deltorphin and Disease-Models--Animal

Several studies have demonstrated that intraoperative remifentanil infusions have been associated with opioid-induced hyperalgesia (OIH). Activation of delta opioid receptor (DOR) and augmentation of N-methyl-d-aspartate (NMDA) receptor expression and function may play an important role in the development of OIH. The aim of this study was to investigate whether DOR inhibition could prevent remifentanil-induced hyperalgesia via regulating spinal NMDA receptor expression and function in vivo and in vitro.. A rat model of remifentanil-induced postoperative hyperalgesia was performed with the DOR agonist deltorphin-deltorphin II or the DOR antagonist naltrindole injected intrathecally 10 min before remifentanil infusion. Mechanical and thermal hyperalgesia were measured at -24h, 2, 6, 24 and 48 h after remifentanil infusion. Western blot was applied to detect the membrane and total expression of DOR and NMDA receptor subunits (NR1, NR2A and NR2B) in spinal cord L4-L6 segments. In addition, whole-cell patch-clamp recording was used to investigate the effect of DOR inhibition on NMDA receptor-induced current in spinal cord slices in vitro.. We found that membrane trafficking of DOR, NR1 and NR2B subunits in the spinal cord increased after remifentanil administration and surgery. The DOR antagonist naltrindole could attenuate mechanical and thermal hyperalgesia without affecting baseline nociceptive threshold, reduce membrane expression of DOR and decrease the membrane and total expressions of NR1 and NR2B subunits. Furthermore, the amplitude and the frequency of NMDA receptor-induced current were significantly increased by remifentanil incubation in neurons of the dorsal horn, which was reversed by the application of naltrindole.. The above results indicate that inhibition of DOR could significantly inhibit remifentanil-induced hyperalgesia via modulating the total protein level, membrane trafficking and function of NMDA receptors in the dorsal horn of spinal cord, suggesting that naltrindole could be a potential anti-hyperalgesic agent for treating OIH.

Topics: Anesthetics, Intravenous; Animals; Disease Models, Animal; Hot Temperature; Hyperalgesia; Lumbar Vertebrae; Male; Naltrexone; Narcotic Antagonists; Oligopeptides; Pain Threshold; Pain, Postoperative; Piperidines; Posterior Horn Cells; Random Allocation; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Receptors, Opioid, delta; Remifentanil; Spinal Cord; Tissue Culture Techniques; Touch

This study was conducted to test the hypothesis that opioid receptor (OR)-mediated cardioprotection is agonist specific when administered prior to coronary artery occlusion and reperfusion in a rat model.. Anesthetized open-chest male Wistar rats were subjected to 45 minutes of left coronary artery occlusion and 2 hours of reperfusion. Opioid agonists were infused 15 minutes prior to coronary artery occlusion. Two control groups and 15 opioid-treated groups were studied. Controls were infused with either saline alone (n = 16) or dimethyl sulfoxide plus hydroxypropyl-β-cyclodextrin in saline (n = 19). The μ-selective agonist DAMGO was infused at either 150 nmol/kg (n = 15) or 1500 nmol/kg (n = 14), and dermorphin-H was infused at 150 nmol/kg (n = 14). The δ₁ -selective agonist d-Pen²(,)⁵ enkephalin (DPDPE) was infused at 150 nmol/kg (n = 16) or 1500 nmol/kg (n = 14). The δ₂ -selective agonists deltorphin II (n = 16), deltorphin-D(variant) (n = 15), and deltorphin-E (n = 14) were infused at 150 nmol/kg. The selective κ₁ opioid agonist U-50488 was infused at 240 nmol/kg (n = 14), 1500 nmol/kg (n = 14), and 2,400 nmol/kg (n = 14). The selective κ₂ opioid agonist GR-89696 was infused at 150 nmol/kg (n = 14) and 1500 nmol/kg (n = 15). Orphinan FQ (nociceptin), also referred to as OR-like 1 (ORL1), was infused at 220 nmol/kg (n = 15) and 1500 nmol/kg (n = 15). The infarct size/area at risk (IS/AAR) ratio was determined after reperfusion by negative staining with patent blue violet dye. Hemodynamic parameters including heart rate, mean arterial blood pressure (MAP), and rate pressure product (RPP) were determined.. Pretreatment with the δ₂ OR agonist deltorphin II (150 nmol/kg) significantly reduced the IS/AAR ratio, while deltorphin-D(variant) and deltorphin-E did not exhibit an infarct-sparing effect at that treatment dose. Activation of δ₁ OR by DPDPE, κ₁ OR by U-50488, κ₂ OR by GR-89696, μ OR by DAMGO, dermorphin-H, and nociceptin had no effect on the IS/AAR ratio. U-50488 at 2,400 nmol/L induced a bradycardic effect. All other opioids had no effect on hemodynamic parameters at the doses tested.. Peripheral δ₂ OR activation by deltorphin II induces infarct size reduction in this animal model. Agonists of μ, δ₁, κ₁, κ₂, and nociceptin receptors at the doses tested did not induce cardiac tolerance to ischemia/reperfusion injury in vivo.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Animals; beta-Cyclodextrins; Coronary Stenosis; Disease Models, Animal; Excipients; Hemodynamics; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Oligopeptides; Random Allocation; Rats; Rats, Wistar; Receptors, Opioid