The amino acid glutamate is the major excitatory neur- otransmitter in the mammalian central nervous system. Glutamate activates ionotropic glutamate ...
Molecular Psychiatry (2001) 6, 615–617 2001 Nature Publishing Group All rights reserved 1359-4184/01 $15.00 www.nature.com/mp
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Metabotropic glutamate receptors on peripheral sensory neuron terminals as targets for the development of novel analgesics The amino acid glutamate is the major excitatory neurotransmitter in the mammalian central nervous system. Glutamate activates ionotropic glutamate receptors (iGluRs) which include the NMDA, AMPA and kainate receptors, and the metabotropic glutamate receptors (mGluRs) which are coupled to G proteins. To date, eight mGluR subtypes have been cloned and are termed mGluRs 1–8. These are broadly classified into group I (mGluRs 1 and 5), II (mGluRs 2 and 3) and III (mGluRs 4, 6, 7 and 8), based on their sequence homology, agonist pharmacology and coupling to intracellular effector systems.1 While the function of glutamate and glutamate receptors in the CNS has been studied in great detail, the importance of these receptors in the peripheral nervous system has only recently been acknowledged. A growing body of evidence indicates that glutamate levels rise in peripheral tissues in response to inflammation. Increases in glutamate levels in the skin have been found in response to inflammatory agents such as intraplantar formalin.2 Electrical stimulation of the sciatic nerve results in a significant increase in glutamate release in the hind paw of rats.3 Interestingly, stimulation of the sciatic nerve by a selective C fiber activator, capsaicin, also results in glutamate release in the rat hind paw,3 suggesting that nociceptive-specific primary afferent fibers are a source of peripheral glutamate. Evidence for physiological relevance of this peripheral glutamate was obtained when intraplantar injection of glutamate caused increased thermal and mechanical sensitivity in rats and mice.4–6 The potential clinical importance of elevated glutamate levels in the periphery is supported by the finding that glutamate levels are markedly elevated in synovial fluid from knee joints of arthritis patients.7 These findings suggest an important role for glutamate as a peripheral inflammatory pain mediator, and that inhibitors of glutamate release, glutamate receptors, or inhibitors of intracellular glutamate-activated pathways may harbor important therapeutic potential. Three recent reports have highlighted the importance of mGluRs on peripheral sensory neurons in the modulation of nociceptive transmission.4,8,9 These studies have utilized a combination of anatomical studies, behavioral pharmacology, and electrophysiology to
Correspondence: RW Gereau IV, Division of Neuroscience, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA. E-mail: rgereau얀bcm.tmc.edu
demonstrate a particularly important role for mGluR subtypes 1 and 5 in models of chronic pain states. In general, the findings indicate that activation of mGluR1 or mGluR5 on peripheral sensory neuron terminals leads to enhanced pain sensitivity in rats and mice. Furthermore, these group I mGluRs appear to be activated in both inflammatory and neuropathic pain states, since antagonists of mGluR1 and 5 reduce hyperalgesia following peripheral inflammation and nerve injury. The expression of mGluR5 in sensory neurons was first suggested several years ago.10,11 At that time, it was generally believed that mGluRs expressed in the dorsal root ganglia were destined for central terminals in the spinal cord, where they would function as autoreceptors as shown in other brain regions.12,13 Taken together with the findings that glutamate is released in response to peripheral inflammation, the expression pattern of mGluR5 in the DRG led to the hypothesis that mGluRs may be transported and expressed on peripheral terminals of sensory neurons, and that these receptors might mediate a component of inflammatory hyperalgesia. As predicted, the expression of mGluR5 was clearly demonstrated by two independent groups.4,8 Electron microscopic studies indicate that both mGluR1 and mGluR5 are expressed on a subset of predominantly nociceptive nerve terminals at the dermalepidermal junction in the hind paw of mice.4 Additional studies at the light microscopic level show that mGluR5 colocalizes with III tubulin in peripheral axons, and confirm that mGluR5 is expressed in a population of nociceptive-specific C fibers based on colocalization with the capsaicin receptor, VR1.8 Based on the demonstration of peripheral expression of group I mGluRs, a series of experiments were carried out that showed clearly that direct activation of group I mGluRs on these peripheral terminals leads to enhanced sensitivity to mechanical and thermal stimuli.4,8 Intraplantar administration of either RS-DHPG, a group I mGluR-selective agonist, or CHPG, an mGluR5selective agonist, induced thermal or mechanical hypersensitivity in mice and rats. Intraplantar administration of CHPG increased the spontaneous firing of wide dynamic range neurons in the dorsal horn of the spinal cord, and this effect was reversed by intraplantar co-injection of MPEP, an mGluR5 receptor-selective antagonist.8 Furthermore, these studies show that pretreatment or co-injection of group I receptor antagonists prevented development of spontaneous pain behavior induced by intraplantar formalin4 or carra-
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geenan-induced inflammatory hypersensitivity.8 Thus, the most important finding of these studies was that antagonists of mGluR54,8 and mGluR14 reduced nociceptive hypersensitivity in mice and rats with already established inflammation. This effect was observed in response to distinct inflammatory agents and in two different species, suggesting that the findings are conserved. The fact that antagonists of mGluR1 and 5 can reduce hyperalgesia during established inflammation is an important finding when considering the potential clinical applicability of these antagonists for painful neuropathies or inflammatory pain conditions such as arthritis. Elucidation of the underlying molecular mechanisms by which group I mGluRs enhance thermal sensitivity could suggest additional targets for the development of analgesics. We propose that glutamate acting via group I mGluRs may play a role in these peripheral processes through a variety of cellular mechanisms, as depicted in Figure 1. Group I mGluRs activate depolarizing, Ca2+ activated, cation non-selective currents (ICa,N) in DRG neurons.11 In the central nervous system, group I mGluRs also increase excitability by inhibiting potassium conductances.1 In addition, group I mGluRs can activate several protein kinases, which may potentiate the function of receptors implicated in the production of hyperalgesia, such as VR1, or voltage gated channels, such as the tetrodotoxin-resistant sodium channel.14,15 By inhibiting K+ channel function or enhancing the function of channels such as VR1, Na+ channels or ICa,N, activation of mGluRs by peripheral glutamate could increase the firing of sensory neurons in
response to noxious stimuli such as heat, leading to hyperalgesia. The therapeutic implications of these studies may be significant. The main goal for treating pain is to safely reduce persistent, pathologic pain without affecting physiologic pain sensations. Peripheral application of analgesics provides a safer administration route by avoiding systemic side effects and is currently utilized with systemically dangerous agents, such as capsaicin and lidocaine.16,17 Peripherally applied glutamate receptor antagonists can reduce pain in various inflammatory pain models.4,5,18,19 However, amongst glutamate receptors, group I mGluRs may be the most useful peripheral targets. Group I mGluR antagonists not only prevent, but also attenuate established hyperalgesia. Ionotropic glutamate receptor antagonists fail to reduce established pain in the formalin model,18 but can reverse pain in carageenan-based models.5,19 The difference between group I mGluR and ionotropic antagonists may be their ability to attenuate pain based solely on peripheral sensitization, such as carageenan models,20 vs pain based both on peripheral activity and sensitization, such as the formalin model.21 Ionotropic antagonists seem active only against the former, while group I mGluR antagonists may also be useful in the latter situation. Therefore, one would predict that group I mGluR antagonists applied peripherally should reduce established pain in a broad spectrum of pain states, including neuropathic pain, where spontaneous peripheral afferent activity plays a role.22 Indeed, intraplantar administration of the mGluR5 antagonist, SIB1757, produces a partial reversal of mechanical allody-
Figure 1 Multiple potential mechanisms could mediate enhancement of thermal sensitivity by activation of group I mGluRs. This diagram represents some of the elements contained in the peripheral terminal of a nociceptive C fiber. Following inflammation, glutamate is released from the C fiber terminal, where it can activate mGluR1 and mGluR5. The observed increase in thermal sensitivity in response to activation of group I mGluRs could be mediated by modulation of a number of ion channels in the peripheral terminals of these neurons. Molecular Psychiatry
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nia, while reversing thermal hyperalgesia completely in rats with experimental neuropathic pain elicited by spinal nerve ligation.9 Taken together, these studies point to exciting possibilities for safely treating both inflammatory and neuropathic pain by targeting peripheral group I mGluRs. F Karim, G Bhave and RW Gereau IV Division of Neuroscience Baylor College of Medicine One Baylor Plaza Houston, TX 77030, USA
1 Conn PJ, Pin J-P. Annu Rev Pharmacol Toxicol 1997; 37: 205–237. 2 Omote K et al. Brain Res 1998; 787: 161–164.
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