Decrease in the expression of N‐methyl‐D‐aspartate receptors in the nucleus tractus solitarii induces antinociception and increases blood pressure

Abstract

N-methyl-D-aspartate receptors (NMDAR) have a role in cardiovascular control at the nucleus tractus solitarii (NTS), eliciting increases or decreases in blood pressure (BP), depending on the area injected with the agonists. In spite of the association between cardiovascular control and pain modulation, the effects of manipulating NMDAR in pain responses have never been evaluated. In this study, we decreased the expression of NMDAR in the NTS using gene transfer to target receptor subunits and evaluate long-term effects. Seven days after the injection of lentiviral vectors containing the NR1a subunit cDNA of NMDAR, in antisense orientation, into the intermediate NTS of Wistar rats, BP was measured, and the formalin test of nociception was performed. The antisense vector induced a decrease of NR1 expression in the NTS and elicited BP rises and hypoalgesia. Antisense vectors inhibited formalin-evoked c-Fos expression in the spinal cord, indicating decreased nociceptive activity of spinal neurons. Using a time-course approach, we verified that the onset of both the increases in BP and the hypoalgesia was at 4 days after vector injection into the NTS. The injection of NMDA into the NTS reversed the effects of antisense vectors in pain behavioral responses and spinal neuronal activation and decreased BP and heart rate. The present study shows that the NR1 subunit of the NMDAR at the NTS is critical in the regulation of tonic cardiovascular and nociceptive control and shows an involvement of the nucleus in the modulation of sustained pain.

Frequency‐dependent facilitation of synaptic throughput via postsynaptic NMDA receptors in the nucleus of the solitary tract

“…; Marques‐Lopes et al . ). However, the specific mechanism(s) by which they contribute to the fidelity of transmission across afferent–NTS neuron synapses are not well understood.…”

“…; Marques‐Lopes et al . ). Consistent with our model, NMDA‐R antagonists only attenuate aortic baroreceptor reflexes initiated by high frequency afferent discharge, while AMPA‐Rs contribute to responses mediated by both low and high afferent discharge (Gordon & Leone, ).…”

“…; Marques‐Lopes et al . ). Electrophysiological experiments have clearly established that AMPA‐R activation following vagal afferent stimulation triggers fast excitatory postsynaptic currents (EPSCs) in NTS neurons (Andresen et al .…”

Norepinephrine and dopamine transmission in 2 limbic regions differentially respond to acute noxious stimulation

“…The medullar (NST and A1) populations are positioned to relay sensory, visceral, cardiorespiratory and nociceptive information between the peripheral and central nervous systems [46; 49]. Studies have found a role for the NST in the baroreflex to noxious thermal stimulation [22] and in the tonic control of nociceptive thresholds [32]. Furthermore, medullar catecholamine neurons are activated by visceral pain [21].…”

GABA acting on GABAB receptors located in a medullary pain facilitatory area enhances nociceptive behaviors evoked by intraplantar formalin injection

“…The 1-week time point was chosen based on previous reports showing that the human synapsin promoter is fully active at this time 22,28,56 and taking into account the time necessary for the retrograde transport of CTb from the DRt to its brain afferents. 1 …”