NMDA receptor mediates chronic visceral pain induced by neonatal noxious somatic stimulation

Abstract

NMDA receptors (NMDAR) are important in the development and maintenance of central sensitization. Our objective was to investigate the role of spinal neurons and NMDAR in the maintenance of chronic visceral pain. Neonatal rats were injected with acidic saline adjusted to pH4.0 in the gastrocnemius muscle every other day for 12 days. In adult rats, NR1 and NR2B subunits were examined in the lumbo-sacral (LS) spinal cord. A baseline, visceromotor response (VMR) to graded colorectal distension (CRD) was recorded before and after administration of the NMDA antagonist, CGS-19755. Extracellular recordings were performed from CRD-sensitive LS spinal neurons and pelvic nerve afferents (PNA) before and after CGS-19755. Rats that received pH 4.0 saline injections demonstrated a significant increase in the expression NR2B subunits and VMR response to CRD >20mmHg. CGS-19755 (i.v. or i.t.) had no effect in naïve rats, but significantly decreased the response to CRD in pH4.0 saline injected rats. CGS-19755 had no effect on the spontaneous firing of SL-A, but decreased that of SL-S. Similarly, CGS-19755 attenuates the responses of SL-S neurons to CRD, but had no effect on SL-A neurons or on the response characteristics of PNA fibers. Neonatal noxious somatic stimulation results in chronic visceral hyperalgesia and sensitizes a specific subpopulation of CRD-sensitive spinal neurons. The sensitization of these SL-S spinal neurons is attenuated by the NMDAR antagonist. The results of this study suggest that spinal NMDARs play an important role in the development of hyperalgesia early in life.

Pharmacokinetics and physiologic/behavioral effects of buprenorphine administered sublingually and intravenously to neonatal foals

“…The American Veterinary Medical Association (AVMA) has stated that “animal pain and suffering are clinically important conditions that adversely affect an animal's quality of life” (American Veterinary Medical Association, ). In addition to the negative impact that occurs at the time of the painful insult, untreated pain in both human and animal neonates may cause hypersensitivity to subsequent painful procedures (McCracken, Waran, Mitchinson, & Johnson, ; Page, ; Taddio, Goldbach, Ipp, Stevens, & Koren, ; Taddio, Katz, Ilersich, & Koren, ) and an increased propensity for long‐term pain (Hermann, Hohmeister, Demirakca, Zohsel, & Flor, ; Miranda et al., ; Page, ; Ren et al., ; Sanada et al., ; Walker, Tochiki, & Fitzgerald, ). These nociceptive responses can be alleviated with the appropriate use of analgesia during the initial painful stimulus (Page, ; Taddio et al., ).…”

Gabapentin Effects on PKC-ERK1/2 Signaling in the Spinal Cord of Rats with Formalin-Induced Visceral Inflammatory Pain

“…In contrast to the extensive literature of somatic pain, studies addressing the mechanism of visceral pain currently remain preliminary. Furthermore, the clinical therapeutic management of visceral pain remains less satisfactory than that of somatic pain, and studies investigating the mechanism of visceral pain with the aim of identifying new therapeutic targets have produced little success [ 1 – 5 ].…”

Early life esophageal acid exposure reduces expression of NMDAR1 in the adult rat dorsal hippocampus and medial prefrontal cortex: Potential relationship with hyperlocomotion

“…1,2 Animal studies have demonstrated that early life stress can lead to behavioral abnormalities and visceral hypersensitivity in adulthood. [3][4][5] Due to a high degree of central neuroplasticity in early life, either chronic or acute exposure to nociceptive stimulus during this period can lead to central sensitization-mediating visceral hypersensitivity. 6 Synaptic plasticity, mediated by the N-methyl-D-aspartate receptor (NMDAR), has been found to be involved in cerebral functions ranging from memory formation to the development of visceral hypersensitivity.…”