Modulation of Chronic Pain by Metabotropic Glutamate Receptors

Abstract

Metabotropic glutamate receptors (mGluRs) belong to class C G-protein-coupled receptors. They are expressed throughout the nervous system on both neurons and glial cells. In the central nervous system (CNS), mGluRs are mainly located in the proximity of the synaptic cleft where they regulate glutamatergic transmission in addition to a number of other neurotransmitters. To date, eight subtypes of mGluRs (mGluR1–mGluR8) have been cloned and classified into three groups on the basis of sequence similarities, and pharmacological and biochemical properties. Consequently, group I mGluRs includes mGluR1 and mGluR5, group II mGluRs includes mGluR2 and mGluR3, and group III mGluRs consists of mGluR4, mGluR6, mGluR7, and mGluR8. With the exception of mGluR6, whose localization is restricted within the retina, all mGluRs are ubiquitously expressed throughout the peripheral and CNS with some subtype specificity in different anatomical regions. mGluRs participate in many physiological processes and play important roles in a number of neurological conditions including anxiety, depression, schizophrenia, and neurodegenerative disorders. mGluRs also participate in the physiological transmission of pain stimuli as well as to mechanisms involved in the establishment of chronic pain. Therefore, these receptors are attractive targets for therapeutic intervention in several neurological disorders including chronic pain. Thus, understanding the physiological function and role of each mGluR subtype in the development of chronic pain will provide a better insight into the potential use of subtype-selective drugs currently being developed as orthosteric or allosteric ligands.

Introduction

Pain is usually classified as either nociceptive, inflammatory, or neuropathic, according to its origin, symptoms, and underlying mechanisms (Costigan, Scholz, & Woolfet, 2009). Although this classification is very useful from a didactic point of view, it does not reflect the complexity of pain disorders in clinical conditions. In chronic pain patients, the presence of more than one component extremely complicates the assessment and management of pain (Baron & Binder, 2004). In this chapter, recent literature describing the role of glutamate transmission via metabotropic glutamate receptor (mGluR) subtypes in the pathophysiology of chronic pain is reviewed.

Glutamate is the main excitatory amino acid in the central nervous system (CNS) and is involved in brain function and pathology. As neurotransmitter, glutamate activates two different types of receptors: ionotropic glutamate receptors (iGluRs) and mGluRs. According to their response to different agonists, iGluRs have been further subdivided into three distinct types: N-methyl-d-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA), and kainate (KA) receptors (Hollmann and Heinemann, 1994, Monaghan et al., 1989). iGluRs are directly coupled to a membrane ion channel and mediate fast excitatory synaptic transmission. On the contrary, mGluRs are cell membrane receptors belonging to the class C of the G-protein-coupled receptor (GPCR) superfamily that modulate rather than mediate neuronal excitability and neurotransmitter release via G-protein-dependent and non-G-protein-dependent signaling pathways (Anwyl, 1999).

By activating iGluRs and/or mGluRs, glutamate participates not only in the physiological transmission of nociceptive information but also in the development of peripheral and central mechanisms of pain hypersensitivity (Latremoliere & Woolf, 2009). Glutamate plays a primary role in the increased synaptic efficacy occurring after injury, a mechanism that has been referred to activity-dependent central sensitization (Woolf, 1983). As for the hippocampal long-term potentiation (LTP) of the synaptic strength (Ji, Kohno, Moore, & Woolf, 2003) which is a key mechanism for memory consolidation (Nicoll, 2003), glutamate-induced plasticity is a fundamental step for the development of the so-called “memory of pain” that is the basis for the establishment of chronic pain symptoms such as hyperalgesia, allodynia, and spontaneous pain (Woolf, 1983). Both NMDA and AMPA receptors, together with a number of metabotropic receptors, can trigger central sensitization through an increase in intracellular calcium levels that activate intracellular pathways strengthening the excitatory synapse (Latremoliere & Woolf, 2009). The blockade of NMDA receptors consistently resulting in the prevention of hyperexcitability of nociceptive neurons suggests the potential use of NMDA antagonist in the treatment of pain hypersensitivity (Woolf & Thompson, 1991). However, besides the selective antagonists of the NMDA receptor NR2B subunit (Boyce et al., 1999), the direct blockade of glutamate transmission by iGluRs antagonists is known to have detrimental effects on learning and memory processes (Chizh, 2007, Nakazato et al., 2005, Wei et al., 2001, Zhang et al., 2009); therefore, an NMDA antagonist-based therapy for chronic pain is unlikely to be developed. Consequently, understanding the function, expression, and role of mGluRs in pain modulation and their involvement in the induction and maintenance of central sensitization may help to find a practicable alternative to reduce hypersensitivity in chronic pain conditions.