Spinal ephrinB/EphB signalling contributed to remifentanil‐induced hyperalgesia via NMDA receptor

Abstract

BackgroundOne of the major unresolved issues in treating pain is the paradoxical hyperalgesia produced by opiates, and accumulating evidence implicate that EphBs receptors and ephrinBs ligands are involved in mediation of spinal nociceptive information and central sensitization, but the manner in which ephrinB/EphB signalling acts on spinal nociceptive information networks to produce hyperalgesia remains enigmatic. The objective of this research was to investigate the role of ephrinB/EphB signalling in remifentanil-induced hyperalgesia (RIH) and its downstream effector.MethodsWe characterized the remifentanil-induced pain behaviours by evaluating thermal hyperalgesia and mechanical allodynia in a rat hind paw incisional model. Protein expression of EphB1 receptor and ephrinB1 ligand in spinal dorsal horn cord was determined by Western blotting, and Fos was determined by immunohistochemistry assay, respectively. To figure out the manner in which ephrinB/EphB signalling acts with N-methyl-d-aspartic acid (NMDA) receptor, we used MK-801, an antagonist of NMDA receptor, trying to suppressed the hyperalgesia induced by ephrinB1-Fc, an agonist of ephrinB/EphB.ResultsContinuing infusion of remifentanil produced a thermal hyperalgesia and mechanical allodynia, which was accompanied with increased protein expression of spinal-level EphB1 receptor, ephrinB1 ligand and Fos; what appeared above was suppressed by pretreatment with EphB1-Fc, an antagonist of ephrinB/EphB or MK-801, and increased pain behaviours induced by intrathecal injection of ephrinB1-Fc, an agonist of ephrinB/EphB, were suppressed by MK-801.ConclusionsOur findings indicated that ephrinB/EphB signalling is involved in RIH. EphrinB/EphB signalling might be the upstream of NMDA receptor.What's already known about this topic?EphBs receptors and ephrinBs ligands are involved in mediation of spinal nociceptive information and central sensitization.The combination of EphB receptor and N-methyl-d-aspartic acid receptor induces long-term potentiation that is critical for causing excitation of spinal neuron and pain hyperalgesia.What does this study add?EphrinB/EphB signalling is involved in remifentanil-induced hyperalgesia (RIH).EphrinB/EphB signalling might be the upstream of N-methyl-d-aspartic acid receptor in RIH.

Attenuation of Remifentanil-Induced Hyperalgesia by Betulinic Acid Associates with Inhibiting Oxidative Stress and Inflammation in Spinal Dorsal Horn

“…To determine the antinociceptive effect of BA in plantar incision model rats, the mechanical allodynia and thermal hyperalgesia were assayed in BA (25 mg/kg, i.g., 7 days) treated incision group (BA + I). According to our previous report and others, we established a stable RIH rat model in this sample size evidenced by the enhanced mechanical allodynia and thermal hyperalgesia [4,5,16,17].…”

“…After being anesthetized with sevoflurane, rats were subcutaneously infused with remifentanil for 30 min to a final dose of 40 μg/kg during plantar incision using an infusion pump as we and others previously reported [4,16]. The plantar surface of the right hind paw was sterilized and 1-cm longitudinal incision was made through the skin and fascia, starting at about 0.5 cm from the edge of the heel and extending towards the toes.…”

“…The paw withdrawal mechanical threshold (PWMT) was measured by the up-down method based on the previous reports [4,19]. The rat was placed into a transparent chamber (20 × 25 × 15 cm 3 ) with a metal mesh floor and the central plantar surface of the right hind paw was vertically touched using von Frey hairs with incremental stiffness.…”

“…The paw withdrawal thermal latency (PWTL) was measured as described in the previous reports [4,20]. The rat was placed in a clear chamber with a glass floor and the central plantar surface of the right hind paw was over the radiant heat source.…”

“…Unfortunately, intraoperative use of remifentanil usually results in prominent hyperalgesia, the socalled remifentanil-induced hyperalgesia (RIH) [1]. Al-Pharmacology 2018;102:300-306 DOI: 10.1159/000493144 though the activation of spinal N-methyl-D-aspartate (NMDA) receptor pathway is well known to play a key role in RIH, it is not feasible to attenuate RIH by inhibiting NMDA receptors owing to the inevitable side effects (e.g., psychogenia) [2][3][4]. Recently, the overproduction of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and reactive oxygen species (ROS) by remifentanil is reported to directly activate neuronal NMDA receptors and matrix metalloproteinase-9 (MMP-9) and facilitate RIH [5][6][7].…”