Neurochemical Mechanisms in Disease P45 doc

Endogenous Antinociceptive Ligands 425 activation (Guo et al., 1996; Ortiz et al., 2008). Some data suggest the role of α 1 - receptors in antinociception at supraspinal level, because ICV administration of an α 1 -receptor antagonist inhibits the antinociceptive potency of monoamine-reuptake inhibitors (Yokogawa et al., 2002). Activation of supraspinal β 2 -adenergic receptors also produces inhibition in nociceptive transmission (Fukui et al., 2004). The role of the noradrenergic system in the control of the activity of spinal neurons involved in the transmission of sensory messages to supraspinal relays is well doc- umented (Eisenach et al., 1996a; Pertovaara, 2006; Skagerberg and Lindvall, 1985; Weil-Fugazza and Godefroy, 1993). NE is released from the descending inhibitory pathways in the spinal cord, and the activation of α 2 -adrenergic receptors plays the most important role in this respect, inasmuch as a very effective antinociception can be reached by their activation (Eisenach et al., 1996a; Ganong et al., 1983; Horvath et al., 1994; Kalso et al., 1991; Kuraishi et al., 1985; Reimann et al., 1999). Peripheral mechanisms might also significantly contribute to their pain- influencing effects, because topical administration of α 2 -receptor agonist compounds produces effective antinociception, whereas E produces hyperalgesia via β 2 - adrenergic receptors (Ansah and Pertovaara, 2007; Chen and Levine, 2005; Khasar et al., 1999; Moon et al., 1999). The activation of peripheral α 2 -adrenoceptors might decrease pain by the inhibition of the activity of C-fibers (Gaumann et al., 1992; Pertovaara, 2006; Yagi and Sumino, 1998). In addition, α 2 -adrenoceptor activation can produce peripheral antinociception via action on the immune system by altering the balance of pro- and anti-inflammatory cytokines, and by inducing a release of endogenous opioids from immune cells (Binder et al., 2004; Romero-Sandoval and Eisenach, 2007). 2.2.2 Dopamine (DA) Dopamine (4-(2-aminoethyl) benzene-1,2-diol) constitutes about 80% of the cat- echolamine content in the brain (Pivonello et al., 2007; Vallone et al., 2000). Projections originating from brain areas that synthesize this neurotransmitter give rise to four axonal pathways: nigro-striatal, mesolimbic, mesocortical, and tuberoin- fundibular. Dopamine receptors (DARs: GPCRs) are widely distributed in the CNS, mainly localized in the striatum, the limbic system, the brain cortex, and the infundibulum, where they mediate the effect of DA on cognition, emotion, regulation of hunger and satiety, locomotor activity, pain, and on the endocrine system (Missale et al., 1998). DARs are widely distributed in the periphery as well, primarily at the level of the cardiovascular system, kidneys and adrenal glands, beyond the peripheral nervous system (PNS). Five distinct DARs receptors have been iso- lated, and subdivided into two subfamilies, D1- and D2-like, on the basis of their biochemical and pharmacological properties. The D1-like subfamily comprises D1 and D5-R, whereas the D2-like includes D2-, D3-, and D4-R (Brucke et al., 1991). D2-like receptors have a presynaptic location, and D1-like receptors are exclusively postsynaptic (Vallone et al., 2000). The signal transduction pathways activated by DARs are numerous, but the best-described effects are the activation or inhibition of 426 G. Horvath the cAMP pathway and modulation of Ca 2+ signaling. Receptors of the D1-like subtype are positive regulators of cAMP, whereas the inhibition of AC activity seems to be a general property of D2-like receptors. DARs are also able to activate other mechanisms of signal transduction, including the modulation of the activity of PLC or phospholipase D (PLD) leading to the release of arachidonic acid, as well as the activity of the calcium and potassium channels (Pivonello et al., 2007; Senogles, 2000). Moreover, DARs also seem to modulate the activity of Na + /H + exchangers and the Na + /K + -ATPase (Missale et al., 1998). Several data have demonstrated a control for dopaminergic neurotransmission in modulating pain perception and natural analgesia within supraspinal regions, including basal ganglia, insula, ACC, thalamus, and PAG (Wood, 2008). The mesolimbic dopaminergic system plays important roles in the suppression of persistent pain, and studies have provided direct evidence that the nucleus accumbens plays a major role in this mechanism (Altier and Stewart, 1999; Carta et al., 1999; Gear et al., 1999; Taylor et al., 2003). The descending dopaminergic system is also involved in pain control. Both DA and its metabolites are present in the spinal cord (Bjorklund and Skagerberg, 1979; Commissiong et al., 1978; Fleetwood-Walker et al., 1988; Jensen and Yaksh, 1984; Takada et al., 1988). The dopaminergic fibers are predominantly localized in the superficial layers of the SDH, and they arise primarily from the hypothalamic areas and from the caudal thalamus, but they can also orig- inate from the substantia nigra (Commissiong et al., 1978). Some dopaminergic sensory neurons in the DRG may innervate the spinal cord, and dopaminergic cell bodies may also be a source for dopamine in the spinal cord (Mouchet et al., 1986; Price and Mudge, 1983). IT administration of the DA agonist apomorphine produces analgesia, and morphine induces an increase in the metabolism of DA in the SDH suggesting that the descending dopaminergic system is involved in the modulation of the activity of the nociceptive neurons induced by morphine (Jensen and Yaksh, 1984; Weil-Fugazza and Godefroy, 1993). Both D1-like and D2-like receptors are found in the SDH, and both D1, D2 and D5 receptors are involved in DA-mediated antinociception (Altier and Stewart, 1998; Dubois et al., 1986; Karper et al., 2000; Morgan and Franklin, 1991). As regards its effect peripherally, it has been shown that the local administration of dopamine causes hyperalgesia by activating primary sensory neurons directly (Steiner et al., 2001). 2.2.3 Serotonin (5-Hydroxi-Tryptamine, 5-HT) Serotonin was discovered as a potent vasotonic ligand. It plays a role in the inflammatory chemical milieu and is released from platelets, mast cells, and basophils in injured or inflamed tissues as a critical factor in the control of nociceptive transmission (Doak and Sawynok, 1997;Dray,1995; Tokunaga et al., 1998; Zeitz et al., 2002). Serotoninergic neurons are found in the raphe nuclei in the midbrain, pons, and medulla and serotoninergic fibres project to the several brain regions and the spinal cord. Molecular cloning studies have confirmed the existence of at least 14 subtypes of 5-HT receptors, each encoded by distinct genes (Raymond et al., 2001). Endogenous Antinociceptive Ligands 427 The 5-HT receptors have been divided into seven subfamilies. All of them except 5-HT3 receptors are GPCRs, whereas 5-HT3 receptors are ion channels. There is multiplicity of coupling mechanisms for each 5-HT receptor subtype (Raymond et al., 2001). As regards the antinociceptive potency of 5-HT at supraspinal level, the results are controversial. Serotoninergicic deficiency is a common factor both in mental depression and chronic pain. It is well known that antidepressants, including the selective serotonin reuptake inhibitors, have antinociceptive effects after systemic or ICV administration (Nayebi et al., 2001; Singh et al., 2001). Increased levels of 5-HT in synaptic clefts are therefore presumed to lead to changes in pain thresh- olds and induce antinociception. A recent study, by using the formalin test in rats, attempted to determine the identity and possible localization of the receptor subtypes predominantly involved in the antinociceptive effects of antidepressants. Thus, it has been shown that ICV administration of 5-HT2 and 5-HT3-receptor antagonists inhibited the antinociceptive potency of serotonin-reuptake inhibitors (Yokogawa et al., 2002). The major site of the antinociceptive action of serotonin seems to be the spinal cord, and various studies have identified several types of serotonin receptors in the SDH (Coggeshall and Carlton, 1997; Fields et al., 1991; Furst, 1999). Data suggest that distinct 5-HT receptors subtypes are employed to generate the 5-HT-induced antiallodynic and antinociceptive effects. Serotonin is released from the descending inhibitory pathways in the spinal cord, and the activation of these pathways lead to antinociception ( Millan, 2002; Reimann et al., 1999; Van Steenwinckel et al., 2008; Willis, Jr., 1988). IT administered 5-HT has an antinociceptive effect in acute pain models, but it has lower potency and efficacy in models of persistent pain. (Bardin et al., 2000a, b;Kuraishietal.,1985). It has been suggested that predominantly 5- HT3 receptors are involved in the antinociception by evoking GABA and enkephalin (ENK) release (Huang et al., 2008; Kesim et al., 2005;Lietal.,2000; Wang et al., 2003b). However, some data suggest that 5-HT3 receptors contribute to the maintenance of chronic pain, because the 5-HT3 receptor antagonist ondenasetron reduces mechanical allodynia, and activation of deep SDH neurons that develops following nerve injury (Hamon and Bourgoin, 1999; Oatway et al., 2004; Suzuki et al., 2004). Endogenous 5-HT shows the highest affinity for 5-HT2A receptors subtype, and this subtype is also able to exert antinociceptive action (Hamon and Bourgoin, 1999). Other data have shown that the antinociceptive effects of IT 5-HT or serotonin reuptake inhibitors were blocked by 5-HT1A, B, 2A, 2C, 3, and 4 antagonists, whereas antagonists at 5-HT1D did not influence them (Honda et al., 2006; Jeong et al., 2004; Van Steenwinckel et al., 2008). 5-HT depletion in the SDH antagonizes the analgesic action of morphine (Murphy and Zemlan, 1990), and selective blockade of 5-HT7, but not of 5-HT1A and 5-HT2 receptors attenuated morphine analgesia (Dogrul and Seyrek, 2006). 5-HT produces an algesic response as a component of the inflammatory process at peripheral level (Giordano and Rogers, 1989;Taiwo and Levine, 1992), but activation of 5-HT3 receptors can blunt the pronociceptive effects on 5-HT2 and 5-HT1A receptors (Kesim et al., 2005). 428 G. Horvath 2.2.4 Histamine The biogenic amine histamine (2-(3H-imidazol-4-yl) ethanamine) is involved in local immune responses, and it is also regarded as a neurotransmitter or modulator in the mammalian brain (Prell and Green, 1986; Schwartz et al., 1991). Histamine is derived from the decarboxylation of the amino acid histidine, a reaction catalyzed by the enzyme L-histidine decarboxylase. In the CNS histamine mostly originates from two cell types, neurons and mast cell. The cell body of histaminergic neurons is localized in the tuberomammillary nucleus of the posterior hypothalamus, and histamine-immunoreactive nerve fibres project widely to the various brain regions and the SDH (Haas and Panula, 2003). Histamine mediates its effects through four histamine receptors (GPCRs) that have been discovered and are designated H1 through H4. As regards the effect of histamine on the pain threshold, it depends on the site of application and the type of the activated receptor. The H1 receptor knock-out animals or systemic injection H1- receptor antagonist drugs show increased pain threshold (Farzin et al., 2002; Mobarakeh et al., 2000; Sakurada et al., 2002; Yanai et al., 2003; Zamfirova et al., 2007). Activation of H2 receptors induced an increase in the mechanical pain threshold, whereas antagonism of H2 receptors can induce either antinociception or hypernociception (Lamberti et al., 1996; Oluyomi and Hart, 1991). ICV administration of low doses of histamine elicits hyperalgesia, and high doses of histamine produce antinociception (Chung et al., 1984; Parolaro et al., 1989). The injection of histamine into the dorsal raphe nucleus and PAG region produces an antinociception, whereas its injection into the median raphe nucleus causes hyperalgesia (Glick and Crane, 1978; Thoburn et al., 1994). Some data suggest that activation of opioid receptors can increase histamine release in PAG (Barke and Hough, 1993). The opposite effects of histamine on the pain threshold may be mediated through different subtypes of receptors (Lamberti et al., 1996; Malmberg-Aiello et al., 1994; Thoburn et al., 1994). Thus, ICV injection of histamine H1 receptor agonist produced hypernociception in hot plate (HP) and writhing tests, and H1 receptor antagonists produce antinociceptive effects (Malmberg-Aiello et al., 1998). However, other reports found that H1 antagonist antagonized the histamine-induced antinociception (Parolaro et al., 1989). The ICV injection of either H2 agonists or antagonists raised the pain threshold (Farzin et al., 2002). Moreover, a series of H2 receptor antagonists reduced the antinociceptive effects of H2 receptor agonist (Netti et al., 1988). However, other data suggest that both H1 and H2 receptor activation inhibit the morphine-induced antinociception at both spinal and supraspinal levels (Mobarakeh et al., 2000; Mobarakeh et al., 2002; Mobarakeh et al., 2006). It seems that H3 receptor activation may also decrease the pain threshold, because receptor antagonists have analgesic properties, as these compounds block presynaptic autoreceptors and increase the release of neuronal histamine (Farzin et al., 2002). Spinal administration of histamine produces nociceptive behavior, and a recent study has suggested that this effect is partially mediated by the activation of N-methyl-D-aspartate (NMDA) receptors at polyamine binding sites (Sakurada Endogenous Antinociceptive Ligands 429 et al., 2002; Yanai et al., 2003). However, the activation of H3 receptors located on spinal terminals increases the pain threshold by inhibiting the release of excitatory neurotransmitters (Cannon et al., 2003; Cannon et al., 2007). It is well known that the peripherally released histamine is a very effective pain-inducing ligand, however, the activation of H3 receptors at peripheral level can also inhibit the pain sensation (Cannon et al., 2007). 2.2.5 Melatonin (MT) Melatonin (5-methoxy-N-acetyltryptamine), a pineal neurohormone and a deriva- tive of serotonin, is critically involved in the regulation of important biological functions including circadian rhythms, sleep, mood, and pain (El Shenawy et al., 2002; Sugden, 1983; Zeng et al., 2008). MT and its receptors (MT1 and MT2) are located in the spinal cord and various brain regions (Morgan et al., 1994; Vitte et al., 1990; Zahn et al., 2003). These receptors are GPCRs, and they are linked to activation of multiple signaling pathways, with the inhibition of cAMP formation being the most common (Dubocovich et al., 2003; Reppert et al., 1996). The action of MT may be mediated through an interaction with NMDA receptors and the NOS pathway too (Hernandez-Pacheco et al., 2008; Mantovani et al., 2003; Tu et al., 2004). It can also inhibit calcium influx, and it may exert its central effects by modulating GABAA receptors, therefore, the inhibitory mechanisms of MT might be complex and are yet to be elucidated in detail (Vanecek, 1998; Wu et al., 1999a). Clinical studies have shown that migraine patients have lower nocturnal plasma MT levels than controls, and migraine patients with superimposed depression exhibit the greatest decrease of MT (Gagnier, 2001; Reiter, 1991). Furthermore, MT administration improved the symptoms, and it could be due to a number of the actions of MT: resetting the biological rhythm, relieving anxiety and insomnia, inhibiting both protaglandin and NO synthesis, depressing calcium uptake, or directly affecting cerebral blood vessels. MT can reduce cluster headache, irritable bowel syndrome, and fibromyalgia, although the relationship between depression and chronic pain was not specifically examined in these clinical reports (Citera et al., 2000; Leone et al., 1996; Song et al., 2005). Systemic administration of MT produced dose-dependent antinociception in HP, and visceral and inflammatory pain tests primarily by supraspinal MT2 receptor activation (El Shenawy et al., 2002;Lietal.,2005b; Sugden, 1983; Tu et al., 2004; Yu et al., 2000a; Zeng et al., 2008). On the other hand, others have shown that systemic MT did not influence the normal pain threshold, but inhibited the development of morphine tolerance (Raghavendra et al., 2000; Raghavendra and Kulkarni, 1999; Raghavendra and Kulkarni, 2000). In contrast, light-induced MT suppression can decrease arthritic pain (Burk, 2008). As regards the activation of the central melatoninergic system, ICV MT produced a significant increase in acute heat pain latency, and reversed the nociception or neuropathy-induced hyperalgesic effects (Li et al., 2005b; Sakurada et al., 2002; Ulugol et al., 2006; Wang et al., 2006b). Its effect can be reversed by naloxone and MT can specifically enhance the antinociception induced by δ-(DOR) , but not by μ-(MOR) opioid agonists (Li et al., 2005b; Yu et al., 2000b). 430 G. Horvath Intra-ACC administration of MT attenuated mechanical allodynia and improved depression-like behavior without changing the nociceptive response in normal rats, and depressive animals exhibited a lower level of plasma MT concentration and intra-ACC MT receptor expression (Zeng et al., 2008). These results indicate that there is a reciprocal relationship between depression-like behavior, and nociceptive behavior and the melatoninergic system within ACC could play a significant role in this relationship. IT administration of MT did not influence the pain threshold in a postoperative pain model, but potentiated the effect of morphine, and it effectively decreased the capsaicin-induced pain behavior and neuropathic allodynia by activation of MT2 receptors (Ambriz-Tututi and Granados-Soto, 2007; Tu et al., 2004; Zahn et al., 2003). The results suggest that the endogenous MT system in the spinal cord can reduce the generation, development, and maintenance of central sensitization, with a resultant inhibition of hyperalgesia, allodynia. Peripheral administration of MT can also decrease formalin- and glutamate-induced behavior via the activation of the NO-cyclic guanosine monophosphate (GMP)-K + -channel opening (Hernandez-Pacheco et al., 2008; Mantovani et al., 2006). 2.2.6 Agmatine (AGM) AGM ( decarboxylated arginine), an endogenous amine derived from arginine and its biosynthetic enzyme (arginine decarboxylase), is broadly distributed in the CNS, including the SDH (Li et al., 1994a; Raasch et al., 1995; Reis and Regunathan, 2000). The distribution of AGM-containing neurons is concentrated in r egions of the brain that subserve visceral and neuroendocrine control, the processing of emotions, pain perception, and cognition (Reis and Regunathan, 2000). The concentration of AGM in the brain i s comparable to that of norepinephrine or dopamine (Li et al., 1994a). AGM possesses modest (micromolar) affinity for α 2 -adrenoceptors, and for imidazoline-binding sites ( I1 and I2) (Li et al., 1994a; Raasch et al., 1995). Features complicating the interpretation of its influence upon nociceptive processing are that AGM behaves as an inhibitor of NOS, expresses antagonist properties at NMDA receptors and blocks the nAChR cation channels (Fairbanks et al., 2000; Gibson et al., 2002; Reis and Regunathan, 2000; Yang and Reis, 1999). Systemic administration of AGM significantly reversed inflammatory hyperalgesia and neuropathic allodynia; furthermore, it potentiated morphine-induced analgesia (Kolesnikov et al., 1996; Paszcuk et al., 2007). ICV administration of AGM had no antinociceptive potency by itself, but potentiated the effects of morphine through activation of both α 2 -adrenoceptors and I2-receptors (Roerig, 2003; Sanchez-Blazquez et al., 2000). AGM suppresses the transmission of nociceptive inputs at the spinal level, primarily through the activation of I-receptors (Auguet et al., 1995; Bradley and Headley, 1997; Hou et al., 2003; Kolesnikov et al., 1996; Pinthong et al., 1995). The single or continuous IT administration of AGM could restore injured hypersensitive animals to normal levels of sensation, but did not influence normal pain sensitivity (Fairbanks et al., 2000; Kekesi et al., 2004). No data are available on the possible effects of AGM at the peripheral level. Endogenous Antinociceptive Ligands 431 2.3 Class III. Amino Acids and Derivatives 2.3.1 Glutamate The excitatory amino acid glutamate plays a key role in the modulation of nociceptive processing by acting through two distinct types of receptors: excitatory ionotropic (tetrameric Ca 2+ /Na + -channels: NMDA, α-amino-3-hydroxyl-5-methyl- 4-isoxazole-propionate: AMPA and kainate) and metabotropic glutamate receptors (mGluRs) (Bleakman et al., 2006). Eight mGluRs have been identified and divided into three groups (I–III) based on their sequence similarity, pharmacology, and G- protein coupling (Conn and Pin, 1997), Group I receptors including mGlu1 and mGlu5 are coupled via G q to PLC. Group II (mGlu2 and mGlu3) and Group III (mGlu4,6,7,8) receptors activate G i and inhibit cAMP formation. Group I mGluRs are primarily located postsynaptically on neurons and contribute to biphasic regulation of glutamate synaptic transmission. Group II and III mGluRs are found to contribute to presynaptic regulation of glutamate and GABA transmission. All three groups are distributed throughout the CNS, and several data proved the antinociceptive effect of activation of group II and III receptors (Goudet et al., 2008; Kim et al., 2002; Pan et al., 2008). Glutamate can produce antinociception at the supraspinal level, because central NMDA receptor activation can lead to the release of endogenous opioid pep- tides (Bach and Yaksh, 1995; Goudet et al., 2008; Kim et al., 2002;Starowicz et al., 2007). The ICV administration of glutamate enhanced the morphine-induced antinociception, indicating the analgesic interaction between the NMDA and MOR (Hunter et al., 1994; Jacquet, 1988). Neurons immunoreactive for the NMDA receptors and glutamate were identified in the PAG, and a subset of these projects to the RVM (Commons et al., 1999; Ito et al., 2008; Wiklund et al., 1988). In an ani- mal model of inflammatory hyperalgesia, intra-RVM injection of NMDA produced facilitation at lower doses, and inhibition at higher doses, whereas AMPA receptor activation produced dose-dependent inhibition (Guan et al., 2002). Thus, activation of both AMPA and NMDA receptors are involved in the descending modulation after inflammatory hyperalgesia. It has been suggested that glutamate release in the RVM activates Off antinociceptive neurons, and its leads to antinociception (Bleakman et al., 2006; Guan et al., 2002; Starowicz et al., 2007). Activation of mGlu receptors in the brainstem can also produce antinociceptive effects (Bleakman et al., 2006; Kim et al., 2002; Oja and Saransaari, 2000). Glutamate (and aspartate) is a well-known excitatory neurotransmitter and pain-inducing substance at spinal and peripheral levels by the activation of the ionotropic receptors (Bleakman et al., 2006). However, data suggest the involvement of spinal group III mGluR in the modulation of acute, inflammatory, and neuropathic pain (Goudet et al., 2008). The selective activation of group III mGluR at the spinal level inhibited the nociceptive behavior of rats submitted to the formalin test and the mechanical hyperalgesia associated with inflammatory or neuropathic pain. This study provides new evidence for supporting the role of spinal group III mGluRs in the modulation of pain perception in different pathological pain states of various etiologies but not in normal conditions. 432 G. Horvath 2.3.2 γ-Amino-butyric Acid (GABA) GABA is the major inhibitory neurotransmitter. Organisms synthesize GABA from glutamate using the enzyme L-glutamic acid decarboxylase and pyridoxal phos- phate (which is the active form of vitamin B6) as a cofactor. This process converts the principal excitatory neurotransmitter (glutamate) into the principal inhibitory one (GABA). GABA receptors can be classified as GABAA and GABAC receptors, which are ionotropic receptors (pentameric chloride channels), and GABAB receptors, which are metabotropic receptors ( Alger and Le Beau, 2001). GABA and its receptors are widely distributed throughout the neuraxis; their concentration in the brain and spinal cord is relatively high (Enna and McCarson, 2006; Willis, Jr., 1988). The activation of GABAA and GABAC receptors increases the neuronal concentration of chloride ion leading to hyperpolarization of the cells. Stimulation of GABAB receptors modifies the level of cAMP, decreases Ca 2+ , and increases K + membrane conductance, leading to cellular hyperpolarization. The function of GABA in the modulation of nociception is crucial and complex. Enna McCarson provided an excellent review of the role of GABA and its receptors in pain transmission, and the results suggest that GABA provides the main neurochemical substrate for local modulation of pain control in different central areas (Enna and McCarson, 2006). With regard to higher brain regions, there are GABAergic projections from the ventral tegmental area and substantia nigra to the PAG and NRM (Kirouac et al., 2004; Williams and Beitz, 1990). GABAA receptors are located on inhibitory neurons projecting from the RVM to the dorsal horn (Gilbert and Franklin, 2001). Thus, local injection of a GABA agonist into this region facilitates transmission of a pain impulse through the spinal cord (Ito et al., 2008). In contrast, central stimulation of GABAA and GABAB receptors induces antinociception in the formalin test, and this effect may be mediated partly through supraspinal opioid receptor mechanisms (Mahmoudi and Zarrindast, 2002). Furthermore, an increase in overall GABAergic activity in the insular cortex induces analgesia by enhancing the descending inhibition of the spinal cord (Jasmin et al., 2003). Activation of GABAA receptors in the amygdala produced a robust reversal of escape/avoidance behavior, and reduced mechanical hypersensitivity in a neuropathic pain model (Pedersen et al., 2007). These data suggest that GABAA receptor activation increases output from amygdala to brainstem and forebrain areas and this process might selectively attenuate affective nociceptive processing. In the spinal cord GABA is a widespread transmit- ter and GABA receptors are located in the SDH on pre- and postsynaptic sites in the region of the Aδ- and C-fiber synapses (Huang et al., 2008; Yang et al., 2002). In the SDH GABA and ENK are colocalized in a large population of neurons, and these neurons may represent local inhibitory interneurons which modulate pain transmission (Todd et al., 1992). Neuropathies cause a loss of GABAergic neurons and GABA transports in the rat spinal cord contributing to the pain syndrome (Drew et al., 2004; Lever et al., 2003; McCarson et al., 2006; Moore et al., 2002). Both GABAA and GABAB receptor activations display antinociceptive activity (Dirig and Yaksh, 1995; Franek et al., 2004; Hwang and Yaksh, 1997; Malan et al., 2002; Patel et al., 2001; Vaught et al., 1985). It has been demonstrated Endogenous Antinociceptive Ligands 433 that the GABAergic system contributed to spinal serotonin-mediated antinociception, inasmuch as GABA release may underlie the antinociceptive effects of the descending serotoninergic pathway (Huang et al., 2008; Kawamata et al., 2002). The analgesic response to GABAB agonist is thought to be mediated, in part, by the activation of spinal cord presynaptic receptors that regulate the release of tachykinins, and the inflammatory pain modifies GABAB receptor expression in the DRG and SDH (Riley et al., 2001). Less is known about the involvement of the GABAC receptors in pain. Zheng et al. (2003) localized the GABAC receptors on lamina I and II of DH and DRG, crucial sites for pain transmission, but no data are available on the effect of GABAC agonist at spinal level. Peripheral activations of both GABAA and GABAC receptors produce antinociception (Carlton et al., 1999; Da Motta et al., 2004; Reis and Duarte, 2007). It is supposed that activation of coupled chloride channels causes a hyperpolarization of peripheral terminals of primary afferents, leading to a decrease in action potential generation. 2.3.3 Glycine (Gly) Glycine, the smallest amino acid, is known to be an inhibitory neurotransmitter, but only a few studies investigated its role in pain modulation (Webb and Lynch, 2007). Initially, Gly was described to be restricted to the mammalian spinal cord, but subsequently it has been detected supraspinally as well (Legendre, 2001). Gly receptors (GlyRs) belong to the superfamily of receptor channels, which are gener- ally composed of five subunits (α1–4, β) (Webb and Lynch, 2007). The different α- and β-subunits are differently localized. The GlyR is a pentameric chloride channel, and it is classically known for mediating inhibitory synaptic transmission between interneurons and motor neurons in reflex circuits of the spinal cord, but they are also found presynaptically, where they modulate neurotransmitter release (Lynch, 2009; Webb and Lynch, 2007). The picture is complicated by the fact that Gly also binds to and activates NMDA receptors, therefore, it can influence the pain threshold by this action as well (see above, Section 2.3.1) (Zeilhofer, 2005). Changes in glycinergic neurotransmission in the spinal cord dorsal horn are critically involved in the development of pathological pain, and GlyR blockade produces allodynia in “normal” animals and enhances nociceptive responses (Cronin et al., 2004; Sherman and Loomis, 1996; Yaksh, 1989). Immunocytochemical and electro- physiological evidence implicates α3β GlyRs as important mediators of glycinergic inhibitory neurotransmission in nociceptive sensory neuronal circuits in the peripheral laminae of the SDH (Lynch, 2009; Webb and Lynch, 2007). Because α3 subunits are targets for prostaglandin modulation in spinal nociceptive neurons, antinociceptive drugs targeting the GlyR should ideally be specific for this subtype. Thus, inflammation-induced decrease of lamina II glycinergic inhibitory postsynaptic current (IPSC) was found to be abolished in the α3β GlyR knock-out mice, and chronic inflammation did not produce pain sensitisation, but these mice responded normally to acute inflammatory pain stimuli (Harvey et al., 2004). Furthermore, the inhibition of glycine uptake at the spinal level produced antinociception in acute pain tests and in different models of neuropathy (Hermanns et al., 2008; Tanabe 434 G. Horvath et al., 2008). No data are available on the glycine effect at both s upraspinal and peripheral levels, but see Section 2.3.5. 2.3.4 D-serine D-serine is one of the recently identified neurotransmitter candidates, and has attracted extensive attention because of its multiple roles in physiological and pathophysiological conditions (Boehning and Snyder, 2003). D-amino acid oxi- dase degrades D-serine physiologically, whereas serine racemase directly converts L-serine to D-serine. Both enzymes and D-serine can be found in the brain in the highest concentrations in the forebrain, where the NMDA receptors f or glutamate are also highly concentrated. Most strikingly, D-serine occurs selectively in proto- plasmic astrocytes, which ensheath synapses in grey matter, whereas most astrocytes are enriched in white matter. The occurrence of D-serine in astrocytes in close prox- imity to NMDA receptors and its release by glutamate suggest that D-serine is an endogenous ligand for the NMDA receptors. It is quite potent in stimulating the Gly site of the NMDA receptor, and it acts as an endogenous and obligatory coagonist for this receptor (Danysz and Parsons, 1998). Some observations have suggested that the activation of the supraspinal NMDA receptors by D-serine may lead to an increased pain threshold. Accordingly, ICV application of D-serine alone produces a dose-dependent antinociception, and potentiates the antinociception of morphine in the tail-flick (TF) and formalin tests (Hunter et al., 1994; Yoshikawa et al., 2007). Other data have shown that D-serine-induced antinociception was attenuated by the ICV application of a GABAA receptor agonist (Ito et al., 2008). These data suggest functional interactions among the GABAA, NMDA receptors, and MOR in the regulation of the antinociception at the supraspinal level. 2.3.5 Taurine Taurine (2-aminoethanesulfonic acid) is a phylogenetically ancient nonessential amino acid; one of the most widespread ligands throughout the CNS (Oja and Saransaari, 2000; Zeilhofer, 2005). Taurine differs from most other amino acids in being a sulfonic acid and a β-amino acid. Taurine has been proposed as a possible inhibitory neurotransmitter in several loci of the CNS through the activation of GlyRs (Frizzo et al., 2003; Legendre, 2001; Mathers et al., 1989; Xu et al., 2004a). Taurine induces hyperpolarization and inhibits firing of neurons; it acts as a modulator of synaptic activity in the brain (Oja and Saransaari, 2000). The increase in extracellular taurine upon excessive stimulation of glutamate receptors and under cell-damaging conditions may serve as an important protective mechanism against excitotoxicity. An increase in oral taurine uptake diminishes chronic nociception, but decreases the normal heat–pain threshold (Belfer et al., 1998). As regards its effect in the brain, intra-ACC injection of taurine effectively reduced neuropathic . administration of the DA agonist apomorphine produces analgesia, and morphine induces an increase in the metabolism of DA in the SDH suggesting that the descending dopaminergic system is involved. 2006). 2.2.6 Agmatine (AGM) AGM ( decarboxylated arginine), an endogenous amine derived from arginine and its biosynthetic enzyme (arginine decarboxylase), is broadly distributed in the CNS, including the. supraspinal opioid receptor mechanisms (Mahmoudi and Zarrindast, 2002). Furthermore, an increase in overall GABAergic activity in the insular cortex induces analgesia by enhancing the descending inhibition

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