naloxone and naltrindole-benzofuran

We studied the role of opioid receptor subtypes in improvement of the functional state of the heart during reperfusion after adaptation to continuous normobaric hypoxia. To this end, male Wistar rats were subjected to continuous normobaric hypoxia (12% O

Topics: Adaptation, Physiological; Animals; Benzylidene Compounds; Creatine Kinase; Hypoxia; Male; Myocardial Reperfusion Injury; Myocardium; Naloxone; Naltrexone; Narcotic Antagonists; Oligopeptides; Organ Culture Techniques; Peptides; Rats; Rats, Wistar; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Tetrahydroisoquinolines

We investigated the involvement of opioid receptors such as the mu and delta receptors in the predominant elevation of corn oil appetite just after 5-day repeated treatment of corn oil ingestion. Rats were given 5% corn oil emulsified with 0.3% xanthan gum for 20 min at the same hour for 5 consecutive days. A strong appetite for fat was formed after the 5 days presentation, and it was inhibited by naloxonazine, a selective antagonist of the mu-1 receptor, at doses of 3 mg/kg, but not by antagonists of the opioid delta receptor. In days 6, after the formation of a strong appetite for corn oil, an additional injection of naloxonazine suppressed fat intake 0-30, 30-60, 60-90 and 90-150 min after the presentation of the corn oil, but antagonists of the opioid delta receptor did not. These data suggested that the opioid mu receptor is involved in the sharp elevation of corn oil appetite during repeated presentation of corn oil to rats.

Topics: Animals; Appetite Regulation; Corn Oil; Feeding Behavior; Male; Naloxone; Naltrexone; Narcotic Antagonists; Polysaccharides, Bacterial; Rats; Rats, Wistar; Receptors, Opioid, delta; Receptors, Opioid, mu; Signal Transduction

Although the importance of the nucleus raphe magnus in descending inhibitory control of nociception is clear, it is not known whether these effects are equivalent for different types of nociception. Thus, we examined the differential inhibition of behavioral responses evoked by A delta or C fiber thermonociceptor activation by electrical stimulation of nucleus raphe magnus neurons as well as the involvement of different classes of opiate receptors in this inhibition. In general, it was necessary to apply twice as much current to the nucleus raphe magnus to produce criterion antinociception for A delta mediated versus C fiber mediated nociceptive responses. Intrathecal administration of the nonselective opioid receptor antagonist, naltrexone, or the delta(1) opioid receptor antagonist, naltrindole, attenuated both A delta and C fiber antinociception induced by nucleus raphe magnus stimulation with similar efficacy. In contrast, intrathecal administration of naloxonazine, a micro specific opioid receptor antagonist, or naltriben, a delta(2) specific opioid receptor antagonist, preferentially attenuated nucleus raphe magnus induced antinociception for C fiber responses when compared with A delta mediated responses. These findings suggest that nociception evoked by the activation of A delta or C fiber nociceptors is under pharmacologically distinguishable descending control from the nucleus raphe magnus.. Opiates differentially inhibit pain produced by the activation of myelinated or unmyelinated pain sensing neurons, a distinction that is clinically important. This article demonstrates that the brain's own pain control system operates with similar selectivity, and that this selectivity is partly mediated by different opiate receptor subtypes.

Topics: Analgesics, Opioid; Animals; Electric Stimulation; Female; Hot Temperature; Injections, Spinal; Naloxone; Naltrexone; Narcotic Antagonists; Nerve Fibers, Myelinated; Nerve Fibers, Unmyelinated; Neural Pathways; Nociceptors; Raphe Nuclei; Rats; Rats, Sprague-Dawley

The effects of the delta2-opioid receptor agonist, deltorphin II, on extracellular levels of dopamine in the rat nucleus accumbens were investigated in awake animals by in vivo brain microdialysis. In agreement with previous studies, perfusion of deltorphin II (50.0 nmol) into the nucleus accumbens significantly increased the extracellular amount of accumbal dopamine. The effect of deltorphin II (50.0 nmol) was not altered by the selective delta2-opioid receptor antagonist, naltriben (1.5 nmol), which alone did not significantly affect the basal levels of dopamine. Selective antagonists of neither the mu-opioid receptors, D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Phe-Thr-NH2 (0.15 nmol), nor the delta1-opioid receptors, (E)-7-benzylidenenaltrexone tartrate (0.15 nmol), failed to significantly alter the effects of deltorphin II. The nonselective opioid receptor antagonist, naloxone (0.75 and 1.5 nmol), which alone did not significantly affect the basal levels of dopamine, also failed to affect the effects of deltorphin II. Moreover, under the condition that the sodium channel blocker, tetrodotoxin (0.1 nmol), was perfused continuously into the nucleus accumbens, the deltorphin II-induced increase in extracellular levels of dopamine was reduced by 72%. These results suggest that deltorphin II enhances extracellular dopamine in the nucleus accumbens via opioid receptor-independent, tetrodotoxin-sensitive mechanisms.

Topics: Analysis of Variance; Anesthetics, Local; Animals; Benzylidene Compounds; Dopamine; Extracellular Space; Male; Microdialysis; Naloxone; Naltrexone; Narcotic Antagonists; Nucleus Accumbens; Oligopeptides; Rats; Rats, Sprague-Dawley; Receptors, Opioid; Somatostatin; Tetrodotoxin; Time Factors

In cellular models, chronic exposure to mu-opioid agonists converts antagonists into inverse agonists at mu-receptors. Such adaptations could contribute to the development of tolerance and/or dependence. To determine whether delta-receptors respond similarly, or whether this adaptation is unique for mu-receptors, this study examined the effects of prolonged agonist exposure on the intrinsic activity of several delta-opioid ligands in GH(3) cells expressing delta-receptors. In opioid naive cells, delta-receptors were constitutively active, and a series of delta-ligands displayed a range of intrinsic activities for G protein activation. Chronic treatment with the full delta-agonist [D-Pen(2,5)]-enkephalin reduced the acute ability of [D-Pen(2,5)]-enkephalin to stimulate and the full inverse agonist N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH (ICI-174864) to inhibit G protein activation. In contrast, although naloxone and naltriben exhibited weak partial agonism in opioid naive cells, both ligands acted as full inverse agonists to produce concentration-dependent inhibition of guanosine 5'-O-(3-[(35)S]thio)triphosphate binding after prolonged exposure to [D-Pen(2,5)]-enkephalin or to the partial agonist morphine. This effect was reversed by a neutral delta-antagonist (N,N-bisallyl)-Tyr-Gly-Gly-psi-(CH(2)S)-Phe-Leu-OH (ICI-154129). Finally, as is also characteristic of inverse agonists, naloxone and naltriben demonstrated higher affinities for uncoupled delta-receptors in cells chronically treated with [D-Pen(2,5)]-enkephalin, relative to opioid naive cells. Therefore, this relatively novel adaptation is shared by both mu- and delta-opioid receptors and therefore may serve as an important common mechanism involved the development of tolerance and/or dependence.

Topics: Adenylyl Cyclases; Analgesics, Opioid; Animals; Cell Line; Cell Membrane; Drug Tolerance; Enkephalin, D-Penicillamine (2,5)-; Guanosine 5'-O-(3-Thiotriphosphate); Morphine; Naloxone; Naltrexone; Narcotic Antagonists; Narcotics; Opioid-Related Disorders; Receptors, Opioid, delta; Receptors, Opioid, mu

Naltriben (NTB) has been used to differentiate the subtypes of delta opioid receptors, delta1 and delta2. However, there is considerable evidence suggesting that NTB may act on other types of opioid receptors too. We examined the effects of NTB on the specific binding of radiolabeled ligands for opioid mu and kappa2 receptors, and the effects on the release of [3H]norepinephrine ([3H]NE) in rat cerebral cortex slices. NTB displaced the specific binding of [3H]DAMGO with Ki value of 19.79 +/- 1.12 nM in rat cortex membranes. Specific binding of [3H]diprenorphine ([3H]DIP) was inhibited by NTB with Ki value of 82.75 +/- 6.32 nM in the presence of DAMGO and DPDPE. High K+ (15 mM)-stimulated release of [3H]NE was attenuated by DAMGO in rat cerebral cortex slices. NTB (30 nM) shifted the dose-response curve of DAMGO to the right and attenuated the maximal effect. In the meantime, NTB inhibited high K+-stimulated [3H]NE release at concentrations above 100 nM. The inhibitory effect of NTB was not attenuated by CTAP (10 nM) and naloxone (3 nM) but by higher concentration of naloxone (30 nM), nor-BNI (300 nM) and bremazocine (3 nM). These results indicate that NTB, depending on the dosage, could acts not only as an antagonist at delta but also as a noncompetitive antagonist for mu receptors, and as an agonist for kappa2 receptors in rat cerebral cortex.

Topics: Animals; Cerebral Cortex; Diprenorphine; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, D-Penicillamine (2,5)-; Ligands; Male; Naloxone; Naltrexone; Narcotic Antagonists; Norepinephrine; Peptide Fragments; Peptides; Potassium; Rats; Rats, Sprague-Dawley; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Somatostatin; Tritium

Two highly selective mu-opioid receptor agonists, endomorphin-1 and endomorphin-2, have been identified and postulated to be endogenous ligands for mu-opioid receptors. Intrathecal (i.t.) administration of endomorphin-1 and endomorphin-2 at doses from 0.039 to 5 nmol dose-dependently produced antinociception with the paw-withdrawal test. The paw-withdrawal inhibition rapidly reached its peak at 1 min, rapidly declined and returned to the pre-injection levels in 20 min. The inhibition of the paw-withdrawal responses to endomorphin-1 and endomorphin-2 at a dose of 5 nmol observed at 1 and 5 min after injection was blocked by pretreatment with a non-selective opioid receptor antagonist naloxone (1 mg/kg, s.c.). The antinociceptive effect of endomorphin-2 was more sensitive to the mu (1)-opioid receptor antagonist, naloxonazine than that of endomorphin-1. The endomorphin-2-induced paw-withdrawal inhibition at both 1 and 5 min after injection was blocked by pretreatment with kappa-opioid receptor antagonist nor-binaltorphimine (10 mg/kg, s.c.) or the delta(2)-opioid receptor antagonist naltriben (0.6 mg/kg, s.c.) but not the delta(1)-opioid receptor antagonist 7-benzylidine naltrexone (BNTX) (0.6 mg/kg s.c.). In contrast, the paw-withdrawal inhibition induced by endomorphin-1 observed at both 1 and 5 min after injection was not blocked by naloxonazine (35 mg/kg, s.c.), nor-binaltorphimine (10 mg/kg, s.c.), naltriben (0.6 mg/kg, s.c.) or BNTX (0.6 mg/kg s.c.). The endomorphin-2-induced paw-withdrawal inhibition was blocked by the pretreatment with an antiserum against dynorphin A-(1-17) or [Met(5)]enkephalin, but not by antiserum against dynorphin B-(1-13). Pretreatment with these antisera did not affect the endomorphin-1-induced paw-withdrawal inhibition. Our results indicate that endomorphin-2 given i.t. produces its antinociceptive effects via the stimulation of mu (1)-opioid receptors (naloxonazine-sensitive site) in the spinal cord. The antinociception induced by endomophin-2 contains additional components, which are mediated by the release of dynorphin A-(1-17) and [Met(5)]enkephalin which subsequently act on kappa-opioid receptors and delta(2)-opioid receptors to produce antinociception.

Topics: Analgesics; Animals; Benzylidene Compounds; Dose-Response Relationship, Drug; Dynorphins; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, Leucine; Enkephalin, Methionine; Immune Sera; Injections, Spinal; Injections, Subcutaneous; Male; Mice; Naloxone; Naltrexone; Narcotic Antagonists; Oligopeptides; Pain; Pain Measurement; Pain Threshold; Peptide Fragments; Time Factors

Given that alcoholics drink for different reasons, it is not likely that a single pharmacotherapeutic agent will be equally effective for all alcoholics. Hence, the development of new pharmacotherapeutic agents that are capable of reducing alcohol intake remains an important focus in the field of alcohol research.. The objective of the present study was to examine the effects of the delta 2 receptor antagonist naltriben (0.60-4.0 mg/kg) on operant responding maintained by the presentation of ethanol (EtOH) or saccharin in alcohol-preferring (P) rats.. P rats were trained under a concurrent schedule [fixed ratio (FR)4-FR4] to press one lever for EtOH (10% v/v) and another for saccharin (0.0125-0.05% w/v) during a 60-min session. Naloxone, a non-specific opioid receptor antagonist, served as a reference antagonist.. When responding maintained by EtOH and saccharin were equated under baseline conditions, naloxone (0.003125-0.75 mg/kg) reduced levels of EtOH-maintained responding by 46-82%. None of the naloxone doses significantly reduced responding maintained by saccharin. Naltriben (0.9-4.0 mg/kg) reduced EtOH-maintained responding by 44-76%, while saccharin-maintained responding was reduced only by the highest dose of naltriben (4.0 mg/kg). Analysis of the EtOH within-session response pattern revealed that naloxone suppressed EtOH-maintained responding during the entire operant session and led to early termination of responding. Low doses of naltriben (0.90 mg/kg and 1.2 mg/kg) suppressed responding during the latter portion of the operant session, while higher doses (2.0, 3.0, 4.0 mg/kg) decreased responding during the entire session and led to early termination of responding.. The results of the present study strengthen previous reports from our laboratory suggesting that naltriben, the selective delta 2 opioid receptor antagonist, suppresses EtOH self-administration in rats selectively bred for high EtOH consumption. The results also suggest that naltriben may be a potential candidate for use as a pharmacotherapeutic agent in the treatment of EtOH dependence.

Topics: Alcohol Deterrents; Alcohol Drinking; Animals; Central Nervous System Depressants; Conditioning, Operant; Ethanol; Female; Motivation; Naloxone; Naltrexone; Narcotic Antagonists; Rats; Rats, Inbred Strains; Receptors, Opioid, delta; Reinforcement Schedule

CD-1 mice were treated intravenously with streptozotocin, 200 mg/kg, and tested 2 weeks later or treated with 60 mg/kg and tested 3 days later. Both treatments changed the tail flick response of heroin and 6-monoacetylmorphine (6 MAM) given intracerebroventricularly from a mu- to delta-opioid receptor-mediated action as determined by differential effects of opioid receptor antagonists. The response to morphine remained mu. Heroin and 6 MAM responses involved delta1 (inhibited by 7-benzylidenenaltrexone) and delta2 (inhibited by naltriben) receptors, respectively. These delta-agonist actions did not synergize with the mu-agonist action of morphine in the diabetic mice. The expected synergism between the delta agonist, [D-Pen2-D-Pen5]enkephalin (DPDPE), and morphine was not obtained in diabetic mice. Thus, diabetes disrupted the purported mu/delta-coupled response. In nondiabetic CD-1 mice, heroin and 6 MAM produced a different mu-receptor response (not inhibited by naloxonazine) from that of morphine (inhibited by naloxonazine). Also, these mu actions, unlike that of morphine, did not synergize with DPDPE. The unique receptor actions and changes produced by streptozotocin suggest that extrinsic in addition to genetic factors influence the opioid receptor selectivity of heroin and 6 MAM.

Topics: Analgesics, Opioid; Animals; Anti-Bacterial Agents; Benzylidene Compounds; Diabetes Mellitus, Experimental; Dose-Response Relationship, Drug; Drug Interactions; Enkephalin, D-Penicillamine (2,5)-; Enkephalins; Heroin; Injections, Intraventricular; Male; Mice; Morphine; Morphine Derivatives; Naloxone; Naltrexone; Narcotic Antagonists; Nociceptors; Pain; Receptors, Opioid, delta; Receptors, Opioid, mu; Streptozocin; Time Factors

An unbiased place preference conditioning procedure was used to examine the role of delta-opioid receptors in mediating the aversive effects of opioid withdrawal. Rats were implanted s.c. with two pellets each containing placebo or 75 mg morphine. Single-trial conditioning sessions with saline and the opioid receptor antagonists naloxone (0.001-1.0 mg/kg, s.c.), naltrindole (0.01-3.0 mg/kg, s.c.) or naltriben (0.01-3.0 mg/kg, s.c.) commenced 4 days later. During these conditioning sessions, physical signs of withdrawal were also quantified. Tests of conditioning were conducted on day 5. Naloxone in doses of 0.01-1.0 mg/kg produced significant conditioned place aversions in morphine-implanted animals. A dose of 0.01 mg/kg produced few physical withdrawal signs whereas higher doses resulted in marked wet dog shakes, body weight loss ptosis and diarrhea. No such effects were observed in control (placebo-implanted) animals. Administration of the selective delta-opioid receptor antagonists naltrindole and naltriben produced dose-related place aversions in morphine-implanted animals. The magnitude of these effects did not differ from that observed with naloxone. The minimum effective doses of naltrindole and naltriben were 0.1 mg/kg. Doses of 0.1-1.0 mg/kg produced few, if any, somatic signs of withdrawal whereas higher doses of these antagonists only produced diarrhea and wet-dog shakes. Other withdrawal signs were absent. In contrast to the opioid receptor antagonists tested, the dopamine D1 receptor antagonist SCH23390 failed to produced conditioned place aversions or physical signs of withdrawal in morphine-pelleted animals. These data demonstrate that the selective blockade of either delta- or mu-opioid receptors is sufficient to induce conditioned aversive effects in morphine-dependent animals. They also indicate that physical symptoms associated with precipitated morphine withdrawal differ depending upon the opioid receptor antagonist employed.

Topics: Animals; Dose-Response Relationship, Drug; Male; Morphine; Naloxone; Naltrexone; Narcotic Antagonists; Rats; Rats, Sprague-Dawley; Receptors, Opioid, delta; Substance Withdrawal Syndrome

Neuroblastoma NS20Y cells possess a high density of stereoselective delta opioid receptors as determined by competition binding with 3H-diprenorphine and various opioid ligands. Scatchard analysis of [3H]diprenorphine saturation binding data revealed a Kd = 0.79 +/- 0.17 nM and Bmax = 370 +/- 50 fmol/mg protein. These opioid binding sites have highest affinity for delta opioid receptor selective agonists and lowest affinity for mu opioid receptor selective agonists. Agonist binding was sensitive to the presence of the monovalent cation, Na+. Activation of receptor with D-Ala2, D-Leu5-enkephalin (DADLE) resulted in dose-dependent inhibition of forskolin-stimulated intracellular [3H]cAMP accumulation, which was antagonized by (-)-naloxone but not (+)-naloxone. Relative potencies of various opioid agonists to inhibit intracellular cAMP production paralleled those observed in neuroblastoma x glioma NG108-15 hybrid cells. Pretreatment of NS20Y cells with pertussis toxin (PTX) eliminated opioid agonist inhibition of adenylyl cyclase activity. Chronic DADLE treatment resulted in desensitization and down-regulation of opioid receptor. An increase in intracellular [3H]cAMP level above the control was observed in the presence of naloxone after chronic DADLE treatment. Therefore, opioid binding sites in neuroblastoma NS20Y cells possess properties of the classical delta opioid receptor type. After neuroblastoma NS20Y was growth arrested by culturing the cells in serum-free medium for 72 hr, proliferation was reinitiated by addition of fetal calf serum (FCS), 0.01% to 12%, and was monitored by either [3H]thymidine incorporation or by dye viability assay. It was demonstrated that naloxone and naltriben but not Met5-enkephalin could attenuate FCS-induced proliferation in a dose-dependent manner. Naltriben was 54-fold more potent than naloxone to attenuate NS20Y proliferation. The maximal level of viable cells per well was reduced (35.2 +/- 1.9%) with no alteration in FCS concentration-dependent stimulation of growth. Similar inhibition by naloxone (37.3 +/- 2.7%) was observed with [3H]thymidine incorporation studies. This naloxone effect was serum concentration-dependent and could be blocked by culturing NS20Y cells in the presence of both naloxone and Met5-enkephalin. Although pretreatment of NS20Y cells with pertussis toxin could attenuate FCS-stimulated proliferation, naloxone effect on growth was not affected by pertussis toxin pretreatment. Furthermore, the naloxo

Topics: Adenylate Cyclase Toxin; Adenylyl Cyclases; Animals; Cell Division; Cyclic AMP; Humans; In Vitro Techniques; Mice; Naloxone; Naltrexone; Neuroblastoma; Pertussis Toxin; Receptors, Opioid, delta; Second Messenger Systems; Signal Transduction; Tumor Cells, Cultured; Virulence Factors, Bordetella

The possible involvement of delta 2 opioid receptors in the development of morphine dependence was investigated using selective delta 2 receptor antagonists, naltriben (NTB) and naltrindole 5'-isothiocyanate (5'-NTII). The degree of morphine dependence was estimated by the ED50 values of naloxone (s.c.) required to precipitate withdrawal jumping and diarrhea 72 hr after morphine pellet implantation. NTB administered s.c. as well as naloxone precipitated jumping and diarrhea in morphine-dependent mice. Chronic treatment with 5'-NTII (both i.c.v. and i.t. routes, 24 hr before, just before, 24 and 48 hr after morphine pellet implantation) increased the ED50 values of naloxone for jumping and diarrhea. These results suggest that both supraspinal and spinal delta 2 opioid receptors are involved in the development of physical dependence on systemically administered morphine. However, chronic treatment with NTB (s.c. route, 30 min before, 24 and 48 hr after morphine pellet implantation) failed to affect the ED50 values of naloxone for both withdrawal signs. These seemingly discrepant results suggest that continuous blockade of delta 2 opioid receptors (by a nonequilibrium and long-lasting antagonist, 5'-NTII) rather than intermittent blockade of delta 2 opioid receptors (by an equilibrium and relatively short-acting antagonist, NTB) is necessary to inhibit the development of morphine dependence.

Topics: Animals; Enkephalin, Leucine; Isothiocyanates; Male; Mice; Morphinans; Morphine Dependence; Naloxone; Naltrexone; Receptors, Opioid, delta; Substance Withdrawal Syndrome; Thiocyanates