Metabotropic glutamate receptor subtype 5 (mGlu5) and nociceptive function

Abstract

The excitatory neurotransmitter, glutamate, is particularly important in the transmission of pain information in the nervous system through the activation of ionotropic and metabotropic glutamate receptors. A potent, subtype-selective antagonist of the metabotropic glutamate-5 (mGlu5) receptor, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), has now been discovered that has effective anti-hyperalgesic effects in models of inflammatory pain. MPEP did not affect rotarod locomotor performance, or normal responses to noxious mechanical or thermal stimulation in naı̈ve rats. However, in models of inflammatory pain, systemic administration of MPEP produced effective reversal of mechanical hyperalgesia without affecting inflammatory oedema. In contrast to the non-steroidal anti-inflammatory drugs, indomethacin and diclofenac, the maximal anti-hyperalgesic effects of orally administered MPEP were observed without acute erosion of the gastric mucosa. In contrast to its effects in models of inflammatory pain, MPEP did not produce significant reversal of mechanical hyperalgesia in a rat model of neuropathic pain.

Introduction

Glutamate has long been recognised to play a principal role in the transmission of pain within the nervous system (Dickenson et al., 1997). The actions of glutamate are mediated either through interaction with ionotropic glutamate (iGlu) receptor channels or by G protein-coupled metabotropic glutamate (mGlu) receptors that are linked to the modulation of second messenger systems (Salt, 1986; Baranauskas and Nistri, 1998). A specific role for group I mGlu receptors (mGlu1 and mGlu5 receptors) in nociceptive processing has been demonstrated by pharmacological, immunohistochemical and in situ hybridisation (Vidnyanszky et al., 1994; Romano et al., 1995, Romano et al., 1996; Valerio et al., 1997; Fisher and Coderre, 1998; Boxall et al., 1998a; Berthele et al., 1999; Jia et al., 1999). A role of dorsal horn group I mGlu receptors, particularly the mGlu1 receptor, in acute nociception has been described in behavioural (Fisher and Coderre, 1996a, Fisher and Coderre, 1996b; Young et al., 1997; Fisher et al., 1998) and electrophysiological studies in vitro (Boxall et al., 1998b) or in vivo (Neugebauer et al., 1999). Both mGlu1 and mGlu5 receptor subtypes are functionally expressed in the rat ventrobasal thalamus (Salt et al., 1999a, Salt et al., 1999b). mGlu1 receptor antagonists have been shown to reduce responses of single rat thalamic somatosensory neurones excited by the application of a noxious thermal stimulus to the receptive field (Salt and Turner, 1998).

Nevertheless, the lack of subtype-selective agonists and antagonists has made it difficult to further define the respective roles of mGlu1 and particularly mGlu5 receptors in nociceptive processes. Recently, the use of screening assays based on agonist-induced changes in intracellular calcium concentrations or phosphoinositide (PI) hydrolysis in a cell line expressing the human mGlu5a (hmGlu5a) receptor led to the discovery of 2-methyl-6-(phenylazo)-pyridin-3-ol, a selective antagonist of the human mGlu5 receptor (Daggett et al., 1995; Veliçelebi et al., 1998; Varney et al., 1999). Derivatisation of this compound produced the more potent antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), with an IC₅₀ of 32 nM on the human mGlu5a receptor in the PI hydrolysis assay (Gasparini et al., 1999). MPEP inhibited dihydroxyphenylglycine (DHPG)-stimulated PI hydrolysis in neonatal rat brain slices with potency and selectivity similar to that observed for human mGlu5 receptors (Gasparini et al., 1999).

In this study we have examined the effects of selective antagonism of the mGlu5 receptor in rat models of pain. Chronic pain syndromes, such as those associated with persistent inflammation or nerve injury, have been shown to differ dramatically in terms of their receptor pharmacology and their therapeutic response to different pharmaceutical agents (Walker et al., 1999). Therefore, we tested the effects of systemic mGlu5 antagonist treatment in a variety of rat pain models, including acute, inflammatory and neuropathic pain, where it was compared to drugs with proven efficacy in comparable human chronic pain syndromes. Systemic mGlu5 antagonist treatment produced significant reversal of inflammatory hyperalgesia in the absence of locomotor side effects, as measured in the rat rotarod assay. Acute gastric erosion is a side effect of many non-steroidal anti-inflammatory drugs (NSAIDs) used for the clinical treatment of inflammatory pain (Allison et al., 1992). Therefore, we compared the acute gastric erosion produced following oral administration of NSAIDs or MPEP in the rat.