammatory and neuropathic hyperalgesia. In the trigeminal system, agonism at 5-HT1B/D receptors reduces neurotransmitter release, whereas actions through the 5-HT2A receptor may underlie chronic headache. Genetic alterations in the 5-HT system may influence the susceptibility to migraine and to other pain disorders. 5-HT is involved in descending inhibitory pathways in the CNS, and modulation of this system is the most likely mechanism of action of antidepressant drugs in analgesia. Recently, facilitatory serotonergic pathways have been discovered, which may be functionally important. Keywords: serotonin (5-HT), pain, hyperalgesia, neurotransmitters, pain pathways, inflammation.

Introduction

Basic physiology of serotonin in pain and pain control

The effect mediated by 5-HT release is dependent on the cell and receptor type the neurotransmitter acts upon, and on the integration of the signal into the respective neuronal network. The classical understanding of serotonin is that of an analgesic action at spinal sites, which is considered part of the system of descending inhibition (Yaksh and Wilson, 1979). Strengthening this system, together with noradrenergic descending pathways, is the most likely mechanism of action of antidepressant drugs in pain control. Many experimental studies have further shown an interaction of the serotonergic system and morphine analgesia. Recently, facilitatory spinal serotonergic pathways have also been described (Suzuki et al., 2004a). In peripheral tissues, 5-HT acts as a proalgesic inflammatory mediator (Moalem et al., 2005). A specific role for 5-HT has been discussed in the pathophysiology of several types of headache (in particular migraine) and facial pain, of the fibromyalgia syndrome, and in neurogenic inflammation. For instance, 5-HT acting on 5-HT1B/D receptors in the trigeminal system blocks the release of excitatory neurotransmitters and is analgesic. Down-regulation of 5HT receptors is considered one of the pathomechanisms of medication-induced headache. This chapter will review the physiology of 5-HT in pain and analgesia, and summarize the evidence for a role of 5-HT in specific painful disorders.

5-HT in the periphery Findings in animal models The 5-HT tissue content increases rapidly in inflammation or injury. The main cellular sources of 5-HT in peripheral tissues are platelets and mast cells. After release of 5HT, its action depends on the receptors present on afferent nerves in the vicinity (Figure 1). The mRNA for the 5-HT1B, 5-HT1D, 5-HT2A-C, 5-HT3, 5-HT4 and 5-HT7 receptor subtypes has been detected in dorsal root ganglia (DRG) (Pierce et al., 1996; Nicholson et al., 2003), suggesting the presence of all these receptors on peripheral sensory nerves. However, which receptors are preferentially expressed may depend on various factors. For example, in isolated DRG neurons, stimulation of 5-HT1 receptors had a hyperpolarizing effect, whereas stimulation 5-HT2 receptors had a depolarizing effect on nociceptors (Todorovic and Anderson, 1992). In most preparations, 5-HT was more potent in enhancing algesic effects of other mediators than in inducing pain by itself (Lang et al., 1990; Abbott et al., 1996). In rats, intradermally injected serotonin produces a dosedependent hyperalgesia with a very short latency, indicating a direct excitatory effect on primary afferent neurons. This hyperalgesia can be mimicked by agonists for the 5-HT1A receptor (Taiwo and Levine, 1992). Application

*

Corresponding author E-mail: [email protected] Christian Müller & Barry Jacobs (Eds.) Handbook of Behavioral Neurobiology of Serotonin ISBN 978-0-12-374634-4

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DOI: 10.1016/B978-0-12-374634-4.00028-9 Copyright 2010 Elsevier B.V. All rights reserved

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Receptor / Channel

5HT7

5HT4 + 5HT3 Mast Cell

+ +

5HT2A

Epidermis

+ 5HT Platelets

5HT1B/D

− +

5HT1A

Figure 1 Simplified schematic drawing of 5-HT action in the periphery. To see the full color version of this figure please refer to the color plate in the back of the book. Copies produced via our print on demand service do not contein color plates. If your copy does not have the color plate, Please go to this website to view the figure in color www. elsevierdirect.com/companions/9780123746344

of 5-HT to nerve roots in rats induced short-term pain behavior similar to that with nucleus pulposus application, suggesting that 5-HT plays a role in the early phase of the pathogenesis of sciatica (Kato et al., 2008). Thus, direct hyperalgesic effects as well as facilitatory effects of 5-HT for other peripheral mediators are possible. In mice lacking the serotonin transporter 5-HTT, which is necessary for 5-HT reuptake into cells from the extracellular space (Bengel et al., 1998), thermal hyperalgesia after nerve injury does not develop, most likely because of the reduced 5-HT levels in peripheral tissues of these mice (Vogel et al., 2003). A similar reduction of thermal hyperalgesia was found in a model of inflammatory pain using complete Freund’s adjuvant (CFA) injection into the mouse hindpaw (Palm et al., 2008). 5-HT levels were increased after inflammation in the sciatic nerves of wild-type mice but not of 5-HTT knockout mice. The phenotype could be rescued by intraplantar injection of 5-HT, giving proof of the role of peripheral 5-HT in this model. In both models, chronic constriction injury (CCI) of the sciatic nerve and CFA-induced inflammation, the development of thermal hyperalgesia was dependent on an increase of 5-HT in the sciatic nerve. This finding may be of clinical relevance, since gene variants in humans modifying 5-HTT function might be one of the factors determining the extent of hyperalgesia in inflammation. Genetic variants are also known for guanosine triphosphate (GTP) cyclohydrolase, the rate-limiting enzyme for tetrahydrobiopterin synthesis, which is a cofactor for serotonin production, among others (Tegeder et al., 2006).

A haplotype leading to low tetrahydrobiopterin synthesis is associated with reduced postoperative and experimental pain. The 5-HT3 receptor, a ligand-gated cation channel, is the most widely studied 5-HT receptor in the concept of peripheral pain and analgesia (for review, see Sommer, 2004). Other investigators have identified 5-HT1 and 5HT4 as the receptors involved in nociceptive behavior in formalin-induced paw inflammation in the rat (Eschalier et al., 1989; Doak and Sawynok, 1997). 5-HT3 receptor antagonists applied subcutaneously reduced formalin and complete Freund’s adjuvant (CFA) induced pain (Giordano and Dyche, 1989; Giordano and Rogers, 1989). Pain but not edema in carrageenin-induced inflammation was blocked by preventive treatment with a 5-HT3 antagonist (Eschalier et al., 1989). Repeated injection of 5-HT into rat masticatory muscle evoked brief afferent fiber discharges, which could be significantly attenuated by the selective 5-HT3 receptor antagonist tropisetron (Sung et al., 2008). 5-HT, through activation of peripheral 5-HT3 receptors, thus excites slowly conducting masticatory muscle afferent fibers. Similar mechanisms might contribute to 5-HT-evoked muscle pain in humans. In mice deficient in 5-HT3 receptors, assays for acute pain, phase 1 of the formalin test, and tests for hyperalgesia and allodynia after partial nerve lesion gave normal results, but pain behavior in phase 2 of the formalin test was reduced, indicating a role of the 5-HT3 receptor in tissueinjury-induced persistent nociception (Zeitz et al., 2002). Furthermore, the visceral response to intraperitoneal

Serotonin in Pain and Pain Control 5-HT was reduced in the mutant mice. In the setting of CFA-induced hindpaw inflammation, the 5-HT3 receptor was found to mediate activation of nociceptors but did not contribute to injury-associated edema. This result was explained by the distribution of 5-HT3 receptor in DRG neurons in a minority of neurons of all sizes, the majority of which do not coexpress substance P or the vanilloid receptor TRPV1, thus defining a new subclass of DRG neurons (Zeitz et al., 2002). Thus, the 5-HT3 receptor is an important, but not the only, receptor mediating the peripheral algesic action of 5-HT. A number of experimental studies point to an important role of the G-protein-coupled 5-HT2 receptor in peripheral 5-HT-mediated pain. 5-HT2 receptors are expressed in CGRP-containing small-diameter DRG neurons. They are upregulated in inflammatory pain, and a 5-HT2A receptor antagonist reduces inflammatory hyperalgesia (Okamoto et al., 2002). 5-HT2 agonists injected into the plantar surface of the paw in rats induced lifting and licking, which was greatly enhanced in combination with prostaglandin E2 and noradrenalin, and could be inhibited by the 5-HT2A/2C antagonist ketanserin (Abbott et al., 1996). The density of 5-HT2A receptor immunoreactive axon terminals in the superficial layers of the dorsal horn was increased in vincristine neuropathy. Furthermore, 5-HT2A knockout mice did not develop neuropathic pain after vincristine administration, indicating that 5-HT2A receptors are involved in peripheral sensitization and spinal nociceptive processing (Thibault et al., 2008). Injection of 5-HT and of the 5-HT2A receptor agonist alpha-methyl 5-HT reduced the paw-withdrawal latency to noxious heat in rats, indicating a role of the 5-HT2A receptor in thermal hyperalgesia (Tokunaga et al., 1998). Treatment with 5-HT2A antagonists reduced the pain response in rats injected with formalin and carrageenan (Abbott et al., 1997; Obata et al., 2000; Wei et al., 2005). Mechanistically, it has been suggested that activation of 5-HT2 receptors depolarizes capsaicin-sensitive DRG neurons by reducing a resting potassium conductance, which might contribute to excitation and sensitization (McMahon et al., 2006). 5-HT4 receptors have been shown to increase tetrodotoxin-resistant sodium currents via stimulation of cyclic AMP production (Cardenas et al., 1997, 2001). This would increase the probability of action potential firing, and thus be proalgesic. 5-HT4 receptor agonists have been mostly discussed in the context of treating irritable bowel syndrome (Tonini and Pace, 2006) and in the prevention of opioid-induced respiratory depression (Manzke et al., 2003; Lötsch et al., 2005). The 5-HT7 receptor has also been implied in peripheral hyperalgesia. Local administration of 5-HT7 antagonist reduced formalin induced flinching in phase 1 and phase 2 (Rocha-Gonzalez et al., 2005).

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The activation of 5-HT1B/D receptors on trigeminal afferents inhibits adenylate cyclase via activation of Gi/o proteins. 5-HT1B/D agonists (called triptans), such as sumatriptan and others, act on 5-HT1B/D receptors and inhibit neuropeptide release from the terminals of these afferents (Arvieu et al., 1996). Sumatriptan also prevented capsaicin-induced hyperemia, a sign of neurogenic inflammation (Zochodne and Ho, 1994). Furthermore, sumatriptan reduced thermal hyperalgesia in mice with peripheral inflammation, but had no effect on nerveinjury-induced hyperalgesia (Bingham et al., 2001). In summary, the majority of data point to a proalgesic action of 5-HT in the periphery at most receptors, with the exception of agonists at the 5-HT1B/D receptor, which may reduce neurogenic inflammation. 5-HT agonists and antagonists in human studies In healthy volunteers, 5-HT infused into muscle did not induce pain or hyperalgesia by itself, but sensitized the tissue to bradykinin (Babenko et al., 2000). 5-HT administered through intradermal microdialysis membranes produced pain and sometimes itching (Lischetzki et al., 2001; Schmelz et al., 2003). Injections of 5-HT into the masseter muscle in healthy human females induced pain and hyperalgesia which could be antagonized by a 5-HT3antagonist (Ernberg et al., 2000, 2006). Topical application of the 5-HT3 receptor antagonist ondansetron reduced capsaicin-induced pain and hyperalgesia in human volunteers (Giordano et al., 1998). In contrast, the application of 5-HT3 receptor antagonists locally in humans with fibromyalgia or similar pain states gave equivocal results (Ernberg et al., 2003; Stratz and Müller, 2003). Mechanisms of 5-HT actions on nociception in the periphery The neuronal mechanism of this pain and hyperalgesia were investigated in in vitro preparations of peripheral nerves. In these preparations, 5-HT has an excitatory effect on peripheral nerve fibers. Some investigators used a mixture of inflammatory mediators (‘inflammatory soup’) (Kessler et al., 1992), and found ectopic excitation and sensitization of acutely axotomized afferent nerve fibers in the rat (Michaelis et al., 1997). In DRG neurons in culture, 5-HT alone had no major effect, but a proton-induced current was increased by the combination of 5-HT with other inflammatory mediators (Kress et al., 1997). Recently, the selective administration of 5-HT and a 5-HT3 receptor agonist has also been shown to sensitize C fibers in isolated segments of rat sural nerve (Moalem et al., 2005). The characteristics of this sensitization were not altered after previous nerve injury, which led the

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authors to conclude that constitutive rather than inducible expression of axonal 5-HT receptors is responsible for this effect. Others provided indirect evidence that 5-HT may have a stronger effect on lesioned or inflamed tissues and peripheral nerve fibers than on intact ones (Aley et al., 2000; Song et al., 2003). Direct and indirect mechanisms of action have been postulated for the peripheral hyperalgesic action of 5-HT. 5-HT modulates tetrodotoxin-resistant (TTX-R) sodium currents, where it increases the magnitude of the current, shifts its conductance–voltage relationship to a hyperpolarized direction, and increases its rate of activation and inactivation (Gold et al., 1996). The 5-HT3 receptor, itself a ligand-gated ion channel, might directly enhance neuronal activity. Since 5-HT can sensitize nerve fibers to the actions of bradykinin, an effect on bradykinin receptors might be expected. Alternatively, downstream signaling of the mediators might converge and mutually enhance the effects. Protein kinase A (PKA) was identified as a factor in the signaling cascade of 5-HT after its intraplantar injection (Aley and Levine, 1999), and NO was suggested to facilitate this process, in analogy to findings with PGE2 (Aley et al., 1998). In an extensive pharmacological study, 5-HT-induced hyperalgesia was significantly reduced by local blockade of the 5-HT3 receptor by tropisetron, by the non-specific selectin inhibitor fucoidan, by the cyclooxygenase inhibitor indomethacin, by guanethidine depletion of norepinephrine in the sympathetic terminals, and by local blockade of the beta1- or beta2-adrenergic receptors. The authors concluded that there is an indirect hyperalgesic action of 5-HT, mediated by a combination of mechanisms involved in inflammation such as neurophil migration and the local release of prostaglandin and norepinephrine (Oliveira et al., 2007).

5-HT in the central nervous system Data from animal experiments Numerous studies have been performed to delineate the role of 5-HT in central pain processing. A variety of approaches were used, including methods to reduce 5-HT levels in the CNS (like dietary tryptophan depletion or inhibition of serotonin biosynthesis, to block or activate 5-HT receptors) and selective lesions of serotonergic projections. Through many experimental studies, 5-HT has been recognized, together with norepinephrine, as one of the main neurotransmitters involved in endogenous supraspinal pain-modulating systems (Basbaum and Fields, 1978). This is in accordance with the clinical use of drugs increasing the availability of 5-HT and norepinephrine, like antidepressants, in the treatment of chronic

pain. However, excitatory effects of spinal 5-HT have repeatedly been described, and have to be integrated into our understanding of the serotonergic system (Figure 2). Spinal 5-HT is largely derived from serotonergic neurons in the rostroventral medulla (RVM), in particular in the nucleus raphe magnus (NRM). Serotonergic tracts descend to the spinal cord through the dorsolateral funiculus and form synapses in laminae I, II, IV and V (Millan, 2002). The serotonergic RVM neurons are activated by noxious stimuli through opioid mechanisms (Zhang et al., 2000). Their electrical stimulation evokes the release of 5-HT in the spinal cord cerebrospinal fluid, and 5-HT antagonists reduce the analgesia produced by this stimulation (Le Bars and Villanueva, 1988). In slice experiments containing RVM, some raphe neurons exhibit spontaneous firing, suggesting that 5-HT is released tonically onto the dorsal horn neurons (Yoshimura and Furue, 2006). Chronic pain states may reduce 5-HT in RVM neurons, thus reducing endogenous pain control and the effect of morphine (Sounvoravong et al., 2004). Stimulation of RVM or injections of 5-HT-receptor agonists into the spinal cord have shown both inhibitory and facilitatory effects on the pain behavior in animals. Electrophysiological studies showed an inhibition of the response of dorsal horn neurons to noxious stimulation when 5-HT was applied by iontophoreses (Duggan and Headley, 1977; Jordan et al., 1978). Spinal administration of 5-HT mostly reduces pain behavior in animals, but results depend on the stimulus quality and the test used (Bardin et al., 1997; Hains et al., 2003). The antinociceptive activity of 5-HT is generally weak in models of neuropathic and inflammatory pain (Bardin et al., 1997; Obata et al., 2001). Excitatory effects have also been reported, mediated via 5-HT7 receptors (Rocha-Gonzalez et al., 2005), and possibly caused by increases in cyclic AMP levels, which shifts the voltage dependence of the cation current to more depolarized potentials and thus increases neuronal excitability (Cardenas et al., 1999). In the spinal cord, 5-HT receptors are present on terminals of primary afferent neurons, on projection neurons, and on excitatory and inhibitory interneurons, which makes the action of 5-HT very complex. Accordingly, blockade or depletion of spinal 5-HT can enhance nociception (Millan et al., 1997; Pertovaara et al., 2001). Excellent reviews on this subject have been published recently (Millan, 2002; Suzuki et al., 2004b; LopezGarcia, 2006; Yoshimura and Furue, 2006). In particular, 5-HT2A and 5-HT3 receptors, among others (Hamon and Bourgoin, 1999; Nicholson et al., 2003), are expressed by primary afferent fibers that convey nociceptive messages from the periphery to the CNS (Hamon et al., 1989; Carlton and Coggeshall, 1997). 5-HT presynaptically

Serotonin in Pain and Pain Control

461

Afferent fibers

Descending tracts To brain

− 5HT? 5HT3 +

WD

R

Glutamate

(A)

Spinal dorsal horn

Descending tracts

To brain

5HT3 − 5HT1A − WDR + 5HT7

Spinal dorsal horn

(B)

Descending tracts To brain

WDR

(C)

+ 5HT2 − GABA + 5HT3

Spinal dorsal horn

Figure 2 Simplified schematic drawing of the 5-HT descending system in the spinal cord. To see the full color version of this figure please refer to the color plate in the back of the book. Copies produced via our print on demand service do not contein color plates. If your copy does not have the color plate, Please go to this website to view the figure in color www. elsevierdirect.com/companions/9780123746344

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inhibits the glutamate release from nociceptors, but the receptor responsible for this effect has not yet been identified (Ito et al., 2000). 5-HT1A and 5-HT1B receptors are present at high densities in superficial dorsal horn neurons, for example on nociceptive-specific or on wide dynamic range (WDR) neurons. 5-HT1A receptors, when activated, cause opening of K⫹ and a closing of Ca2⫹ channels through coupling negatively to adenylate cyclase. Their activation should thus directly hyperpolarize substantia gelatinosa neurons and produce an inhibitory effect on the sensory transmission. However, application of 5-HT1A and 5-HT1B receptor agonist was also shown to increase responses of WDR neurons to peripheral stimulation (Zhang et al., 2001a). This may be mediated by the presence of 5-HT1 receptors on GABAergic interneurons, which would consequently be inhibited upon stimulation of the 5-HT1 receptors (Millan et al., 1996). 5-HT2 receptors are positively coupled to phospholipase C, and thus exert excitatory influcences on neuronal activity. The antinociceptive effects attributed to the 5-HT2A subtype (Courade et al., 2001; Kjorsvik et al., 2001; Radhakrishnan et al., 2003; Sasaki et al., 2003) would thus also have to be caused by the activation of inhibitory interneurons. Interestingly, 5-HT2A receptors are scarce in normal spinal cord but are up-regulated after inflammation, indicating a state-specific action of 5-HT on these receptors (Zhang et al., 2001b). The ionotropic 5-HT3 receptor increases neuronal excitability, and has been found to mediate descending facilitation through serotonergic pathways (Rahman et al., 2004; Suzuki et al., 2004a). A study with mice deficient of the 5-HT3 receptor came to the conclusion that this receptor was proalgesic at peripheral and spinal sites (Zeitz et al., 2002). If 5-HT acts on a presynaptic spinal 5-HT3 receptor, excitatory neurotransmitter release is increased. Concordantly, ondansetron, a 5-HT3 antagonist, reduces pain behavior upon mechanical stimuli after nerve injury (Suzuki et al., 2004a) and mechanical allodynia after spinal cord injury in rats (Oatway et al., 2004). Furthermore, from experiments ablating NK1positive neurons in the spinal cord it was postulated that NK1 positive lamina I projection neurons form the origin of a spino-bulbo–spinal loop, which controls spinal excitability through the activation of a descending serotonergic pathway (Suzuki and Dickenson, 2005; Suzuki et al., 2005). On the other hand, there is an inhibitory action of spinal 5-HT through the release of GABA from inhibitory interneurons via 5-HT3 receptors (Alhaider et al., 1991). This is in accordance with the recent finding of a colocalization of 5-HT3 receptors and GABA in the spinal cord dorsal horn (Huang et al., 2008). In the formalin model, 5-HT1B, 5-HT2C, 5-HT3 and 5-HT4 receptors have been implied in 5-HT mediated

analgesia (Jeong et al., 2004). Kayser and colleagues investigated mice deficient in 5-HT1A, 5-HT1B, 5-HT2A and 5-HT3A in parallel with a panel of behavioral tests in the attempt to dissect out spinal, supraspinal and peripheral effects of 5-HT (Kayser et al., 2007). 5-HT1A knockout mice differed from wild types by higher thermal sensitivity, and 5-HT1B knockout mice by higher thermal and formalin sensitivity. Both 5-HT2A and 5-HT3A knockout mice differed from wild types by a dramatic decrease in the formalin-induced nociceptive responses for phase 2. The authors concluded that 5-HT1B and to a lesser degree 5-HT1A receptors were responsible for endogenous inhibitory control of nociception by 5-HT, whereas 5-HT2A and 5-HT3 receptors had a role in peripheral hyperalgesia. 5-HT released from the brainstem nuclei was first shown to have an analgesic action at spinal sites as part of the system of descending inhibition (Yaksh and Wilson, 1979). Stimulation in the PAG and NRM releases 5-HT in the dorsal horn and excites 5-HT2 or 5-HT3 receptors on inhibitory interneurons, which in turn inhibit dorsal horn neurons (Peng et al., 1996). However, more recently data have accumulated, first questioning a major role of 5-HT in descending analgesia, then showing even a facilitatory effect of 5-HT on nociceptive transmission. Depending upon the stimulus parameters, brainstem stimulation can cause hyperalgesia, and there is evidence that this is also mediated by descending serotonergic pathways (Zhuo and Gebhart, 1991). One reason underlying this two-fold action of 5-HT may lie in the fact that the result of RVM stimulation depends on whether ‘on cells’ or ‘off cells’ are activated (Fields et al., 1983). Accordingly, 5-HT receptor antagonists can reduce both the painfacilitating and pain-inhibiting effects of stimulation of the RVM. Some of the serotonergic RVM neurons appear to be ‘on cells’ themselves, because they are labeled with the neural activity marker c-fos after noxious stimulation of a rat hindpaw (Suzuki et al., 2002). However, others dispute that either ‘on’ or ‘off ’ cells are serotonergic (Fields, 2004), and regard the RVM-serotonergic system as a parallel but distinct pain-controlling system that may be under opioidergic control (Fields, 2004). In analogy to the opioidergic system of ‘on’ and ‘off ’ cells, 5-HT is supposed to act in an activity-dependent mode, thus eliciting different behaviors at different times. A very telling model to study the role of central 5-HT is provided by conditional knockout mice selectively deficient of 5-HT in central neurons. This was achieved by generating mice deficient of a transcription factor required for the differentiation of postmitotic 5-HT neurons (Ding et al., 2003). These Lmx1bf/f/p mice are less sensitive to mechanical stimuli, but showed normal thermal and visceral pain responses. The mice had increased mechanical hypersensitivity after capsaicin injection, and increased

Serotonin in Pain and Pain Control pain behavior in the second phase of the formalin test (Zhao et al., 2007a). The phenotype could be rescued by intrathecal injection of 5-HT. Antidepressants (fluoxetine, amitriptyline and duloxetine) had no effect on thermal pain in the Lmx1bf/f/p mice. Flinching in the second phase of the formalin test was attenuated by duloxetine, but not by the selective 5-HT reuptake inhibitor fluoxetine. Together, the findings from this study support the view that 5-HT is of fundamental importance for the analgesic effect of antidepressants (Zhao et al., 2007a). Lmx1bf/f/p mice were also helpful in delineating the role of 5-HT in the action of opioids (Zhao et al., 2007b). 5-HT is also involved in other complex regulatory circuits. For example, rapid eye movement (REM) sleep deprivation facilitates pain sensitivity. REM sleep deprivation in rats produced marked hypersensitivity to tactile stimuli via endogenous 5-HT acting on 5-HT1A and 5-HT2C receptors (Wei et al., 2008). Thus, sustained activation of these receptors contributes to maintenance of cutaneous hypersensitivity in sleep-deprived animals. 5-HT receptor agonism and antagonism for pain relief As mentioned above, the 5-HT1B/D agonist sumatriptan, 5-HT2A antagonists, and the 5-HT3 receptor antagonist tropisetron have been shown to reduce pain behavior in certain animal models. Furthermore, a state-dependent analgesic effect of the 5-HT1A agonist F 13640 was found in rat models of acute and chronic nociceptive and neuropathic pain (Deseure et al., 2007). In contrast, the spinal excitatory action of 5-HT on 5HT3 receptors was shown to be necessary for the analgesic effect of gabapentin (Suzuki et al., 2005). This finding may be of clinical relevance, since not all patients with neuropathic pain respond favorably to gabapentin. The 5HT3-mediated spino-bulbo spinal loop, influenced by the affective state of the patient, might be part of determining this response (Suzuki et al., 2005). The greatly reduced analgesic effect of antidepressants in mice lacking central serotonergic neurons (Zhao et al., 2007a) also indicates a dependence of their effect on 5HT, even in dual antidepressants like duloxetine. By studying the expression of norepinephrine transporter, the authors could largely exclude a secondary effect through the norepinephrine system. 5-HT and the action of opioids Various experimental studies have shown an interaction of the serotonergic system and morphine analgesia. Serotonergic pathways are thought to be functionally distinct from but to interact with the opioid-mediated painmodulatory circuit (Fields, 2004). 5-HT in the NRM may be necessary for the action of morphine (Sounvoravong

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et al., 2004). Morphine has direct actions at the 5-HT3 receptor, suppressing 5-HT-induced currents in neurons in a competitive way (Wittmann et al., 2006). Using the selective receptor antagonist SB-269970, the analgesic effects of systemic morphine in mice were shown to be dependent on the 5-HT7 receptor (Dogrul and Seyrek, 2006). Interactions between the serotonergic, GABAergic and opioidergic system have been shown (Nemmani and Mogil, 2003). Lmx1bf/f/p mice which lack central serotonergic neurons have no analgesia after administration of a kappa opioid receptor agonist and significantly reduced analgesic effects of μ- and δ-opioid receptor agonists at both spinal and supraspinal sites. In contrast, morphine tolerance and morphine reward behavior developed normally in these mice (Zhao et al., 2007b). Thus, the central serotonergic system is a necessary component of the supraspinal pain modulatory circuitry mediating opioid analgesia. In contrast, morphine tolerance and morphine reward appear to be independent of the central serotonergic system. Interestingly, tramadol, a drug successfully used in pain management, acts through a combination of μ-opioid receptor and 5-HT1A receptors (Berrocoso et al., 2007).

Data from human studies Plasma 5-HT levels were found to be increased in several painful conditions (Table 1) – for example, in the complex regional pain syndrome (CRPS) (Wesseldijk et al., 2008). Also, interstitial concentrations of 5-HT in the trapezius muscle were increased in patients with whiplashassociated disorders (Gerdle et al., 2008) and with work-associated trapezius muscle pain (Larsson et al., 2008). Both findings point to a role of 5-HT as a peripheral pain mediator, among others, in these conditions. In an earlier study, blood 5-HT levels correlated negatively with pain detection thresholds but not with pain tolerance, also indicating a peripheral nociceptive effect of 5-HT (Pickering et al., 2003). As detailed above in the section on 5-HT agonists and antagonists, 5-HT injection in human volunteers induces sensitization to other mediators (Babenko et al., 2000), or pain and itching (Lischetzki et al., 2001; Schmelz et al., 2003), or hyperalgesia (Ernberg et al., 2000, 2006). An indirect indication for the role of 5-HT in experimental pain comes from the study on the GTP cyclohydrolase haplotype (Tegeder et al., 2006), the rate-limiting enzyme for tetrahydrobiopterin synthesis, a cofactor for serotonin production. Low tetrahydrobiopterin (and thus presumably low 5-HT synthesis) was associated with reduced experimental pain. Genetic variants in 5-HT receptors or in the 5-HT transporter have been hypothesized to underlie the variability

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Table 1 List of painful disorders where a role of 5-HT has been suggested Disorder

Finding

Reference

Migraine, between attacks Migraine, during attacks Medication overuse in migraine Migraine, between attacks

Lower plasma 5-HT, higher 5-HIAA Higher plasma 5-HT, lower 5-HIAA Lower plasma 5-HT levels Increased availability of the 5-HTT in brainstem 5-HT1B/1D receptor agonists abort migraine attacks Higher frequency of the short allele of the 5-HTTLPR Platelet 5-HT uptake increased Plasma 5-HT levels increased

Ferrari et al., 1989; Sicuteri et al., 1961 Ferrari et al., 1989

Migraine treatment

Migraine with aura

Medication overuse headache Complex regional pain syndrome (CRPS) Whiplash associated Interstitial 5-HT pain concentrations in the trapezius muscle increased Work-associated Interstitial 5-HT trapezius muscle pain concentrations in the trapezius muscle increased Fibromyalgia Reduced 5-HT levels syndrome in CSF Fibromyalgia syndrome Fibromyalgia syndrome Fibromyalgia syndrome

Hering et al., 1993 Schuh-Hofer et al., 2007 Ferrari et al., 2002

pain by a Valsalva maneuver (Martikainen et al., 2007). This led to the conclusion that brain 5-HT1A receptors influence pain thresholds and the capacity for analgesia in healthy subjects. In a PET study using the 5-HT2A receptor antagonist [(18)F]altanserin for imaging, positive correlations were found between tonic pain ratings and binding in orbitofrontal, medial inferior frontal, primary sensory-motor and posterior cingulate cortices (Kupers et al., 2009). The authors concluded that 5-HT2A receptor availability co-varies with responses to tonic pain, and that the correlation between 5-HT2A receptor availability in prefrontal cortex and tonic pain suggests a possible role of this brain region in the modulation or cognitive appreciation of pain.

Borroni et al., 2005; Marziniak et al., 2005 Ayzenberg et al., 2008 Wesseldijk et al., 2008

Gerdle et al., 2008

Larsson et al., 2008

Houvenagel et al., 1990; Russell et al., 1992a Reduced serum 5-HT Russell et al., 1992b; levels Stratz et al., 1993 Higher frequency of Offenbaecher et al., the short allele of the 1999; but see also 5-HTTLPR Gürsoy et al., 2002 Bondy et al., 1999; T102C polymorphism of the Gürsoy et al., 2001 5-HT2A-receptor

Abbreviations: 5-HIAA, 5-hydroxyindole-acetic acid; 5-HTT, 5-HT transporter; 5-HTTLPR, 5-HTT-gene linked polymorphic region; CSF, cerebrospinal fluid.

in pain sensations in normal and diseased states. Recently, the intensity of cold pressure pain was investigated in 11 volunteers who had undergone positron emission tomography (PET) examination to quantify their 5-HT1A binding potential. Cold pressure pain intensity inversely correlated with the 5-HT1A binding potential in multiple cortical and subcortical areas. Subjects with high availability of 5-HT1A receptors had low cold pressure pain intensity and a high capacity for central suppression of

5-HT in headache The study of 5-HT in headache, in particular in migraine, has a long history (Sicuteri et al., 1961). Lower plasma 5HT and relatively higher levels of 5-hydroxyindole-acetic acid, a metabolite of serotonin degradation, were reported in patients with migraine between attacks (Sicuteri et al., 1961; Ferrari et al., 1989). In contrast, during an attack increases in plasma 5-HT concomitant with decreases in 5-HIAA levels have been found (Ferrari et al., 1989; for review, see Hamel, 2007). This led to the hypothesis that a chronic 5-HT deficit may be at the biochemical basis of migraine, while intermittent increases in 5-HT are triggers for migraine attacks. The 5-HT inhibitor methysergide was the first potent drug for migraine prophylaxis (Koehler and Tfelt-Hansen, 2008). 5-HT binds to the 5-HT1B/D receptors with higher affinity than to 5-HT2A receptors. Binding of 5-HT to the 5-HT1B/D receptors, when present at low concentrations in the migraine-free period results in stabilization of the perivascular nociceptors. When released at higher concentrations, 5-HT will bind to the proalgesic 5-HT2A receptors and may thus trigger a migraine attack. This is another example of the dual action of 5-HT in the nociceptive system depending on concentration, receptor availability and receptor affinity. Medication overuse further leads to reduced 5-HT levels in the blood of migraine patients (Hering et al., 1993). This in turn may lead to upregulation of 5-HT2 receptors, which when stimulated can increase the occurrence of migraine attacks, possibly via NO (Srikiatkhachorn et al., 2002). These changes are reversible after medication withdrawal (Smith, 2004). In a single photon emission computed tomography (SPECT) study using a selective 5-HTT ligand, increased availability of 5-HTT was found in the brainstem interictally in migraine patients (Schuh-Hofer et al., 2007). This

Serotonin in Pain and Pain Control finding is compatible with decreased extracellular levels of 5-HT at the synaptic cleft and thus deregulation of the 5-HT system in the brainstem. Physiological studies found that the amplitude of auditory- and visual-evoked potentials increased in migraineurs interictally, indicative of low 5-HT transmission. This was attributed to a deficit in cortical habituation (Coppola et al., 2005). The triptans, 5-HT1B/1D receptor agonists, activate inhibitory presynaptic 5-HT1B/1D autoreceptors to decrease 5-HT synthesis. They increase the amplitude of auditory-evoked potentials in both normal subjects and migraine patients (Proietti-Cecchini et al., 1997). Treatment with the β-blocker propranolol increases the rate of brain 5-HT synthesis, which may be the mechanism of action of β-blockers in migraine prophylaxis (Chugani et al., 1999). There is some experimental evidence for a connection between 5-HT, cortical spreading depression (which is thought to underlie the migraine aura) and trigemino-vascular activation (which is thought to underlie the cephalalgia in migraine). Rats with low 5-HT had enhanced cortical spreading depression waves and an increased number of activated neurons in the trigeminal nucleus caudalis (Supornsilpchai et al., 2006). Thus, chronically low brain 5-HT may facilitate trigeminal nociception through induction of cortical spreading depression, consistent with a deficit in the serotonergic descending pain inhibitory system (Panconesi, 2008). The triptans, 5-HT1B/1D receptor agonists, are the most successful drugs for acute migraine attacks (Ferrari et al., 2002). It is assumed that their action via the 5-HT1B/D receptors inhibits excitation of the perivascular trigeminal fibers, and thus blocks the release of vasoactive peptides (substance P, calcitonin gene-related peptide/CGRP) in the dura mater (Potrebic et al., 2003). Triptans may exert part of their actions on trigeminal nuclei, inhibiting the activity trigeminal fibers centrally (Edvinsson and Uddman, 2005). Serotonergic RVM neurons project to cerebral vessels (Bradley et al., 2002), where they regulate microcirculation (Cohen et al., 1996). When raphe nuclei are activated, they can increase cerebral blood flow (Goadsby, 2005). Triptans also bind to receptors on the dorsal raphe and periaqueductal gray (Bonaventure et al., 1998), indicating that, if they penetrate the blood–brain barrier, they may also act at these nuclei. Genetic factors within the serotonergic pathways have been investigated for their role in migraine susceptibility. Most studies investigating 5-HT receptors, the TPH gene or MAOA, MAOB polymorphisms were negative. The most convincing evidence so far for a genetic association between the serotonergic system and migraine has been obtained for the association of polymorphisms in 5-HTT, which controls 5-HT brain homeostasis.

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We examined a functional deletion/insertion polymorphism in the transcriptional control region 1 kb upstream of the 5-HTT gene’s transcription initiation site (5-HTTlinked polymorphic region, HTTLPR). In vitro and in vivo studies have demonstrated the functional relevance of this polymorphism with reduced transcriptional activity and low 5-HT reuptake activity determined by the short form of the allele (Lesch et al., 1996). Patients with migraine with aura had a significantly higher frequency of the short allele of the 5-HTTLPR in comparison to a control population and to patients with migraine without aura (Marziniak et al., 2005). These results were confirmed in an independent Italian population (Borroni et al., 2005), while a Hungarian group found an association with migraine in general in women (Gonda et al., 2007) and yet another group reported a link with increased frequency of migraine attacks (Kotani et al., 2002). Interestingly, platelet 5-HT uptake is increased in patients with medication-overuse headache concomitantly with a transient increase in 5-HTT activity, and normalizes after withdrawal in parallel to the improvement of headache frequency (Ayzenberg et al., 2008).

Fibromyalgia syndrome Fibromyalgia syndrome (FMS) is a complex of symptoms associated with chronic widespread pain and tenderness upon pressure on at least 11 of 18 predefined anatomical points (Wolfe et al., 1990). Additional symptoms are fatigue, sleep disturbance, depression, and gastrointestinal symptoms such as diarrhea and constipation. An effect of systemic 5-HT3 antagonists was occasionally reported (Spath et al., 2004). Together with the constellation of symptoms, this led to the hypothesis that 5-HT might be involved in the pathophysiology of FMS. Two studies investigating 5-HT levels in CSF found a reduction in patients with FMS compared to controls (Russell et al., 1992a) or to reference data from the general population (Houvenagel et al., 1990). In serum, reduced levels of serotonin were found in three studies (Russell et al., 1992b; Stratz et al., 1993; Wolfe et al., 1997). Others investigated whether antibodies against serotonin or serotonin receptors were present in patients with FMS (Klein et al., 1992; Werle et al., 2001), and found these in a higher percentage than in controls. It is unclear if these antibodies play a pathophysiological role in FMS. Of two studies investigating an association of FMS with polymorphisms in the 5-HTT promoter region, one found a higher percentage of the S/S genotype; these patients had higher scores in tests for depression and psychosocial impairment (Offenbaecher et al., 1999). In the other study, however, no association was found (Gürsoy, 2002). Of the

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four studies that investigated serotonin receptors (Bondy et al., 1999; Gürsoy et al., 2001; Frank et al., 2004; Tander et al., 2008), two were positive, both of them for the T102C polymorphism of the 5-HT2A-receptor (Bondy et al., 1999; Gürsoy et al., 2001). A study investigating other 5-HT2A receptor gene polymorphisms (Tander et al., 2008) and one studying variations in the 5-HT3A and 5HT3B genes (Frank et al., 2004) were negative. 5-HT3 antagonists have been repeatedly studied in open trial in FMS. However, in contrast to chemotherapyinduced vomiting, where 5-HT3 antagonists are extremely successful (Faerber et al., 2007), in FMS only one randomized controlled trial has shown a moderate effect upon short-term treatment (Färber et al., 2000). In summary, a definite role of 5-HT in the pathogenesis of FMS is possible, but has not yet been proven.

of 5-HT, depending on receptor availability and affinity, ligand concentration, and the neural network involved. The situation is even more complicated concerning the algesic or analgesic action of 5-HT in descending pathways and in the spinal cord (Figure 2). The concept of state-dependent actions, as recently proposed for the opioid system (Fields, 2004), may have to be adapted to the serotonergic system as well. Analgesics aiming at the serotonergic system have to take all these points into account.

Acknowledgements The author’s work cited in this review was supported by Volkswagen-Stiftung, by Bundesministerium für Bildung und Forschung (BMBF, Deutscher Forschungsverbund Neuropathischer Schmerz, DFNS) and by research funds of the University of Würzburg.

Implications for the treatment of chronic pain with antidepressants References Metareviews indicate that combined serotonergic and noradrenergic reuptake inhibitors such as the tricyclic antidepressants (TCA) are efficient analgesics, in particular in neuropathic pain, while selective serotonin reuptake inhibitors (SSRIs) are less efficient (Saarto and Wiffen, 2005). Similarly, the effect of SSRIs in the prevention of migraine and tension-type headache is also poor (Moja et al., 2005). Since relative selective noradrenalin reuptake inhibitors are also less effective in pain treatment, it has been suggested that a combined serotonergic and noradrenergic mechanism is needed. In view of the dual role of 5-HT in the pain-modulating system, it is not surprising that an increased availability of 5-HT at synapses may not in all instances lead to analgesia. Since the good pain control with TCA is set off by their side effects, combined serotonin–noradrenalin reuptake inhibitors (SNRIs) such as venlafaxine and duloxetine have been studied in clinical trials; these have fewer side effects and efficacy only slightly inferior to that of TCA (Sindrup et al., 2005). In particular, in FMS, SNRIs appear to be effective in reducing pain levels (Clauw et al., 2008; Üceyler et al., 2008a, 2008b). Conclusion There is no simple answer regarding the question of the role of 5-HT in pain and in pain control. It may be most easily solved in the periphery, where 5-HT, released into inflamed or injured tissues, contributes to peripheral sensitization of nerve fibers (Figure 1). In the trigeminovascular system and in the CNS there are dual actions

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