Opiate receptor agonists (especially dynorphin - a kappa receptor agonist) have found to increase in the injuried segment of spinal cord. It is known to cause spinal cord damage when injected intrathecally. Nalbuphine is a kappa opiate receptor agonist/partial mu antagonist, and fentanyl is selective mu receptor agonist. To determine the effect of nalbuphine and fentanyl on experimental spinal cord injuries of Spague-Dawley rats (N=125): 1) I determinded the MAC (or ED50) values of enflurane, fentanyl, nalbuphine-enflurane in 65% N2O; 2) produced spinal cord injury model by different epidural ballooning time in the control (enflurane) gmup ; 3) produced spinal cord injuries in the experimental (fentanyl, nalbuphine-enflurane) group. The results were as follows ; 1) The MAC value of enflurane was 1.16+/-0.05%, and the ED50 values of fentanyl were 26.8, 36.2, 39.7, 44.7 ug/kg after 15, 30, 45, 60 min of injection, respectively. Also the MAC values of enflurane with 20 mg/kg nalbuphine were 1.08, 0.99% after 60, 90 min of injection, respectively. 2) We produced the graded spinal cord injuries by different epidural ballooning time. 3) The total neurological scores of fentanyl experimental group were significantly higher than control group on the 10th, 14th, and 21st postinjury day.
Animals ; Dynorphins ; Enflurane ; Fentanyl* ; Nalbuphine* ; Rats ; Receptors, Opioid ; Receptors, Opioid, kappa ; Receptors, Opioid, mu ; Spinal Cord Injuries* ; Spinal Cord*

A series of aralkyl-ketone-4-piperidol derivatives were synthesized and tested for their analgesic activities. All of the novel 30 compounds were prepared from 4-piperidone and alpha-halo-aralkyl-ketone through five steps, including Boc protection, nucleophilic addition in presence of CeCl3/NaI catalyst, deprotection, condensation and salification. Their structures were confirmed by 1H NMR and HRMS. Preliminary in vivo pharmacological trials showed that most of the synthesized compounds revealed analgesic effects. Among the tested compounds, 8, 13 and 22 exhibited potent analgesic activities in both mice writhing and mice hot plate model. The three compounds have low affinity for mu, delta, kappa receptors, which is a chance to find a better precursor of non-opioid analgesic for further optimization.
Analgesics, Non-Narcotic ; chemical synthesis ; chemistry ; pharmacology ; Animals ; Mice ; Molecular Structure ; Pain Measurement ; Pain Threshold ; drug effects ; Piperidones ; chemical synthesis ; chemistry ; pharmacology ; Receptors, Opioid, delta ; metabolism ; Receptors, Opioid, kappa ; metabolism ; Receptors, Opioid, mu ; metabolism ; Structure-Activity Relationship

AIMTo design and synthesize new chiral 8-(substituted) amino-analogues of 3-[(tetrahydro-2-furanyl)methyl] benzomorphans, to expand knowledge of the structure-activity relationship (SAR) for 8-aminobenzomorphan.

METHODSTarget compounds were synthesized from the 8-triflate of the optically active 3-[(tetrahydro-2-furanyl)methyl]-2,6-methano-benzomorphans using Pd-catalyzed aminations. Opioid receptor binding experiments were performed to evaluate their biological activities.

RESULTSBoth 8-amino and 8-phenylamino analogues showed lower binding affinity for mu, delta and kappa receptors than corresponding 8-hydroxy-3-[(tetrahydro-2-furanyl)methyl]-2,6-methano-benzomorphan in vitro.

CONCLUSIONThe relative poor binding affinity of the target compounds did not warrant conducting the in vivo studies to determine if they have the profile(kappa agonist/mu antagonist) that will be potentially useful in the treatment of drug addiction. Further study is in progress.

Animals ; Benzomorphans ; chemical synthesis ; chemistry ; pharmacology ; Brain ; metabolism ; Furans ; chemical synthesis ; chemistry ; pharmacology ; Guinea Pigs ; Molecular Structure ; Narcotic Antagonists ; chemical synthesis ; chemistry ; pharmacology ; Radioligand Assay ; Receptors, Opioid ; metabolism ; Receptors, Opioid, delta ; metabolism ; Receptors, Opioid, kappa ; metabolism ; Receptors, Opioid, mu ; metabolism ; Structure-Activity Relationship

BACKGROUND: Previous reports have described that the local administration of opioid receptor agonist can attenuate the nociceptive responses induced by a variety of inflammatory states. This study evaluated the effects of mu or kappa opioid receptor agonists peripherally administered at a site of injury on the state of thermal hyperalgesia induced by mild burn injury. METHODS: Thermal injury was induced after briefly anesthetizing with halothane, by applying the left hindpaw to a hot plate (52.5 degree C) for 45 seconds. Paw withdrawal latency of the hindpaw was determined using an underglass thermal stimulus, which allowed the response latency of the injured paw to be obtained. In this work, the mu receptor agonist, morphine (10, 30, 100 microgram), or the kappa receptor agonist, U50,488H (10, 30, 100 microgram), was administered respectively at the injured site on the right hindpaw in rats. To compare the systemic effects of the drug, the same drug was administered at the normal left hindpaw site with mild burn injury. Naloxone (40 microgram/kg) was administered at the injured site or at the normal site to determine the reversibility of the opioid used. RESULTS: Mild burn injury produced thermal hyperalgesia manifested as reduced paw withdrawal latency. Administration of either morphine (10, 30, 100 microgram) or U50,488H (10, 30, 100 microgram) at the injured site attenuated hyperalgesia in a dose-dependent manner. But the administration of drugs at the normal site had no effect on hyperalgesia at the injured site. In addition, naloxone had the effect of morphine and U50,488H reversed significantly. CONCLUSIONS: These results suggest that peripheral mu or kappa opioid receptor administration at an injured site may play an important role in the hyperalgesia induced by mild burn injury.
3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer ; Animals ; Burns ; Halothane ; Hyperalgesia* ; Morphine ; Naloxone ; Rats* ; Reaction Time ; Receptors, Opioid ; Receptors, Opioid, kappa* ; Receptors, Opioid, mu

Humans ; Dynorphins/metabolism* ; Receptors, Opioid, kappa/metabolism* ; Cryoelectron Microscopy

BACKGROUNDPreconditioning with repeated electroacupuncture (EA) could mimic ischemic preconditioning to induce cerebral ischemic tolerance in rats. The present study was designed to investigate whether mu (micro)-, delta (delta)- or kappa (kappa)-opioid receptors are involved in the neuroprotection induced by repeated EA preconditioning.

METHODSThe rats were pretreated with naltrindole (NTI), nor-binaltorphimine (nor-BNI) or D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP), which is a highly selective delta-, kappa- or micro-opioid receptor antagonist respectively, before each EA preconditioning (30 minutes per day, 5 days). Twenty-four hours after the last EA treatment, the middle cerebral artery occlusion (MCAO) was induced for 120 minutes. The brain infarct volume was determined with 2, 3, 5-triphenyltetrazolium chloride staining at 24 hours after MCAO and compared with that in rats which only received EA preconditioning. In another experiment, the met-enkephalin-like immunoreactivity in rat brain was investigated by immunohistochemistry in both EA preconditioning and control rats.

RESULTSThe EA preconditioning reduced brain infarct volume compared with the control rats (P = 0.000). Administration of both NTI and CTOP attenuated the brain infarct volume reduction induced by EA preconditioning, presenting with larger infarct volume than that in the EA preconditioning rats (P < 0.001). But nor-BNI administration did not block the infarct volume reduction induced by EA preconditioning, presenting with smaller infarct volume than the control group rats (P = 0.000). The number of met-enkephalin-like immunoreactivity positive neurons in the EA preconditioning rats was more than that of the control rats (P = 0.000).

CONCLUSIONRepeated EA preconditioning stimulates the release of enkephalins, which may bind delta- and micro-opioid receptors to induce the tolerance against focal cerebral ischemia.

Animals ; Brain Ischemia ; prevention & control ; Electroacupuncture ; Enkephalin, Methionine ; analysis ; Immunohistochemistry ; Ischemic Preconditioning ; Male ; Naltrexone ; analogs & derivatives ; pharmacology ; Rats ; Rats, Sprague-Dawley ; Receptors, Opioid, delta ; physiology ; Receptors, Opioid, mu ; physiology ; Somatostatin ; analogs & derivatives ; pharmacology

Spinal cord stimulation (SCS)-induced analgesia was characterized, and its underlying mechanisms were examined in a spared nerve injury model of neuropathic pain in rats. The analgesic effect of SCS with moderate mechanical hypersensitivity was increased with increasing stimulation intensity between the 20% and 80% motor thresholds. Various frequencies (2, 15, 50, 100, 10000 Hz, and 2/100 Hz dense-dispersed) of SCS were similarly effective. SCS-induced analgesia was maintained without tolerance within 24 h of continuous stimulation. SCS at 2 Hz significantly increased methionine enkephalin content in the cerebrospinal fluid. The analgesic effect of 2 Hz was abolished by μ or κ opioid receptor antagonist. The effect of 100 Hz was prevented by a κ antagonist, and that of 10 kHz was blocked by any of the μ, δ, or κ receptor antagonists, suggesting that the analgesic effect of SCS at different frequencies is mediated by different endorphins and opioid receptors.
Analgesics ; Animals ; Narcotic Antagonists/pharmacology* ; Neuralgia/therapy* ; Opioid Peptides ; Rats ; Receptors, Opioid/physiology* ; Receptors, Opioid, kappa ; Spinal Cord ; Spinal Cord Stimulation

Amygdala ; drug effects ; metabolism ; Animals ; Conditioning (Psychology) ; Morphine ; adverse effects ; Rats ; Receptors, Opioid, kappa ; metabolism

BACKGROUND: Remifentanil is an ultra-short-acting mu opioid receptor agonist. However, there are few reports of its use in children. Therefore, this study compared propofol-remifentanil anesthesia (PR) with a desflurane-N2O anesthesia (D) in children. METHODS: One hundred children (5-12 years), who were scheduled for a tonsillectomy, were randomly assigned to either Group PR (n=50) or Group D (n=50). After inducing anesthesia with propofol and rocuronium, group PR was maintained with an infusion of propofol and remifentanil. Group D was maintained with desflurane. At the end of surgery all the anesthetics were terminated without tapering. The systolic and diastolic blood pressure, and heart rate were measured upon arrival at the operation room, after induction, after intubation, at the beginning of the operation, 5, 10, 20 minutes after beginning of surgery and the end of anesthesia. RESULTS: There was a significantly lower heart rate in group PR than in group D but there was no significant difference in blood pressure between the two groups. CONCLUSIONS: In children, propofol-remifentanil anesthesia is a well-tolerated method of anesthesia, with a lower heart rate compared with desflurane-N2O based anesthesia.
Anesthesia* ; Anesthetics ; Blood Pressure* ; Child ; Heart Rate* ; Heart* ; Humans ; Intubation ; Propofol ; Receptors, Opioid, mu ; Tonsillectomy*

The mu opioid receptor (MOR) has been regarded as the main site of interaction with analgesics in major clinical use, particularly morphine. The repressor element-1 silencing transcription factor (REST) functions as a transcriptional repressor of neuronal genes in non-neuronal cells. However, it is expressed in certain mature neurons, suggesting that it may have complex and novel roles. In addition, the interactions between MOR and REST and their functions remain unclear. In this study, we examined the effects of morphine on the expression of REST mRNA and protein in human neuroblastoma NMB cells to investigate the roles of REST induced by MOR activation in neuronal cells. To determine the effects of morphine on REST expression, we performed RT-PCR, real-time quantitative RT-PCR, western blot analysis and radioligand binding assays in NMB cells. By RT-PCR and real-time quantitative RT-PCR, the expression of REST was found to be unchanged by either the MOR agonist morphine or the MOR specific antagonist CTOP. By western blot, morphine was shown to significantly inhibit the expression of REST, but this suppression was completely blocked by treatment with CTOP. In the radioligand binding assay, the overexpression of REST led to an increased opioid ligand binding activity of endogenous MOR in the NMB cells. These results together suggest that morphine inhibits the expression of REST in human neuroblastoma cells through a post-transcriptional regulatory mechanism mediated through MOR.
Analgesics ; Blotting, Western ; Humans ; Morphine ; Neuroblastoma ; Neurons ; Receptors, Opioid, mu ; RNA, Messenger ; Somatostatin ; Transcription Factors