Actions of the systemically active metabotropic glutamate antagonist MPEP on sensory responses of thalamic neurones

Abstract

It is known that metabotropic glutamate receptors of the subtypes mGlu1 and mGlu5 participate in nociceptive processing in the thalamus, an area of prime importance in supra-spinal sensory processing. Antagonists of these receptors thus have potential as centrally-acting analgesics. We have investigated whether intravenous administration of the novel mGlu5-receptor antagonist 6-methyl-2-(phenylethynyl)-pyridine (MPEP) is able to reduce nociceptive responses of thalamic neurones. Extracellular recordings were made from single thalamic neurones of adult male Wistar rats anaesthetised with urethane. MPEP (1 mg/kg) reduced neuronal responses to noxious thermal stimuli to a mean of 24±4% of control within 10 min, whereas saline injections had no significant effect. Partial recovery was seen within 30–45 min after injection. Responses of neurones to non-noxious stimuli were not significantly affected by MPEP administration. In addition, MPEP caused an increase in the power of the slow-wave component (<1 Hz) of the electroencephalogram (EEG), but had no significant effect on peak frequency of the EEG or on heart rate. These results confirm that nociceptive responses of thalamic neurones are mediated in part by mGlu5 receptors. Furthermore, the effectiveness of intravenous MPEP suggests that such antagonists may be useful as centrally-acting analgesics.

Introduction

The role of metabotropic glutamate (mGlu) receptors in central synaptic processing has become well-established (Conn and Pin, 1997), and several studies have indicated that they play a role in nociceptive processing at various levels of the neuraxis. The mGlu receptors can be placed into one of three Groups (I–III) on the basis of their sequence homology, their agonist and antagonist pharmacology, and their coupling to intracellular transduction mechanisms in expression systems (Nakanishi, 1992, Conn and Pin, 1997). The Group I (mGlu1 and mGlu5) receptors, which are known to couple to postsynaptic inositol phosphate metabolism (Conn and Pin, 1997), have in particular been implicated in nociceptive responses in the periphery, the spinal cord and the thalamus (Eaton et al., 1993, Neugebauer et al., 1994, Fisher and Coderre, 1996, Fundytus et al., 1998, Salt and Turner, 1998, Young et al., 1998, Bowes et al., 1999, Chen et al., 2000). Although mGlu receptor antagonists of varying selectivity and potency have been available for a number of years, it is only recently that Group I antagonists that are centrally-active following peripheral administration have become available (Gasparini et al., 1999).

The ventrobasal (VB) thalamus is of prime importance in the relay and processing of somatosensory information en route from the spinal cord to the cerebral cortex (Jones, 1985). Neurones responsive to noxious stimuli have been identified in this area in several species (Guilbaud et al., 1980, Kenshalo et al., 1980, Yokota et al., 1988), and this area has been suggested to be important in the sensory-discriminatory aspects of pain (Peschanski et al., 1983). Previous work from this laboratory has shown that both mGlu1 and mGlu5 receptors appear to participate in responses of rat thalamic neurones to noxious thermal stimuli (Eaton et al., 1993, Salt and Eaton, 1994, Salt and Turner, 1998, Salt and Binns, 2000). This raises the possibility that antagonists of these receptors may be suitable as analgesics with a supra-spinal site of action. The novel antagonist MPEP has been shown to be selective for mGlu5 receptors in a number of in vitro and in vivo tests, and to be centrally-active after intravenous (i.v.) administration (Gasparini et al., 1999). We have therefore investigated whether i.v. administration of this compound, at a dose that is known to be selective for mGlu5 receptors (Gasparini et al., 1999), is able to reduce nociceptive responses of thalamic neurones. Some of these results have been presented in abstract form (Salt et al., 1999a, Salt et al., 1999b).