Roles of mGluRs in Pain Plasticity

Transmission of nociceptive (pain) signals from the periphery to the spinal cord occurs through sensory neurons whose cell bodies lie in dorsal root ganglia. Noxious stimuli to the periphery activate receptors on the sensory neuron terminal, causing it to fire action potentials resulting in release of its neurotransmitter, glutamate, from the axon terminals in the spinal cord. The sensory neuron terminals form synaptic contacts with neurons in the dorsal horn of the spinal cord, and these cells project to sensory centers in the brain. Glutamate released from the sensory neuron terminal exerts its actions on the dorsal horn neurons via activation of two major classes of receptors: the ionotropic glutamate receptors (iGluRs) and the metabotropic glutamate receptors (mGluRs). The iGluRs are ligand gated ion channels, and are composed of multimeric assemblies of channel subunits. The resulting channels include NMDA, AMPA, and kainate receptors, and these channels mediate fast synaptic transmission from the sensory neuron onto dorsal horn neurons. The mGluRs comprise a family of receptors coupled to various intracellular second messenger systems through G proteins, and these receptors mediate the neuromodulatory actions of glutamate. While there is clear evidence that multiple mGluR subtypes are expressed pre- and post-synaptically at the sensory neuron-dorsal horn neuron synapse and throughout the pain neuraxis, very little is known of the roles of mGluRs in regulating nociceptive transmission.  

Transmission at this "first" synapse from peripheral sensory neurons to central dorsal horn neurons can be profoundly and protractedly modified by experience. Both presynaptic and postsynaptic changes in transmission at this synapse are thought to underlie the development of chronic pain conditions. Several in vivo and in vitro models of pain plasticity have been developed and studied extensively, and in almost every case, plasticity at glutamatergic synapses in the spinal cord (as in the brain) requires activation of NMDA receptors. In many instances, this plasticity also requires or is modulated by activation of mGluR

Studies in our lab are aimed at determining which of the mGluR subtypes mediate the various actions of mGluR agonists in the cord and identifying the molecular mechanisms responsible for these effects. We utilize a variety of approaches, including behavioral analysis, patch clamp electrophysiology, molecular and biochemical analysis and genetics, to address these questions in mouse models of chronic pain conditions.

Our current studies are focusing on the role of mGluRs in three main regions of the pain neuraxis (the primary sensory neuron s, dorsal horn neurons, and the amygdala) to address the role of different mGluR subtypes and their signaling pathways in modulation of nociception. Current studies include:

• Modulation of thermal nociception and vanilloid receptor function by mGluRs expressed in primary afferent neurons.
• Activation of ERK signaling and modulation of downstream targets of ERKS by mGluRs in spinal cord dorsal horn neurons.
• The role of mGluRs and their signaling pathways in amygdala plasticity associated with inflammatory pain.