Inflammatory sensitization of nociceptors depends on activation of NMDA receptors in DRG satellite cells

Abstract

The present study evaluated the role of N-methyl-D-aspartate receptors (NMDARs) expressed in the dorsal root ganglia (DRG) in the inflammatory sensitization of peripheral nociceptor terminals to mechanical stimulation. Injection of NMDA into the fifth lumbar (L5)-DRG induced hyperalgesia in the rat hind paw with a profile similar to that of intraplantar injection of prostaglandin E 2 (PGE 2 ), which was significantly attenuated by injection of the NMDAR antagonist D(-)-2-amino-5-phosphonopentanoic acid (D-AP-5) in the L5-DRG. Moreover, blockade of DRG AMPA receptors by the antagonist 6,7-dinitroquinoxaline-2,3-dione had no effect in the PGE 2 -induced hyperalgesia in thepaw, showing specific involvement of NMDARs in this modulatory effect and suggesting that activation of NMDAR in the DRG plays an important role in the peripheral inflammatory hyperalgesia. In following experiments we observed attenuation of PGE 2 -induced hyperalgesia in the paw by the knockdown of NMDAR subunits NR1, NR2B, NR2D, and NR3A with antisense-oligodeoxynucleotide treatment in the DRG. Also, in vitro experiments showed that the NMDAinduced sensitization of cultured DRG neurons depends on satellite cell activation and on those same NMDAR subunits, suggesting their importance for the PGE 2 -induced hyperalgesia. In addition, fluorescent calcium imaging experiments in cultures of DRG cells showed induction of calcium transients by glutamate or NMDA only in satellite cells, but not in neurons. Together, the present results suggest that the mechanical inflammatory nociceptor sensitization is dependent on glutamate release at the DRG and subsequent NMDAR activation in satellite glial cells, supporting the idea that the peripheral hyperalgesia is an event modulated by a glutamatergic system in the DRG.T he involvement of excitatory amino acids in the transmission of the nociceptive information from the primary afferent neurons to the spinal cord is, at present, supported by an immense number of studies (1-3). In fact, a role of the amino acid glutamate (GLU) as a synaptic mediator has been demonstrated by electrophysiological experiments that showed its release by stimulation and consequent increase in the probability that the target cell will fire an action potential (3, 4). In addition, glutamatergic receptors, especially the N-methyl-D-aspartate receptor (NMDAR), detected throughout the entire nervous system (5, 6), have been associated with the development and maintenance of spinal cord neuron sensitization (7,8). Stimulation of spinal neurons by GLU through NMDARs was also associated to inflammatory processes (3, 9). For instance, sensitization of spinal nerves has been frequently related to the wind-up phenomenon, an increase in the electrical activity of spinal cord neurons and pain sensation independent of primary nociceptor input (10).The detection of glutamatergic receptors in the presynaptic membrane of afferent fibers associated with nociception and hyperalgesia raised the hypothesis that GLU released into the synaptic cleft cou...

The NMDA receptor functions independently and as an LRP1 co-receptor to promote Schwann cell survival and migration

“…Satellite glial cells in DRGs apparently express the NMDA-R, which might contribute to interactions with neurons (Castillo et al, 2013). NMDA-R activation in satellite cells has been linked to sensitization of nociceptors and peripheral hyperalgesia (Ferrari et al, 2014). The NMDA-R also has been identified in oligodendrocyte precursor cells, where it might function in differentiation and myelination (Li et al, 2013).…”

GluN2B N-methyl-D-aspartate receptor and excitatory amino acid transporter 3 are upregulated in primary sensory neurons after 7 days of morphine administration in rats

“…4). Since protein lysates from whole DRG include small and large neurons, as well as satellite glial cells, all of which express NMDARs [13; 42; 54], we used patch clamp recording to confirm neuron-specific upregulation. Patch clamp of DRG neurons confirmed that the GluN2B containing NMDARs were increased after morphine treatment, whereas AMPA, KA and mGluR1 receptor responses remained unchanged.…”

Physiological Roles of Non-Neuronal NMDA Receptors

“…In dorsal root ganglia (DRG) and at local sites of peripheral injury [58], for example, glutamate sensitizes sensory neurons to nociceptive stimulation in a manner dependent on NMDARs [59]. Satellite glial cells (SGCs) play an important role in this process by expressing glutamate transporters that regulate glutamate neurotransmission [60], but SGCs also express Ca 2+ -permeable, Mg 2+ -insensitive NMDARs required for sensitization of DRG neurons [61]. Although the involvement of SGC NMDARs in DRG sensitization remains to be demonstrated with conditional silencing approaches in vivo, these data highlight the possibility that PNS glial NMDARs are important nociceptive intermediates.…”