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*

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

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: 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

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

BACKGROUND: Selective inhibitors of cyclooxygenase (COX)-2 are commonly used analgesics in various pain conditions. Although their actions are largely thought to be mediated by the blockade of prostaglandin (PG) biosynthesis, evidences suggesting endogenous opioid peptide link in spinal antinociception of COX inhibitor have been reported. We investigated the roles of opioid receptor subtypes in the spinal antinociception of selective COX-2 inhibitor. METHODS: To examine the antinociception of a selective COX-2 inhibitor, DUP-697 was delivered through an intrathecal catheter, 10 minutes before the formalin test in male Sprague-Dawley rats. Then, the effect of intrathecal pretreatment with CTOP, naltrindole and GNTI, which are micro, delta and kappa opioid receptor antagonist, respectively, on the analgesia induced by DUP-697 was assessed. RESULTS: Intrathecal DUP-697 reduced the flinching response evoked by formalin injection during phase 1 and 2. Naltrindole and GNTI attenuated the antinociceptive effect of intrathecal DUP-697 during both phases of the formalin test. CTOP reversed the antinociception of DUP-697 during phase 2, but not during phase 1. CONCLUSIONS: Intrathecal DUP-697, a selective COX-2 inhibitor, effectively relieved inflammatory pain in rats. The delta and kappa opioid receptors are involved in the activity of COX-2 inhibitor on the facilitated state as well as acute pain at the spinal level, whereas the micro opioid receptor is related only to facilitated pain.
Acute Pain ; Aluminum Hydroxide ; Analgesia ; Analgesics ; Animals ; Carbonates ; Catheters ; Cyclooxygenase 2 ; Formaldehyde ; Humans ; Male ; Naltrexone ; Opioid Peptides ; Pain Measurement ; Prostaglandin-Endoperoxide Synthases ; Rats ; Rats, Sprague-Dawley ; Receptors, Opioid ; Receptors, Opioid, kappa ; Somatostatin ; Thiophenes

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

This study investigates whether kappa-opioid receptor and ORL1 receptor may interact to form a heterodimer. In immunofluorescence and co-immunoprecipitation experiments, differentially epitope-tagged receptors, colocalization and heterodimerization of kappa-opioid receptor and ORL1 receptor were used and examined in primary culturing rat neurons, Chinese hamster ovary (CHO) or human embryonic kidney 293 (HEK293) cells. The results show that fluorescence of both kappa-opioid receptor and ORL1 receptor were overlapping in primary culturing hippocampal and cortical neurons. Similarly in co-expressing CHO or HEK293 cells, HA-KOR and Myc-ORL1 were almost exclusively confined to the membranes, revealing extensive colocalization. When Flag-KOR and Myc-ORL1 were co-expressing in CHO cells, heterodimerization was identified to have the ability to co-immunoprecipitate ORL1-receptors with kappa-opioid receptor and vice versa. In the current study, further evidence was provided for the direct interaction of two subtypes of opioid receptors, kappa-opioid receptor and ORL1-receptor, to form the heterodimerization. The finding represents the novel pharmacological mechanism for modulation of opioid receptor function as well as diversity of G protein-coupled receptors.
Animals ; CHO Cells ; Cells, Cultured ; Cerebral Cortex ; cytology ; metabolism ; Cricetinae ; Cricetulus ; Dimerization ; Female ; HEK293 Cells ; Hippocampus ; cytology ; metabolism ; Humans ; Immunoprecipitation ; Male ; Neurons ; cytology ; metabolism ; Rats ; Rats, Wistar ; Receptors, Opioid ; metabolism ; Receptors, Opioid, kappa ; metabolism

BACKGROUND: We investigated the effects of pre-emptive administration of ketamine and norBNI on pain behavior and the expression of DREAM, c-Fos, and prodynorphin proteins on the ipsilateral side of the rat spinal cord at 2 and 4 hours after formalin injection. METHODS: Eighty-four male Sprague Dawley rats were divided into 4 major groups consisting of control rats (C) (n = 12), rats given only formalin injections (F) (n = 24), and rats treated with pre-emptive administration of either ketamine (K+F) (n = 24) or norBNI (N+F) (n = 24). The non-control groups were further divided into subgroups consisting of rats that were sacrificed at 2 and 4 hours (n = 12 for each group) after formalin injection. Pain behavior was recorded for 1 hour. After 2 and 4 hours, the rats were sacrificed and the spinal cords (L4-L5 sections) were removed for immunohistochemistry and Western blot analysis. RESULTS: The pain behavior response was reduced in the K+F group compared to the other groups during the second phase of the formalin pain response. We detected an increase in the nuclear DREAM protein level in the K+F group at 2 and 4 hours and a transient decrease in the N+F group at 2 hours; however, it increased at 4 hours after injection. Fos-like immunoreactivity (FLI) and Prodynorphin-like immunoreactivity (PLI) neurons decreased in the K+F group but increased in the N+F group at 2 hours after injection. While FLI decreased, PLI increased in all groups at 4 hours after injection. CONCLUSIONS: We suggest that NMDA and kappa opioid receptors can modulate DREAM protein expression, which can affect pain behavior and protein transcriptional processes at 2 hours and bring about either harmful or protective effects at 4 hours after formalin injection.
Animals ; Blotting, Western ; Enkephalins ; Formaldehyde ; Humans ; Immunohistochemistry ; Ketamine ; Male ; N-Methylaspartate ; Neurons ; Pain Measurement ; Protein Precursors ; Proteins ; Rats ; Rats, Sprague-Dawley ; Receptors, Opioid, kappa ; Spinal Cord