Molecular Psychiatry (2001) 6, 615–617  2001 Nature Publishing Group All rights reserved 1359-4184/01 $15.00 www.nature.com/mp NEWS & COMMENTARY Metabotropic glutamate receptors on peripheral sensory terminals as targets for the development of novel analgesics

The amino acid glutamate is the major excitatory neur- demonstrate a particularly important role for mGluR otransmitter in the mammalian central . subtypes 1 and 5 in models of chronic states. In Glutamate activates ionotropic glutamate receptors general, the findings indicate that activation of mGluR1 (iGluRs) which include the NMDA, AMPA and kainate or mGluR5 on peripheral terminals receptors, and the metabotropic glutamate receptors leads to enhanced pain sensitivity in rats and mice. (mGluRs) which are coupled to G proteins. To date, Furthermore, these group I mGluRs appear to be acti- eight mGluR subtypes have been cloned and are vated in both inflammatory and termed mGluRs 1–8. These are broadly classified into states, since antagonists of mGluR1 and 5 reduce hyp- group I (mGluRs 1 and 5), II (mGluRs 2 and 3) and III eralgesia following peripheral inflammation and (mGluRs 4, 6, 7 and 8), based on their sequence hom- injury. ology, agonist pharmacology and coupling to intra- The expression of mGluR5 in sensory was cellular effector systems.1 first suggested several years ago.10,11 At that time, it was While the function of glutamate and glutamate recep- generally believed that mGluRs expressed in the dorsal tors in the CNS has been studied in great detail, the root ganglia were destined for central terminals in the importance of these receptors in the peripheral nervous , where they would function as autorecep- system has only recently been acknowledged. A grow- tors as shown in other regions.12,13 Taken together ing body of evidence indicates that glutamate levels with the findings that glutamate is released in response rise in peripheral tissues in response to inflammation. to peripheral inflammation, the expression pattern of Increases in glutamate levels in the skin have been mGluR5 in the DRG led to the hypothesis that mGluRs found in response to inflammatory agents such as intra- may be transported and expressed on peripheral ter- plantar formalin.2 Electrical stimulation of the sciatic minals of sensory neurons, and that these receptors nerve results in a significant increase in glutamate might mediate a component of inflammatory hyperal- release in the hind paw of rats.3 Interestingly, stimu- gesia. As predicted, the expression of mGluR5 was lation of the sciatic nerve by a selective C fiber acti- clearly demonstrated by two independent groups.4,8 vator, capsaicin, also results in glutamate release in the Electron microscopic studies indicate that both rat hind paw,3 suggesting that nociceptive-specific pri- mGluR1 and mGluR5 are expressed on a subset of pre- mary afferent fibers are a source of peripheral gluta- dominantly nociceptive nerve terminals at the dermal- mate. Evidence for physiological relevance of this per- epidermal junction in the hind paw of mice.4 ipheral glutamate was obtained when intraplantar Additional studies at the microscopic level show injection of glutamate caused increased thermal and that mGluR5 colocalizes with ␤III tubulin in peripheral mechanical sensitivity in rats and mice.4–6 The poten- , and confirm that mGluR5 is expressed in a tial clinical importance of elevated glutamate levels in population of nociceptive-specific C fibers based on the periphery is supported by the finding that gluta- colocalization with the capsaicin , VR1.8 mate levels are markedly elevated in synovial fluid Based on the demonstration of peripheral expression from knee joints of arthritis patients.7 These findings of group I mGluRs, a series of experiments were carried suggest an important role for glutamate as a peripheral out that showed clearly that direct activation of group inflammatory pain mediator, and that inhibitors of glu- I mGluRs on these peripheral terminals leads to tamate release, glutamate receptors, or inhibitors of enhanced sensitivity to mechanical and thermal stim- intracellular glutamate-activated pathways may harbor uli.4,8 Intraplantar administration of either RS-DHPG, a important therapeutic potential. group I mGluR-selective agonist, or CHPG, an mGluR5- Three recent reports have highlighted the impor- selective agonist, induced thermal or mechanical tance of mGluRs on peripheral sensory neurons in the hypersensitivity in mice and rats. Intraplantar adminis- modulation of nociceptive transmission.4,8,9 These tration of CHPG increased the spontaneous firing of studies have utilized a combination of anatomical stud- wide dynamic range neurons in the dorsal horn of the ies, behavioral pharmacology, and electrophysiology to spinal cord, and this effect was reversed by intraplantar co-injection of MPEP, an mGluR5 receptor-selective antagonist.8 Furthermore, these studies show that pre- Correspondence: RW Gereau IV, Division of , Baylor treatment or co-injection of group I receptor antagon- College of Medicine, One Baylor Plaza, Houston, TX 77030, USA. ists prevented development of spontaneous pain E-mail: rgereauȰbcm.tmc.edu behavior induced by intraplantar formalin4 or carra- News & Commentary 616 geenan-induced inflammatory hypersensitivity.8 Thus, response to noxious stimuli such as heat, leading to the most important finding of these studies was that . antagonists of mGluR54,8 and mGluR14 reduced The therapeutic implications of these studies may be nociceptive hypersensitivity in mice and rats with significant. The main goal for treating pain is to safely already established inflammation. This effect was reduce persistent, pathologic pain without affecting observed in response to distinct inflammatory agents physiologic pain sensations. Peripheral application of and in two different species, suggesting that the find- analgesics provides a safer administration route by avo- ings are conserved. The fact that antagonists of mGluR1 iding systemic side effects and is currently utilized and 5 can reduce hyperalgesia during established with systemically dangerous agents, such as capsaicin inflammation is an important finding when consider- and lidocaine.16,17 Peripherally applied glutamate ing the potential clinical applicability of these antagon- receptor antagonists can reduce pain in various ists for painful neuropathies or inflammatory pain con- inflammatory pain models.4,5,18,19 However, amongst ditions such as arthritis. glutamate receptors, group I mGluRs may be the most Elucidation of the underlying molecular mechanisms useful peripheral targets. Group I mGluR antagonists by which group I mGluRs enhance thermal sensitivity not only prevent, but also attenuate established hyper- could suggest additional targets for the development of algesia. Ionotropic glutamate receptor antagonists fail analgesics. We propose that glutamate acting via group to reduce established pain in the formalin model,18 but I mGluRs may play a role in these peripheral processes can reverse pain in carageenan-based models.5,19 The through a variety of cellular mechanisms, as depicted difference between group I mGluR and ionotropic in Figure 1. Group I mGluRs activate depolarizing, Ca2+ antagonists may be their ability to attenuate pain based

activated, cation non-selective currents (ICa,N) in DRG solely on peripheral sensitization, such as carageenan neurons.11 In the , group I models,20 vs pain based both on peripheral activity and mGluRs also increase excitability by inhibiting potass- sensitization, such as the formalin model.21 Ionotropic ium conductances.1 In addition, group I mGluRs can antagonists seem active only against the former, while activate several protein kinases, which may potentiate group I mGluR antagonists may also be useful in the the function of receptors implicated in the production latter situation. Therefore, one would predict that of hyperalgesia, such as VR1, or voltage gated chan- group I mGluR antagonists applied peripherally should nels, such as the tetrodotoxin-resistant sodium chan- reduce established pain in a broad spectrum of pain nel.14,15 By inhibiting K+ channel function or enhancing states, including neuropathic pain, where spontaneous the function of channels such as VR1, Na+ channels or peripheral afferent activity plays a role.22 Indeed, intra-

ICa,N, activation of mGluRs by peripheral glutamate plantar administration of the mGluR5 antagonist, SIB- could increase the firing of sensory neurons in 1757, 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 inflam- mation, 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 News & Commentary 617 nia, while reversing thermal hyperalgesia completely 3 deGroot J et al. Neuroreport 2000; 11:497–502. in rats with experimental neuropathic pain elicited by 4 Bhave G et al. Nat Neurosci 2001; 4:417–423. 9 5 Jackson DL et al. Eur J Pharmacol 1995; 284:321–325. ligation. Taken together, these studies 6 Carlton SM et al. Neuroscience Lett 1995; 197:25–28. point to exciting possibilities for safely treating both 7 McNearney T et al. J Rheumatol 2000; 27: 739–745. inflammatory and neuropathic pain by targeting per- 8 Walker K et al. Neuropharmacology 2001; 40:10–19. ipheral group I mGluRs. 9 Dogrul A et al. Neurosci Lett 2000; 292:115–118. 10 Valerio A et al. Neurosci Res 1997; 28:49–57. 11 Crawford JH et al. J Neurophysiol 1997; 77: 2573–2584. F Karim, G Bhave and RW Gereau IV 12 Gereau RW, Conn PJ. J Neurosci 1995; 15: 6879–6889. Division of Neuroscience 13 Manzoni O, Bockaert J. Eur J Neurosci 1995; 7: 2518–2523. Baylor College of Medicine 14 Caterina MJ et al. Nature 1997; 389:816–824. One Baylor Plaza 15 Gold MS et al. J Neurosci 1998; 18: 10345–10355. 16 Rosenstein ED. Rheum Dis Clin North Am 1999; 25:899–918, viii. Houston, TX 77030, USA 17 Argoff CE. Clin J Pain 2000; 16 (2 Suppl): S62–S66. 18 Davidson EM et al. Neuroreport 1997; 8:941–946. 19 Lawand NB et al. Eur J Pharmacol 1997; 324:169–177. 20 Kocher L et al. Pain 1987; 29: 363–373. 21 McCall WD et al. Neurosci Lett 1996; 208:45–48. 1 Conn PJ, Pin J-P. Annu Rev Pharmacol Toxicol 1997; 37:205–237. 22 Devor M, Seltzer Z. In: Wall PD, Melzack R (eds).Textbook of Pain. 2 Omote K et al. Brain Res 1998; 787: 161–164. Churchill Livingstone: Edinburgh, 1999, pp 129–164.

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