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

Abstract

The contribution of the peripheral nervous system to opiate-induced hyperalgesia (OIH) is not well understood. Here, we determined the changes in excitability of primary sensory neurons after sustained morphine administration for 7 days. Changes in expression of glutamate receptors and glutamate transporters after morphine administration were ascertained in dorsal root ganglions (DRGs). Patch clamp recordings from intact DRGs (ex-vivo preparation) of morphine-treated rats showed increased excitability of small diameter (≤ 30 μm) neurons with respect to rheobase and membrane threshold, whereas the excitability of large diameter (> 30 μm) neurons remained unchanged. Small diameter neurons also displayed increased responses to glutamate, which were mediated mainly by GluN2B containing NMDA receptors (NMDARs), and to a lesser degree by the neuronal excitatory amino acid transporter 3 /excitatory amino acid carrier 1 (EAAT3/EAAC1). Co-administration in vivo of the GluN2B selective antagonist Ro 25-6981 with morphine for 7 days prevented the appearance of OIH and increased morphine-induced analgesia. Administration of morphine for 7 days led to an increased expression of GluN2B and EAAT3/EAAC1, but not of the AMPA, kainate or Group I metabotropic glutamate receptors, or of the vesicular glutamate transporter 2 (VGLUT2). These results suggest that peripheral glutamatergic neurotransmission contributes to OIH and that GluN2B subunit of NMDARs in the periphery may be a target for therapy.

P2X4-receptor participates in EAAT3 regulation via BDNF-TrkB signaling in a model of trigeminal allodynia

“…Similar to our findings, Kerui GongM demonstrated that sustained administration of morphine for seven days resulted in hyperalgesia and upregulated EAAT3 in dorsal root ganglia neurons. 36 Previous studies of neuropathic pain also reported that spinal EAAT3 exhibits a biphasic change following chronic constriction nerve injury (CCI), with an initial upregulation followed by downregulation. 13 , 37 An explanation for EAAT3 downregulation may be that CCI results in degenerative changes in primary afferents.…”

N-acetyl-cysteine attenuates remifentanil-induced postoperative hyperalgesia via inhibiting matrix metalloproteinase-9 in dorsal root ganglia

“…The phosphorylation of MAPK family and the activation of glial cells in spinal dorsal horn induced by intraoperative remifentanil infusion can result in the production and release of multiple inflammatory mediators, and produce RIH [7, 36–38]. In addition to glia, the phosphorylation and activation of NMDAR in spinal neurons also resulted in the synaptic plasticity and enhanced sensory responses after intraoperative remifentanil infusion [4, 39–41]. The present study found that NAC can effectively decrease the phosphorylation of NR1, NR2B and MAPK family, decrease sensory neuron excitability and inhibit glial activation in spinal dorsal horn caused by remifentanil infusion.…”

Sustained Morphine Administration Induces TRPM8-Dependent Cold Hyperalgesia

“…35, 36 Briefly, rats were anaesthetized with sodium pentobarbital (40 mg/kg, i.p.). A lumbar laminectomy was performed; the L4 and L5 DRGs were removed and placed into carbogenized artificial cerebrospinal fluid (aCSF).…”

“…Animal studies have linked OIH to specific molecular changes involving the N-methyl-D-aspartate (NMDA) receptor, glutamate transporters, adenosine-A1 receptor, serotonin receptor, K+/Cl- co-transporter, transient receptor potential vanilloid 1 (TRPV1), ephrinB receptor, intracellular messenger molecules including mammalian target of rapamycin (mTOR), protein kinase A (PKA) and calcium/calmodulin-dependent protein kinase II (CaMKII), as well as epigenetic mechanisms. 2, 3, 35, 54, 76 …”