naltrindole and Nervous-System-Diseases

Opioid agonists have been implicated in neuroprotection from hypoxic injury through regulating mitogen-activated protein kinases and cytokines. We determined the effects of remifentanil in focal brain ischemia and reperfusion (I/R) injury. Mechanisms linked to mitogen-activated protein kinases, including extracellular signaling-regulated kinase (ERK) 1/2, p38 kinases, and c-Jun N-terminal kinase (JNK), and various cytokines were also examined.. Male Sprague-Dawley rats were subjected to an I/R insult consisting of 90 minutes' middle cerebral artery occlusion (MCAO) followed by reperfusion under general anesthesia. Neurological deficit scores and infarct volume were determined after 24 hours of reperfusion. Remifentanil (5 μg/kg/min) was given alone or combined with naltrindole (δ-opioid receptor antagonist; 1 mg/kg), D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH(2) (μ-opioid receptor antagonist; 1 mg/kg), or 5'-guanidinonaltrindole (κ-opioid receptor antagonist; 1 mg/kg). Opioid antagonists were administered 20 minutes before MCAO. Remifentanil infusion was started 10 minutes before MCAO and continued throughout. The control group was without drugs. The expression levels of ERK1/2, p38, and JNK, and also those of tumor necrosis factor-α (TNF-α) and interleukin-6, were determined after 1, 3, and 24 hours of reperfusion.. Remifentanil significantly improved the functional outcome and reduced the infarct volumes (69.0±24.3 mm(3) vs. 108.9±24.8 mm(3)), which were not affected by D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH(2) or 5'-guanidinonaltrindole, but were abolished by naltrindole. The I/R insult enhanced the phosphorylation of ERK 1/2 and the expression of TNF-α, which were significantly reduced by remifentanil. Neither the phosphorylation of p38 and JNK nor the production of interleukin-6 was altered throughout the experiment.. Remifentanil may be neuroprotective against focal I/R injury, possibly through the activation of δ-opioid receptors and attenuation of ERK 1/2 activity and TNF-α production, in the rat brain.

Topics: Anesthetics, Intravenous; Animals; Blood Pressure; Blotting, Western; Carbon Dioxide; Dose-Response Relationship, Drug; Infarction, Middle Cerebral Artery; Interleukin-6; Ischemic Attack, Transient; Male; Mitogen-Activated Protein Kinases; Naltrexone; Narcotic Antagonists; Nervous System Diseases; Neuroprotective Agents; Piperidines; Rats; Rats, Sprague-Dawley; Remifentanil; Reperfusion Injury; Tumor Necrosis Factor-alpha

1DMe, a neuropeptide FF (NPFF) analogue, has been shown to produce antinociception and to enhance morphine analgesia in rats after intrathecal administration. To determine whether 1DMe could correct hyperalgesia and restore morphine efficacy in mononeuropathic (MN) and diabetic (D) rats we examined the spinal effect of 1DMe in MN and D rats without and after spinal blockade of mu- and delta-opioid receptors with CTOP and naltrindole, respectively. The influence of 1DMe on morphine-induced antinociception was assessed in the two models using isobolographic analysis. Whereas 1DMe intrathecally injected (0.1, 1, 7.5 microg rat(-1)) was ineffective in normal (N) rats, it suppressed mechanical hyperalgesia (decrease in paw pressure-induced vocalisation thresholds) in both MN and D rats. This effect was completely cancelled by CTOP (10 microg rat(-1)) and naltrindole (1 microg rat(-1)) suggesting that it requires the simultaneous availability of mu- and delta-opioid receptors. The combinations of morphine: 1DMe (80.6:19.4% and 99.8:0.2%, in MN and D rats, respectively) followed by isobolographic analysis, showed a superadditive interaction, relative to the antinociceptive effect of single doses, in D rats only. In N rats, the combination of morphine: 1DMe (0.5 mg kg(-1), i.v.: 1 microg rat(-1), i.t., ineffective doses) resulted in a weak short-lasting antinociceptive effect. These results show a different efficacy of 1DMe according to the pain model used, suggesting that the pro-opioid effects of the NPFF in neuropathic pain are only weak, which should contribute to hyperalgesia and to the impaired efficacy of morphine.

Topics: Analgesia; Analgesics; Analgesics, Opioid; Animals; Behavior, Animal; Diabetes Mellitus, Experimental; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Hyperalgesia; Injections, Spinal; Male; Morphine; Naltrexone; Narcotic Antagonists; Nervous System Diseases; Oligopeptides; Pain; Rats; Rats, Sprague-Dawley; Somatostatin; Time Factors; Vocalization, Animal