The Modulation of Pain by Metabotropic Glutamate Receptors 7 and 8 in the Dorsal Striatum

Abstract

The dorsal striatum, apart from controlling voluntary movement, displays a recently demonstrated pain inhibition. It is connected to the descending pain modulatory system and in particular to the rostral ventromedial medulla through the medullary dorsal reticular nucleus. Diseases of the basal ganglia, such as Parkinson's disease, in addition to being characterized by motor disorders, are associated with pain and hyperactivation of the excitatory transmission. A way to counteract glutamatergic hyperactivation is through the activation of group III metabotropic glutamate receptors (mGluRs), which are located on presynaptic terminals inhibiting neurotransmitter release. So far the mGluRs of group III have been the least investigated, owing to a lack of selective tools. More recently, selective ligands for each mGluR of group III, in particular positive and negative allosteric modulators, have been developed and the role of each subtype is starting to emerge. The neuroprotective potential of group III mGluRs in pathological conditions, such as those characterized by elevate glutamate, has been recently shown. In the dorsal striatum, mGluR7 and mGluR8 are located at glutamatergic corticostriatal terminals and their stimulation inhibits pain in pathological conditions such as neuropathic pain. The two receptors in the dorsal striatum have instead a different role in pain control in normal conditions. This review will discuss recent results focusing on the contribution of mGluR7 and mGluR8 in the dorsal striatal control of pain. The role of mGluR4, whose antiparkinsonian activity is widely reported, will also be addressed.

Keywords: chronic pain; descending pain modulatory system; dorsal striatum; hyperglutamatergism; mGluR7; mGluR8..

Fig. (1)

Schematic representation of the expression of mGluRs of group III within the ascending (white) and descending (black) pain pathways. Areas which are common to the two pathways are represented in grey. With the exception of mGluR6 that is confined to the retina, the other mGluR subtypes of group III are expressed in the peripheral, spinal and supraspinal structures of the pain neuraxis where they modulate responses to pain. PAG, periaqueductal grey; RVM, rostral ventromedial medulla; DH, dorsal horn; DRG, dorsal root ganglia.

Fig. (2)

Graphical representation of the expression of group III mGluR subtypes (mGluR4, mGluR7 and mGluR8) within the basal ganglia direct and indirect pathways. The cerebral cortex sends excitatory projections to the dorsal striatum, which in turn sends inhibitory projections which form two parallel pathways: the direct and indirect one. In the direct pathway, dorsal striatum sends inhibitory projections straight to the interal globus pallidus (GPi)/substantia nigra pars reticulata (SNr). In the indirect pathway, dorsal striatum sends inhibitory projections to the external globus pallidus (GPe), and hence to the subthalamic nucleus, which in turn sends excitatory projections to the GPi/SNr. This latter in turn sends inhibitory projections to the thalamus that finally comes back to the cortex through excitatory inputs. The distribution of group III mGluRs is represented by placing different symbols for each mGluR subtypes on axon terminals: triangle (mGluR4), circle (mGluR7) and square (mGluR8).

Fig. (3)

Schematic representation of the connection of the basal ganglia with the descending pain modulatory system. The convergence point among the two pathways lies into the dorsal reticular nucleus (DRt), a pronocicettive area projecting in turn to the rostral ventromedial medulla and to the dorsal horn of the spinal cord. The stimulation of mGluR7 in the dorsal striatum inhibits the output projections to the direct and indirect pathway of the basal ganglia. In normal conditions the stimulation of mGluR7 reduces the activity of dorsal striatum and its inhibitory control on DRt, the dis-inhibition of which produces pain facilitation: such effect involves the indirect pathway. In pathological conditions such as neuropathic pain, the stimulation of mGluR7 reduces the activity of dorsal striatum and its inhibitory control on GPi/SNr, the dis-inhibition of which depresses the pronociceptive activity of DRt and produces antinociception. This effect involves the direct pathway. Abbreviations: SNr/GPi, substantia nigra pars reticulata and the internal globus pallidus; DRt, dorsal reticular nucleus; RVM, rostral ventromedial medulla; GPi, internal globus pallidus; STN, subthalamic nucleus; DH, dorsal horn. Excitatory and inhibitory projections are represented by grey or black arrows, respectively. The indirect paway of the basal ganglia is represented by dotted line.