Metabotropic glutamate receptors as novel therapeutic targets on visceral sensory pathways

Abstract

Metabotropic glutamate receptors (mGluR) have a diverse range of structures and molecular coupling mechanisms. There are eight mGluR subtypes divided into three major groups. Group I (mGluR1 and 5) is excitatory; groups II (mGluR2 and 3) and III (mGluR 4, 6, and 7) are inhibitory. All mGluR are found in the mammalian nervous system but some are absent from sensory neurons. The focus here is on mGluR in sensory pathways from the viscera, where they have been explored as therapeutic targets. Group I mGluR are activated by endogenous glutamate or constitutively active without agonist. Constitutive activity can be exploited by inverse agonists to reduce neuronal excitability without synaptic input. This is promising for reducing activation of nociceptive afferents and pain using mGluR5 negative allosteric modulators. Many inhibitory mGluR are also expressed in visceral afferents, many of which markedly reduce excitability. Their role in visceral pain remains to be determined, but they have shown promise in inhibition of the triggering of gastro-esophageal reflux, via an action on mechanosensory gastric afferents. The extent of reflux inhibition is limited, however, and may not reach a clinically useful level. On the other hand, negative modulation of mGluR5 has very potent actions on reflux inhibition, which has produced the most likely candidates so far as therapeutic drugs. These act probably outside the central nervous system, and may therefore provide a generous therapeutic window. There are many unanswered questions about mGluR along visceral afferent pathways, the answers to which may reveal many more therapeutic candidates.

Keywords: gastro-esophageal reflux; lower esophageal sphincter; vagal afferents; visceral pain.

Figure 1

Classification of Glutamate receptors.

Figure 2

Responses of gastro-esophageal vagal afferents to mechanical stimulation in mice deficient in mGluR4 (A*) or mGluR8 (B). (i) The effects of disrupting mGluR on the responses to circumferential tension (average impulses s⁻¹ over stimulus duration of 1 min) of tension receptors. (ii) The effects of disrupting mGluR on the responses to mucosal stroking (impulses per stroke, mean of eight strokes) of mucosal receptors. The graphs show the mean ± SEM. Significant differences between mGluR+/+ (•) and −/− (◦) mice (assessed using two-way ANOVA) is indicated adjacent to the response curves (*p < 0.05). n = number of afferents recorded. *Previously presented. The metabotropic glutamate receptor mGluR4 is required for normal visceral mechanotransduction (Page et al., 2004).

Figure 3

Mechanism of mGluR action on transient lower esophageal sphincter relaxations (TLESR). Vagal tension receptors in the proximal stomach detect stretch of the wall by gastric content. They project into the brainstem where they synapse mainly on interneurons. A central program generator is triggered which probably comprises several inhibitory and excitatory neurons interacting pre- and post-synaptically. The output from the program generator is an episodic, powerful activation of vagal efferents projecting to the myenteric plexus of the LES. At this point they activate inhibitory intrinsic motorneurons which release inhibitory transmitter onto smooth muscle. mGluR may be found at several points throughout this circuit, both peripherally and centrally. Their role appears to be mainly presynaptic, and in some cases mainly peripheral (see text). Their role within the program generator and along vagal motor pathways is not known.