scholarly journals Agmatine preferentially antagonizes GluN2B-containing N-methyl-d-aspartate receptors in spinal cord

2019 ◽  
Vol 121 (2) ◽  
pp. 662-671
Author(s):  
Jonathan J. Waataja ◽  
Cristina D. Peterson ◽  
Harsha Verma ◽  
Cory J. Goracke-Postle ◽  
Philippe Séguéla ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Chronic Pain ◽  
Nmda Receptor ◽  
Side Effects ◽  
Dorsal Horn ◽  
Motor Impairment ◽  
Spinal Cord Dorsal Horn ◽  
Decay Kinetics ◽  
Mouse Spinal Cord ◽  
Dorsal Horn Neurons

The role of the N-methyl-d-aspartate receptor (NMDAr) as a contributor to maladaptive neuroplasticity underlying the maintenance of chronic pain is well established. Agmatine, an NMDAr antagonist, has been shown to reverse tactile hypersensitivity in rodent models of neuropathic pain while lacking the side effects characteristic of global NMDAr antagonism, including sedation and motor impairment, indicating a likely subunit specificity of agmatine’s NMDAr inhibition. The present study assessed whether agmatine inhibits subunit-specific NMDAr-mediated current in the dorsal horn of mouse spinal cord slices. We isolated NMDAr-mediated excitatory postsynaptic currents (EPSCs) in small lamina II dorsal horn neurons evoked by optogenetic stimulation of Nav1.8-containing nociceptive afferents. We determined that agmatine abbreviated the amplitude, duration, and decay constant of NMDAr-mediated EPSCs similarly to the application of the GluN2B antagonist ifenprodil. In addition, we developed a site-specific knockdown of the GluN2B subunit of the NMDAr. We assessed whether agmatine and ifenprodil were able to inhibit NMDAr-mediated current in the spinal cord dorsal horn of mice lacking the GluN2B subunit of the NMDAr by analysis of electrically evoked EPSCs. In control mouse spinal cord, agmatine and ifenprodil both inhibited amplitude and accelerated the decay kinetics. However, agmatine and ifenprodil failed to attenuate the decay kinetics of NMDAr-mediated EPSCs in the GluN2B-knockdown mouse spinal cord. The present study indicates that agmatine preferentially antagonizes GluN2B-containing NMDArs in mouse dorsal horn neurons. NEW & NOTEWORTHY Our study is the first to report that agmatine preferentially antagonizes the GluN2B receptor subunit of the N-methyl-d-aspartate (NMDA) receptor in spinal cord. The preferential targeting of GluN2B receptor is consistent with the pharmacological profile of agmatine in that it reduces chronic pain without the motor side effects commonly seen with non-subunit-selective NMDA receptor antagonists.

The effect of tail-docking neonate piglets on ATF-3 and NR2B immunoreactivity in coccygeal dorsal root ganglia and spinal cord dorsal horn neurons: Preliminary data

2012 ◽  
Vol 3 (3) ◽  
pp. 184-185
Author(s):  
D.A. Sandercock ◽  
A. Monteiro ◽  
E.M. Scott ◽  
A.M. Nolan
Keyword(s):  
Spinal Cord ◽  
Chronic Pain ◽  
Dorsal Horn ◽  
Dorsal Root Ganglia ◽  
Dorsal Root ◽  
Spinal Cord Dorsal Horn ◽  
Neuronal Regeneration ◽  
Neonatal Piglets ◽  
Dorsal Horn Neurons ◽  
Tail Docking

AbstractBackground/aimsTail docking neonatal piglets remains a controversial animal welfare issue. Although banned in the UK, it is widely practiced in many countries as a safeguard against tail biting among pigs reared in intensive systems. Concerns exist whether tail docking can induce chronic pain in later life. This preliminary study examined the effects of partial tail amputation on activating transcription factor 3 (ATF3), a marker of peripheral nerve injury and regeneration and NMDA-glutamate receptor NR2B subunit which participates in the mediation of chronic pain.MethodsProcedures were performed according to the ethical guidelines for the study of experimental pain in animals. Six piglets (2–3 days old) were tail-docked (a portion of the tail amputated with sterile surgical cutters), six piglets (2–3 days old) were sham-docked. Three animals from each treatment were euthanised 7 and 56 days post-amputation. Coccygeal dorsal root ganglia (DRG) and spinal cord were collected post-mortem for immunohistochemistry.ResultsATF3 immunoreactivity (IR) was significantly increased (p <0.05) in the DRG neurons from tail-docked piglets 7 days after tail amputation, compared with sham-docked piglets. ATF3-IR was not different in sham and tail-docked piglets 56 days post amputation. NR2B-IR was significantly increased (p < 0.05) in dorsal horn neurons in tail-docked piglets compared with intact piglets 7 days after docking. There was no difference in NR2B-IR in neurons 56 days post amputation, compared with intact piglets.ConclusionsIncreased ATF3 and NR2B-IR 7 days after tail-docking suggests that injury to the peripheral nerves in the tail was sufficient to trigger neuronal regeneration and altered dorsal horn signaling respectively, however the effects of tail-docking on neuronal regeneration and nociceptive signaling were relatively short lasting. Tail-docking neonatal piglets does not cause sustained changes in ATF3, which might suggest ongoing nerve fibre damage and NR2B which might be implicated in chronic pain.

Response Characteristics of Spinal Cord Dorsal Horn Neurons in Chronic Allodynic Rats After Spinal Cord Injury

2004 ◽  
Vol 92 (3) ◽  
pp. 1391-1399 ◽  
Author(s):  
Jing-Xia Hao ◽  
Ron C. Kupers ◽  
Xiao-Jun Xu
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Chronic Pain ◽  
Dorsal Horn ◽  
Spinal Cord Dorsal Horn ◽  
Cold Stimulation ◽  
Response Characteristics ◽  
Dorsal Horn Neurons ◽  
Cord Injury ◽  
Wdr Neurons

The physiological mechanisms of chronic pain in patients with spinal cord injury (SCI) are poorly understood. In the present study, we explored response characteristics of dorsal horn neurons of spinally injured rats exhibiting chronic pain (pain-like response to innocuous mechanical and cold stimulation). Several abnormalities were found in the distribution and response characteristics of dorsal horn neurons in chronic allodynic rats. First, 17% of the recorded neurons (vs. 0% in control animals) had no receptive field. Most of these units were located at or close to the lesioned spinal segment, and they discharged spontaneously at high frequencies. Allodynic rats also showed a significant decrease in the proportion of low-threshold (LT) neurons and an increase in the proportion of wide dynamic range (WDR) neurons. The rate of spontaneous activity of high-threshold (HT) neurons was significantly higher in allodynic compared with control rats. Moreover, HT neurons in allodynic animals showed increased neuronal responses to mechanical stimulation. WDR neurons responded with higher discharge rates to innocuous von Frey hair stimulation in allodynic compared with control rats. The percentage of WDR and HT neurons showing afterdischarges to noxious pinch was also significantly increased in the allodynic rats. The proportion of WDR and HT neurons responding to innocuous cold stimulation respectively increased from 53 and 25% in control rats to 91 and 75% in allodynic animals. These results suggest that the chronic pain-like behaviors in spinally injured rats may be generated and maintained by abnormalities in dorsal horn neurons.

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