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

Cognition and pain share common neural substrates and interact reciprocally: chronic pain compromises cognitive performance, whereas cognitive processes modulate pain perception. In the present study, we established a non-drug-dependent rat model of context-based analgesia, where two different contexts (dark and bright) were matched with a high (52°C) or low (48°C) temperature in the hot-plate test during training. Before and after training, we set the temperature to the high level in both contexts. Rats showed longer paw licking latencies in trials with the context originally matched to a low temperature than those to a high temperature, indicating successful establishment of a context-based analgesic effect in rats. This effect was blocked by intraperitoneal injection of naloxone (an opioid receptor antagonist) before the probe. The context-based analgesic effect also disappeared after optogenetic activation or inhibition of the bilateral infralimbic or prelimbic sub-region of the prefrontal cortex. In brief, we established a context-based, non-drug dependent, placebo-like analgesia model in the rat. This model provides a new and useful tool for investigating the cognitive modulation of pain.
Action Potentials ; drug effects ; physiology ; Analgesics ; pharmacology ; therapeutic use ; Animals ; Disease Models, Animal ; Electric Stimulation ; Female ; In Vitro Techniques ; Naloxone ; pharmacology ; Narcotic Antagonists ; pharmacology ; Optogenetics ; Pain ; drug therapy ; pathology ; physiopathology ; Pain Measurement ; drug effects ; Pain Threshold ; drug effects ; physiology ; Patch-Clamp Techniques ; Physical Stimulation ; Prefrontal Cortex ; drug effects ; metabolism ; pathology ; Pyramidal Cells ; drug effects ; physiology ; Rats ; Rats, Sprague-Dawley ; Time Factors

OBJECTIVETo investigate the effect of µ-opioid receptors (µ-ORs) in the central nucleus of the amygdala (CeA) on feeding and drinking behaviors in rats and evaluate the role of glutamate signaling in opioid-mediated ingestive behaviors.

METHODSStainless steel cannulas were implanted in the unilateral CeA for microinjection of different doses of the selective µ-OR agonist DAMGO in satiated or water-deprived male SD rats. The subsequent food intake or water intake of the rats was measured at 60, 120, and 240 min after the injection. The rats receiving microinjections of naloxone (NTX, a nonselective opioid antagonist) or D-AP-5 (a selective N-methyl-D-aspartic acid-type glutamate receptor antagonist) prior to DAMGO microinjection were tested for food intake at 60, 120, and 240 min after the injections.

RESULTSInjections of DAMGO (1-4 nmol in 0.5 µl) into the CeA significantly increased food intake in satiated rats, but did not affect water intake in rats with water deprivation. NTX (26.5 nmol in 0.5 µl) injected into the CeA antagonized DAMGO-induced feeding but D-AP-5 (6.3-25.4 nmol in 0.5 µl) injections did not produce such an effect.

CONCLUSIONµ-ORs in the CeA regulate food intake rather than water intake in rats, and the orexigenic role of µ-ORs is not dependent on the activation of the NMDA receptors in the CeA.

2-Amino-5-phosphonovalerate ; pharmacology ; Animals ; Central Amygdaloid Nucleus ; physiology ; Drinking ; physiology ; Eating ; physiology ; Enkephalin, Ala(2)-MePhe(4)-Gly(5)- ; pharmacology ; Excitatory Amino Acid Antagonists ; pharmacology ; Male ; Naloxone ; pharmacology ; Narcotic Antagonists ; pharmacology ; Rats ; Rats, Sprague-Dawley ; Receptors, Opioid, mu ; physiology

The purpose of this study was to investigate the differences in subjective acute effects of alcohol and naltrexone among those who prefer spicy food to varying degrees. Acute biphasic alcohol effects scale (BAES), visual analogue scale for craving (VAS-C), blood alcohol concentration (BAC) and food preference scale were measured in 26 men. Repeated measures ANOVA (2 preference groupsx4 time blocks) on the stimulative subscale of BAES revealed a significant group by block interaction in naltrexone condition (N+) (P<0.001), but not in non-naltrexone condition (N-). Furthermore, repeated measures ANOVA (2 drug groupsx4 time blocks) on the stimulative subscale of BAES revealed a significant group by block interaction in strong preference for spicy food (SP) (P<0.001), but not in lesser preference for spicy food (LP). The paired t-test revealed that significant suppression of the stimulative subscale of BAES was observed at 15 min (P<0.001) and 30 min (P<0.001) after drinking when N+ compared with N- in SP. For those who prefer spicy food, the stimulative effect of acute alcohol administration was suppressed by naltrexone. This result suggests that the effect of naltrexone may vary according to spicy food preference.
Adult ; Alcohol Drinking/*adverse effects ; Alcoholism/*drug therapy ; Capsaicin/pharmacology ; Food Preferences/*drug effects ; Humans ; Male ; Naltrexone/adverse effects/*therapeutic use ; Narcotic Antagonists/adverse effects/*therapeutic use ; Questionnaires ; Sensory System Agents/pharmacology ; Young Adult

PURPOSE: Nociceptin/orphanin FQ (N/OFQ) as an endogeneous hexadecapeptide is known to exert antinociceptive effects spinally. The aims of this study were to demonstrate the antinociceptive effects of i.t. N/OFQ and to investigate the possible interaction between N/OFQ and endogenous opioid systems using selective opioid receptor antagonists in rat formalin tests. MATERIALS AND METHODS: I.t. N/OFQ was injected in different doses (1-10 nmol) via a lumbar catheter prior to a 50 microL injection of 5% formalin into the right hindpaw of rats. Flinching responses were measured from 0-10 min (phase I, an initial acute state) and 11-60 min (phase II, a prolonged tonic state). To observe which opioid receptors are involved in the anti-nociceptive effect of i.t. N/OFQ in the rat-formalin tests, naltrindole (5-20 nmol), beta-funaltrexamine (1-10 nmol), and norbinaltorphimine (10 nmol), selective delta-, micro- and kappa-opioid receptor antagonists, respectively, were administered intrathecally 5 min after i.t. N/OFQ. RESULTS: I.t. N/OFQ attenuated the formalin-induced flinching responses in a dose-dependent manner in both phases I and II. I.t. administration of naltrindole and beta-funaltrexamine dose-dependently reversed the N/OFQ-induced attenuation of flinching responses in both phases; however, norbinaltorphimine did not. CONCLUSION: I.t. N/OFQ exerted an antinociceptive effect in both phases of the rat-formalin test through the nociceptin opioid peptide receptor. In addition, the results suggested that delta- and micro-opioid receptors, but not kappa-opioid receptors, are involved in the antinociceptive effects of N/OFQ in the spinal cord of rats.
Analgesics/administration & dosage/*pharmacology ; Animals ; Formaldehyde/toxicity ; Injections, Spinal ; Male ; Naltrexone/administration & dosage/analogs & derivatives/pharmacology ; Narcotic Antagonists/administration & dosage/*pharmacology ; Opioid Peptides/administration & dosage/*pharmacology ; Pain Measurement ; Rats ; Rats, Sprague-Dawley ; Receptors, Opioid/*agonists/drug effects

The purpose of this study is to determine 1) whether morphine postconditiong (MPostC) can attenuate the intercellular adhesion molecules-1 (ICAM-1) expression after reoxygenation injury and 2) the subtype(s) of the opioid receptors (ORs) that are involved with MPostC. Human umbilical vein endothelial cells (HUVECs) were subjected to 6 hr anoxia followed by 12 hr reoxygenation. Three morphine concentrations (0.3, 3, 30 microM) were used to evaluate the protective effect of MPostC. We also investigated blockading the OR subtypes' effects on MPostC by using three antagonists (a micro-OR antagonist naloxone, a kappa-OR antagonist nor-binaltorphimine, and a delta-OR antagonist naltrindole) and the inhibitor of protein kinase C (PKC) chelerythrine. As results, the ICAM-1 expression was significantly reduced in the MPostC (3, 30 microM) groups compared to the control group at 1, 6, 9, and 12 hours reoxygenation time. As a consequence, neutrophil adhesion was also decreased after MPostC. These effects were abolished by coadministering chelerythrine, nor-binaltorphimine or naltrindole, but not with naloxone. In conclusion, it is assumed that MPostC could attenuate the expression of ICAM-1 on endothelial cells during reoxygenation via the kappa and delta-OR (opioid receptor)-specific pathway, and this also involves a PKC-dependent pathway.
Animals ; Benzophenanthridines/pharmacology ; Endothelial Cells/cytology/*drug effects/*metabolism ; Endothelium, Vascular/cytology ; Humans ; Intercellular Adhesion Molecule-1/genetics/*metabolism ; Morphine/*pharmacology ; Naloxone/pharmacology ; Naltrexone/analogs & derivatives/pharmacology ; Narcotic Antagonists/pharmacology ; Narcotics/*pharmacology ; Protein Isoforms/metabolism ; Protein Kinase C/antagonists & inhibitors/metabolism ; Receptors, Opioid/metabolism ; Reperfusion Injury/*metabolism ; Signal Transduction/physiology ; Umbilical Veins/cytology

OBJECTIVEThis study aimed to investigate the possible role of Orphanin FQ (OFQ) in the regulation of hypo-thalamic gonadotropin-releasing hormone (GnRH) secretion.

METHODSThe method of push-pull perfusion and radioimmuno-assay (RIA) were adopted to examine the secretory profile of GnRH in the median eminence (ME) in freely moving ovari-ectomized (OVX) rats after intracerebroventricular (icv) injection of OFQ and/or [Nphe(1)]NC(1-13)NH(2) (NC13), a competitive antagonists of the opioid receptor-like 1 receptor (ORL1 receptor).

RESULTSGnRH release from ME significantly decreased from 40 min to 80 min after the administration of 20 and 200 nmol OFQ in OVX rats (P < 0.05). This inhibitory effect of 20 nmol OFQ could be abolished by pretreatment with equal dose of NC13. More interestingly, GnRH secretion from ME was increased markedly 60 min after icv injection of 100 and 200 nmol NC13 (P < 0.05).

CONCLUSIONOur results suggested central administration of OFQ could inhibit the release of GnRH in the ME of hypothalamus through ORL1 receptor, providing further in vivo evidence supporting the role of OFQ in the control of GnRH secretion.

Analysis of Variance ; Animals ; Dose-Response Relationship, Drug ; Female ; Gonadotropin-Releasing Hormone ; metabolism ; Median Eminence ; metabolism ; Narcotic Antagonists ; Opioid Peptides ; pharmacology ; Ovariectomy ; methods ; Peptide Fragments ; pharmacology ; Radioimmunoassay ; Rats ; Rats, Sprague-Dawley ; Receptors, Opioid ; metabolism ; Secretory Pathway ; drug effects ; Vasodilator Agents ; pharmacology ; Wakefulness ; physiology

AIMTo determine whether testosterone is involved in morphine withdrawal syndrome (WS).

METHODSIn order to induce dependency, rats were treated with subcutaneous injection of morphine (days 1-2, 5 mg/kg; days 3-5, 7.5 mg/kg; days 6-8, 10 mg/kg), and after the last dose of morphine (day 8) WS was induced by intraperitoneal injection of naloxone (1 mg/kg). Wet dog shake (WDS), abdomen writhing (AW), and jumps (J) were recorded as indicators of WS.

RESULTSThe severity of WDS, AW, and J in male rats was greater than that in females. Accordingly, in 4-week castrated and flutamide-treated (10 mg/kg/day for 8 days, i.p.) male rats, WDS, AW, and J were significantly decreased compared to male control rats. Testosterone replacement therapy (10 mg/kg/day for 8 days, i.m.) in 4-week castrated rats restored the severity of WDS, AW, and J behaviors to the level of non-castrated male rats, whereas testosterone potentiated the WDS behavior in non-castrated male rats.

CONCLUSIONIt can be concluded that testosterone might be effectively involved in morphine WS.

Androgen Antagonists ; pharmacology ; Androgens ; pharmacology ; physiology ; Animals ; Behavior, Animal ; Female ; Flutamide ; pharmacology ; Male ; Morphine ; pharmacology ; Morphine Dependence ; physiopathology ; Naloxone ; pharmacology ; Narcotic Antagonists ; pharmacology ; Narcotics ; pharmacology ; Orchiectomy ; Rats ; Rats, Wistar ; Severity of Illness Index ; Substance Withdrawal Syndrome ; physiopathology ; Testosterone ; pharmacology ; physiology

BACKGROUNDOpioid preconditioning (PC) reduces anoxia/reoxygenation (A/R) injury to various cells. However, it remains unclear whether opioid-induced delayed PC would show anti-apoptotic effects on pulmonary artery endothelial cells (PAECs) suffering from A/R injury. The present study was conducted to elucidate this issue and to investigate the potential mechanism of opioid-induced delayed PC.

METHODSCultured porcine PAECs underwent 16-hour anoxia followed by 1-hour reoxygenation 24 hours after pretreatment with saline (NaCl; 0.9%) or morphine (1 micromol/L). To determine the underlying mechanism, a non-selective K(ATP) channel inhibitor glibenclamide (Glib; 10 micromol/L), a nitric oxide (NO) synthase blocker NG-nitro-L-arginine methyl ester (L-NAME; 100 micromol/L), and an opioid receptor antagonist naloxone (Nal; 10 micromol/L) were given 30 minutes before the A/R load. The percentage of apoptotic cells was assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining. eNOS mRNA level was measured by real-time polymerase chain reaction (PCR). NO content of PAECs supernatants was measured with the Griess reagent.

RESULTSCompared to the A/R PAECs, morphine-induced delayed PC significantly reduced PAECs apoptosis ((18.1 +/- 1.9)% vs (5.5 +/- 0.3)%; P < 0.05), increased NO release ((11.4 +/- 1.3) micromol/L vs (20.5 +/- 2.1) micromol/L, P < 0.05), and up-regulated eNOS gene expression nearly 9 times (P < 0.05). The anti-apoptosis effect of morphine was abolished by pretreatment with Glib, L-NAME and Nal, but the three agent-selves did not aggravate the A/R injury. Furthermore, L-NAME and Nal offset the enhanced release of NO caused by pretreatment with morphine.

CONCLUSIONSMorphine-induced delayed PC prevents A/R injury of PAECs. This effect may be mediated by activation of K(ATP) channel via opioid receptor and NO signaling pathways.

Analgesics, Opioid ; pharmacology ; Animals ; Apoptosis ; drug effects ; Cell Hypoxia ; Cells, Cultured ; Endothelial Cells ; cytology ; drug effects ; metabolism ; Enzyme Inhibitors ; pharmacology ; Glyburide ; pharmacology ; In Situ Nick-End Labeling ; Morphine ; pharmacology ; NG-Nitroarginine Methyl Ester ; pharmacology ; Naloxone ; pharmacology ; Narcotic Antagonists ; pharmacology ; Nitric Oxide ; metabolism ; Nitric Oxide Synthase Type III ; antagonists & inhibitors ; genetics ; metabolism ; Oxygen ; pharmacology ; Pulmonary Artery ; cytology ; RNA, Messenger ; genetics ; metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Swine

Previous studies have indicated that the thalamic nucleus submedius (Sm) and the anterior pretectal nucleus (APtN) are involved in the descending modulation of nociception. The aim of the present study was to examine whether the opioid receptors in the Sm and APtN mediated the electroacupuncture (EA)-produced analgesia. The latency of tail flick (TF) reflex induced by radiant heat was used as an index of nociceptive response. The effects of microinjection of opioid receptor antagonist naloxone (1.0 microg, 0.5 ml) into Sm or APtN on the inhibition of the TF reflex induced by EA of "Zusanli" point (St. 36) with high- (5.0 mA) and low- (0.5 mA) intensity were examined in the lightly anesthetized rats. Sm microinjection of naloxone blocked the high- but not low-intensity EA-induced inhibition of the TF reflex. In contrast, naloxone applied to APtN blocked the low- but not high-intensity EA-induced inhibition. When naloxone applied to other brain regions adjacent to Sm or APtN, the EA-induced inhibition was not influenced under either high- or low-intensity condition. These results suggest that opioid receptors in Sm are involved in mediating the analgesia by high-intensity EA for exciting small (A-delta and C group) afferent fibers, while opioid receptors in APtN are involved in mediating the analgesia induced by low-intensity EA for only exciting large (A-beta) afferent fibers.
Acupuncture Analgesia ; Animals ; Electroacupuncture ; Naloxone ; pharmacology ; Narcotic Antagonists ; Nociceptors ; physiology ; Pain Measurement ; Rats ; Receptors, Opioid ; physiology ; Thalamic Nuclei ; physiology