u-50488 has been researched along with naltrindole* in 42 studies
42 other study(ies) available for u-50488 and naltrindole
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Delta and kappa opioid receptors on mouse sperm cells: Expression, localization and involvement on in vitro fertilization.
The endogenous opioid peptides have been reported to be involved in the regulation of reproductive physiology. Many of the studies conclude with sentences around the harmful effect of opioids in male fertility but, actually, there is only one study regarding the real fertility potential of spermatozoa that have been exposed to mu specific opioids. The aim of the present study was to see if the modulation of delta (OPRD1) and kappa (OPRK1) opioid receptors in mouse sperm during capacitation was able to vary the embryo production after in vitro fertilization (IVF). The presence of OPRD1 and OPRK1 in mouse mature spermatozoa was analyzed by RT-PCR and immunofluorescence. Incubating the sperm with, on one hand, the delta specific agonist DPDPE and/or antagonist naltrindole, and, on the other hand, the kappa specific agonist U-50488 and antagonist nor-binaltorphimine, we analyzed the involvement of OPRD1 and OPRK1 on IVF and preimplantational embryo development. We verified the presence of OPRD1 and OPRK1 in mouse mature spermatozoa, not only at the mRNA level but also at protein level. Moreover, the sperm incubation with DPDPE, before the IVF, had an effect on the fertilization rate of sperm and reduced the number of reached blastocysts, which was reverted by naltrindole. Instead, the use of the kappa agonist U-50488 and the antagonist nor-binaltophimine did not have any effect on the amount and the quality of the achieved blastocysts. Although nowadays the pure delta or kappa opioid ligands are not used for the clinic, clinical trials are being conducted to be used in the near future, so it would be interesting to know if the modulation of these receptors in sperm would generate any consequence in relation to fertilization capacity. Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Blastocyst; Embryo, Mammalian; Embryonic Development; Enkephalin, D-Penicillamine (2,5)-; Fertilization in Vitro; Male; Mice; Naltrexone; Narcotic Antagonists; Oocytes; Receptors, Opioid, delta; Receptors, Opioid, kappa; Sperm Capacitation; Spermatozoa | 2020 |
Anti-nociception mediated by a κ opioid receptor agonist is blocked by a δ receptor agonist.
The opioid receptor family comprises four structurally homologous but functionally distinct sub-groups, the μ (MOP), δ (DOP), κ (KOP) and nociceptin (NOP) receptors. As most opioid agonists are selective but not specific, a broad spectrum of behaviours due to activation of different opioid receptors is expected. In this study, we examine whether other opioid receptor systems influenced KOP-mediated antinociception.. We used a tail withdrawal assay in C57Bl/6 mice to assay the antinociceptive effect of systemically administered opioid agonists with varying selectivity at KOP receptors. Pharmacological and genetic approaches were used to analyse the interactions of the other opioid receptors in modulating KOP-mediated antinociception.. Etorphine, a potent agonist at all four opioid receptors, was not anti-nociceptive in MOP knockout (KO) mice, although etorphine is an efficacious KOP receptor agonist and specific KOP receptor agonists remain analgesic in MOP KO mice. As KOP receptor agonists are aversive, we considered KOP-mediated antinociception might be a form of stress-induced analgesia that is blocked by the anxiolytic effects of DOP receptor agonists. In support of this hypothesis, pretreatment with the DOP antagonist, naltrindole (10 mg·kg(-1) ), unmasked etorphine (3 mg·kg(-1) ) antinociception in MOP KO mice. Further, in wild-type mice, KOP-mediated antinociception by systemic U50,488H (10 mg·kg(-1) ) was blocked by pretreatment with the DOP agonist SNC80 (5 mg·kg(-1) ) and diazepam (1 mg·kg(-1) ).. Systemic DOP receptor agonists blocked systemic KOP antinociception, and these results identify DOP receptor agonists as potential agents for reversing stress-driven addictive and depressive behaviours mediated through KOP receptor activation.. This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2. Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesia; Analgesics, Non-Narcotic; Analgesics, Opioid; Animals; Behavior, Animal; Benzamides; Diazepam; Etorphine; Female; Hot Temperature; Male; Mice, Inbred C57BL; Mice, Knockout; Naltrexone; Nociceptin Receptor; Nociception; Piperazines; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Stress, Psychological | 2015 |
Effects of systemic opioid receptor ligands on ethanol- and sucrose seeking and drinking in alcohol-preferring (P) and Long Evans rats.
The endogenous opioid system has been implicated in mediating the reinforcing effects of ethanol (EtOH). Naltrexone (NTX), an opioid antagonist with concentration-dependent selectivity for the mu receptor, naltrindole (NTI), a selective delta receptor antagonist, and U50,488H, a selective kappa receptor agonist were examined in both alcohol-preferring (P) and nonselected (Long Evans (LE)) rats to determine whether they differentially affected the seeking and consumption of EtOH and sucrose. Using the sipper-tube model, rats reinforced with either 2% sucrose or 10% EtOH were injected with vehicle and either NTI (2.5, 5.0, or 10.0 mg/kg), U50 (2.5, 5.0, or 10.0 mg/kg), low-dose NTX (0.1, 0.3, or 1.0 mg/kg), or high-dose NTX (1.0, 3.0, or 10.0 mg/kg). Subsequent intakes (consummatory) or lever responses (seeking) were assessed. Overall, NTI, U50, and NTX attenuated intake and responding for sucrose and EtOH, with EtOH-reinforced P rats being the most sensitive to the effects of NTI on intake and seeking. U50 treatment decreased intake and seeking in both P and LE rats but did not selectively reduce EtOH intake or seeking in either line. P rats were more sensitive than LE rats to lower doses of NTX, and these doses more selectively attenuated responding for EtOH than sucrose. Higher doses of NTX suppressed intake and responding across both lines and reinforcers. These results suggest that drugs selective for the opioid receptors may be good pharmacotherapeutic targets, particularly in those with an underlying genetic predisposition for greater EtOH preference/intake. Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics, Non-Narcotic; Animals; Behavior, Addictive; Behavior, Animal; Ethanol; Ligands; Male; Naltrexone; Narcotic Antagonists; Rats; Rats, Long-Evans; Receptors, Opioid; Sucrose | 2014 |
Opioidergic modulation of ethanol self-administration in the ventral pallidum.
Striatopallidal medium spiny neurons have been viewed as a final common path for drug reward and the ventral pallidum as an essential convergent point for hedonic and motivational signaling in the brain. The medium spiny neurons are GABAergic, but they colocalize enkephalin. Purpose of this study was to investigate the role of the opioidergic mechanisms of the ventral pallidum in ethanol self-administration behavior.. Effects of bilateral microinjections of μ-, δ-, and κ-opioid receptor agonists and antagonists into the ventral pallidum on voluntary ethanol consumption were monitored in alcohol-preferring Alko Alcohol (AA) rats using the 90-minute limited access paradigm.. Stimulation of μ-opioid receptors with DAMGO (0.01 to 0.1 μg) or morphine (1 to 10 μg) in the ventral pallidum decreased ethanol intake dose-dependently. Conversely, blocking μ-receptors with CTOP (0.3 to 3 μg) increased ethanol intake significantly. Unlike CTOP, DAMGO also increased locomotor activity. Consumption of ethanol was not modified significantly by a broad-spectrum opioid receptor antagonist naltrexone, by δ-opioid receptor agonist DPDPE or antagonist naltrindole, or by a κ-opioid receptor agonist U50,488H or antagonist nor-BNI.. The study provides evidence for μ- but not δ- or κ-opioid receptors in the ventral pallidum playing a role in the regulation of voluntary ethanol consumption. Furthermore, present findings give support to earlier work, suggesting an essential role of pallidal opioidergic transmission in drug reward. Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Alcohol Drinking; Analgesics, Opioid; Animals; Dose-Response Relationship, Drug; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, D-Penicillamine (2,5)-; Globus Pallidus; Male; Microinjections; Morphine; Motor Activity; Naltrexone; Narcotic Antagonists; Rats; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Self Administration; Somatostatin | 2012 |
Involvement of the kappa-opioid receptor in nitrous oxide-induced analgesia in mice.
Nitrous oxide (N(2)O)-induced analgesia is thought to be mediated by endogenous opioids. We previously showed that the mu-opioid receptor is not required for the analgesic action of N(2)O in mice using a gene knockout approach. In this study, we examined the effect of kappa- (KOP)- or delta-opioid receptor (DOP)-selective antagonists on N(2)O-induced analgesia. The analgesic effect of N(2)O was evaluated using a writhing test. Male C57BL/6 mice aged 7-8 weeks were assigned to control, N(2)O, KOP agonist, and DOP agonist groups. According to the group assignment, mice were pretreated with a KOP antagonist, nor-binaltorphimine (nor-BNI), a DOP antagonist, naltrindole hydrochloride (NTI), a KOP agonist U50488, and a DOP agonist SNC80. Mice in the control, KOP agonist, and DOP agonist groups were exposed to 25% oxygen/75% nitrogen for 30 min, and mice in the N(2)O group were exposed to 25% oxygen/75% N(2)O for 30 min. Nor-BNI [10 mg kg(-1), subcutaneously (s.c.)] significantly suppressed the analgesic effect of N(2)O and U50488. In contrast, NTI (10 mg kg(-1) s.c.) did not significantly affect the analgesic action of N(2)O, but almost completely inhibited the analgesic effect of SNC80. These results suggest that KOP plays an important role in the analgesic effect of N(2)O in mice. Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesia; Analgesics, Non-Narcotic; Animals; Benzamides; Male; Mice; Mice, Inbred C57BL; Naltrexone; Narcotic Antagonists; Nitrous Oxide; Pain; Piperazines; Receptors, Opioid, delta; Receptors, Opioid, kappa; Treatment Outcome | 2010 |
Alteration of intravenous nicotine self-administration by opioid receptor agonist and antagonists in rats.
The role played by endogenous opioids in mediating the reinforcing properties of nicotine is unclear. As with preclinical studies, clinical trials with naloxone, a prototypic opioid receptor antagonist have yielded equivocal findings with regard to its efficacy in reducing cigarette smoking.. The aim of the present study was to examine the effects of three opioids that exhibit relative selectivity at mu-, kappa- and delta-opioid receptors on nicotine self-administration in male hooded Lister rats.. Graded doses (0.3, 1.0, and 3.0 mg/kg IP) of each opioid agonist or antagonist were tested in different groups of rats repeatedly over three consecutive nicotine intravenous nicotine-self administration (0.03 mg/kg/infusion) sessions. The same treatments were tested in parallel groups of rats trained to respond for food reinforcement.. Naloxone was very effective in attenuating the levels of nicotine self-administered across all doses tested. The selective kappa-opioid receptor agonist U50,488, reduced nicotine self-administration in doses of 1 and 3 mg/kg, while the 0.3 mg/kg dose produced a small increase in nicotine intake. Finally, the specific delta-opioid receptor antagonist, naltrindole did not significantly modify nicotine self-administration behaviour. In contrast, all three opioids failed to modify behaviour maintained by food reinforcement.. These findings suggest endogenous opioids are crucial in mediating the reinforcing effects of nicotine and that the mu-opioid receptor subtype may represent a potential target for selectively reducing nicotine-taking behaviour as part of a pharmacological approach to develop smoking cessation aids. Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Dose-Response Relationship, Drug; Feeding Behavior; Male; Naloxone; Naltrexone; Narcotic Antagonists; Nicotine; Rats; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Self Administration; Tobacco Use Disorder | 2010 |
Selectivity of delta- and kappa-opioid ligands depends on the route of central administration in mice.
The existence of heterodimeric opioid receptors has introduced greater complexity to the in vivo characterization of pharmacological selectivity of agonists by antagonists. Because of the possibility of cooperativity between receptors organized as heterodimers, it is conceivable that selective antagonists may antagonize an agonist bound to a neighboring, allosterically coupled receptor. As a consequence, the in vivo selectivity of an opioid antagonist may depend on the organizational state of receptors that mediate analgesia. In this regard, phenotypic delta- and kappa-opioid receptors have been proposed to arise from different organizational states that include oligomeric delta-kappa heterodimers and homomeric delta and kappa receptors. In view of the evidence for analgesia mediated by delta-kappa heterodimers in the spinal cord, but not the brain, we have investigated the selectivity of pharmacologically selective delta and kappa antagonists in mice by both i.t. and i.c.v. routes of administration to evaluate changes in selectivity. Using pharmacologically selective delta (benzylidenenaltrexone, naltrindole, and naltriben) and kappa (norbinaltorphimine) antagonists versus delta ([D-Pen(2),D-Pen(5)]-enkephalin and deltorphin II) and kappa [3,4-dichloro-N-methyl-N-[(1R,2R)-2-(1-pyrrolidinyl)cyclohexyl]-benzeneacetamide (U50488) and bremazocine] agonists, the delta-1/delta-2 selectivity ratios were found to be dependent on the route of administration (i.t. versus i.c.v.). The data from different routes of administration suggest that differences in molecular recognition between spinal delta-kappa heterodimers and supraspinal homomeric delta and kappa receptors may contribute to the divergent selectivity ratios of selective antagonists. In view of the observed tissue-dependent selectivity, we suggest that multiple opioid antagonists be employed routinely in establishing agonist selectivity in vivo. Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Benzylidene Compounds; Enkephalin, D-Penicillamine (2,5)-; Injections, Intraventricular; Injections, Spinal; Ligands; Male; Mice; Mice, Inbred ICR; Naltrexone; Narcotic Antagonists; Receptors, Opioid, delta; Receptors, Opioid, kappa | 2007 |
Relative contribution of peripheral versus central opioid receptors to antinociception.
Opioid effects are mediated by central and peripheral opioid receptors. Here we examine the relative contribution of each receptor population to antinociception elicited by systemically administered centrally penetrating opioids, and by loperamide (a peripherally restricted opioid). Nociception (abdominal writhes) was induced by intraperitoneally (i.p.) injected 0.6% acetic acid in mice. We analyzed opioid receptor expression in peritoneum by immunohistochemistry, antinociception after i.p. injected agonists at mu (morphine, loperamide)-, delta (SNC80)- and kappa (U50488)-receptors, and its reversibility by subcutaneously (s.c.) administered centrally penetrating antagonists beta-funaltrexamine (mu), naltrindole (delta) and nor-binaltorphimine (kappa), and by the peripherally restricted antagonist naloxone methiodide (NLXM). NLXM was also injected intracerebroventricularly (i.c.v.) before i.p. loperamide. Mu-, kappa- and, to a lesser degree, delta-receptors were expressed on peripheral nerve terminals in the peritoneum. The anatomical distribution of the opioid receptor staining was very similar to the staining for calcitonin gene-related peptide, a marker of sensory neurons. Morphine, U50488 and, to a lesser degree, SNC80 blocked acetic and acid induced writhes. These effects were reversed by beta-funaltrexamine, nor-binaltorphimine and naltrindole, respectively. NLXM (s.c.) reversed antinociceptive effects of morphine, SNC80 and U50488 by 57%, 80% and 47%, respectively. Loperamide (0.05 mg/kg)-induced antinociception was reversed by s.c. beta-funaltrexamine and NLXM. Loperamide (0.1 mg/kg)-induced antinociception was completely blocked by s.c. beta-funaltrexamine but was only attenuated (by 50%) by s.c. or i.c.v. NLXM. In conclusion, systemically administered centrally penetrating mu-, delta- and kappa-agonists produced a substantial part of antinociception through peripheral opioid receptors. Higher dose loperamide-induced antinociception involved also central opioid receptors. Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Acetic Acid; Analgesics, Non-Narcotic; Analgesics, Opioid; Analysis of Variance; Animals; Calcitonin Gene-Related Peptide; Dose-Response Relationship, Drug; Drug Administration Routes; Drug Interactions; Gene Expression; Loperamide; Male; Mice; Mice, Inbred C57BL; Naltrexone; Narcotic Antagonists; Pain; Receptors, Opioid | 2007 |
Involvement of kappa opioid receptors in formalin-induced inhibition of analgesic tolerance to morphine in mice.
This study examined the role of kappa opioid receptors (KOR) in the mechanism underlying tolerance to the analgesic effects of morphine induced by chronic pain. The analgesic effect of morphine (10 mg kg(-1)), estimated by the tail-flick test in mice, gradually decreased during repeated daily morphine treatment. A significant decrease in the analgesic effect of morphine was seen on the fifth day of repeated morphine treatment compared with the first day. Chronic pain was induced by subcutaneous administration of 2% formalin into the dorsal part of the left hind paw, which significantly inhibited development of tolerance to morphine analgesia. The effect of formalin-induced pain on inhibition of morphine tolerance was reversed by the KOR antagonist nor-binaltorphimine. Furthermore, an antisense oligodeoxynucleotide, but not a missense oligodeoxynucleotide, against KOR completely suppressed the inhibitory effect of formalin-induced pain on morphine tolerance. Naltrindole, an antagonist of delta opioid receptor, did not affect chronic-pain-induced tolerance to morphine. Our findings show that the inhibitory effect of chronic pain on analgesic tolerance to morphine is mediated by KOR rather than delta opioid receptors. Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics, Opioid; Animals; Chronic Disease; Drug Tolerance; Formaldehyde; Male; Mice; Morphine; Naltrexone; Oligonucleotides, Antisense; Pain; Pain Measurement; Pain Threshold; Receptors, Opioid, delta; Receptors, Opioid, kappa; Tail | 2007 |
A bivalent ligand (KDAN-18) containing delta-antagonist and kappa-agonist pharmacophores bridges delta2 and kappa1 opioid receptor phenotypes.
To characterize delta- and kappa-opioid receptor phenotypes, bivalent ligands (KDAN series) containing delta-antagonist (naltrindole) and kappa(1)-agonist (ICI-199,441) pharmacophores were synthesized and evaluated by the intrathecal route using the mouse tail-flick assay and binding studies. The data have suggested that KDAN-18 (2) bridges phenotypic delta(2)- and kappa(1)-receptors. A conceptual model is presented to explain the organizational differences between the opioid receptors that give rise to the phenotypes (delta(1), delta(2), kappa(1), kappa(2)). Topics: Allosteric Regulation; Amides; Animals; Binding, Competitive; Cell Line; Humans; Injections, Spinal; Ligands; Mice; Naltrexone; Phenotype; Pyrrolidines; Radioligand Assay; Receptors, Opioid, delta; Receptors, Opioid, kappa; Structure-Activity Relationship | 2005 |
A Tyr-W-MIF-1 analog containing D-Pro2 acts as a selective mu2-opioid receptor antagonist in the mouse.
The antagonistic properties of Tyr-d-Pro-Trp-Gly-NH(2) (d-Pro(2)-Tyr-W-MIF-1), a Tyr-Pro-Trp-Gly-NH(2)(Tyr-W-MIF-1) analog, on the antinociception induced by the mu-opioid receptor agonists Tyr-W-MIF-1, [d-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin (DAMGO), Tyr-Pro-Trp-Phe-NH(2) (endomorphin-1), and Tyr-Pro-Phe-Phe-NH(2) (endomorphin-2) were studied in the mouse paw-withdrawal test. d-Pro(2)-Tyr-W-MIF-1 injected intrathecally (i.t.) had no apparent effect on the thermal nociceptive threshold. d-Pro(2)-Tyr-W-MIF-1 (0.1-0.4 nmol) coadministered i.t. showed a dose-dependent attenuation of the antinociception induced by Tyr-W-MIF-1 without affecting endomorphin- or DAMGO-induced antinociception. However, higher doses of d-Pro(2)-Tyr-W-MIF-1 (0.8-1.2 nmol) significantly attenuated endomorphin-1- or DAMGO-induced antinociception, whereas the antinociception induced by endomorphin-2 was still not affected by d-Pro(2)-Tyr-W-MIF-1. Pretreatment i.t. with various doses of naloxonazine, a mu(1)-opioid receptor antagonist, attenuated the antinociception induced by Tyr-W-MIF-1, endomorphin-1, endomorphin-2, or DAMGO. Judging from the ID(50) values for naloxonazine against the antinociception induced by the mu-opioid receptor agonists, the antinociceptive effect of Tyr-W-MIF-1 is extremely less sensitive to naloxonazine than those of endomorphin-1 or DAMGO. In contrast, endomorphin-2-induced antinociception is extremely sensitive to naloxonazine. The present results clearly suggest that d-Pro(2)-Tyr-W-MIF-1 is the selective antagonist to be identified for the mu(2)-opioid receptor in the mouse spinal cord. d-Pro(2)-Tyr-W-MIF-1 may also discriminate between Tyr-W-MIF-1-induced antinociception and the antinociception induced by endomorphin-1 or DAMGO, all of which show a preference for the mu(2)-opioid receptor in the spinal cord. Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics, Opioid; Animals; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Male; Mice; MSH Release-Inhibiting Hormone; Naloxone; Naltrexone; Narcotic Antagonists; Oligopeptides; Receptors, Opioid, mu | 2005 |
Characterisation of opioid receptors involved in modulating circular and longitudinal muscle contraction in the rat ileum.
1. The aim of the present investigation was to characterise the opioid receptor subtypes present in the rat ileum using a method that detects drug action on the enteric nerves innervating the circular and longitudinal muscles. 2. Neurogenic contractions were reversibly inhibited by morphine (circular muscle pEC50, 6.43+/-0.17, Emax 81.7+/-5.0%; longitudinal muscle pEC50, 6.65+/-0.27, Emax 59.7+/-7.8%), the mu-opioid receptor-selective agonist, DAMGO ([D-Ala2,N-Me-Phe4,Gly5-ol]enkephalin acetate) (circular pEC50, 7.85+/-0.04, Emax 97.8+/-3.6%; longitudinal pEC50, 7.35+/-0.09, Emax 56.0+/-6.1%), the delta-selective agonist DADLE ([D-Ala2,D-Leu5]enkephalin acetate) (circular pEC50, 7.41+/-0.17, Emax, 93.3+/-8.4%; longitudinal pEC50, 6.31+/-0.07, Emax 66.5+/-5.2%) and the kappa-selective agonist U 50488H (trans-(+/-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide methanesulphonate) (circular pEC50, 5.91+/-0.41, Emax, 83.5+/-26.8%; longitudinal pEC50, 5.60+/-0.08, Emax 74.3+/-7.2%). Agonist potencies were generally within expected ranges for activity at the subtype for which they are selective, except for U 50488H, which was less potent than expected. 3. The mu and delta receptor-selective antagonists, CTAP (H-D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2) and naltrindole, caused progressive, parallel rightward shifts in the DAMGO and DADLE curves, respectively. Analysis indicated conformity to theoretical simple competitive antagonist behaviour. U 50488H effects were insensitive to the kappa-selective antagonist, n-BNI. A high concentration (1 microM) of naltrexone caused apparent potentiation of U 50488H effects. 4. CTAP pK(B) estimates were consistent with previously reported values for mu receptor antagonism (circular 7.84+/-0.17, longitudinal 7.64+/-0.35). However, the naltrindole pK(B) estimates indicated lower antagonist potency than expected (circular 8.22+/-0.23, longitudinal 8.53+/-0.35). 5. It is concluded that mu and possibly atypical delta receptors (but not kappa receptors) mediate inhibition of contraction in this model. Nonopioid actions of U 50488H are probably responsible for the inhibitory effects seen with this compound. Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics, Non-Narcotic; Analgesics, Opioid; Animals; Electric Stimulation; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, Leucine-2-Alanine; Enteric Nervous System; Female; Guinea Pigs; Ileum; In Vitro Techniques; Male; Morphine; Muscle Contraction; Naltrexone; Narcotic Antagonists; Rats; Rats, Wistar; Receptors, Opioid, delta; Receptors, Opioid, mu | 2005 |
Lack of the nociceptin receptor does not affect acute or chronic nociception in mice.
The peptide nociceptin/orphanin FQ (N/OFQ) and its receptor ORL-1, also designated opioid receptor 4 (OP(4)) are involved in the modulation of nociception. Using OP(4)-knockout mice, we have studied their response following opioid receptor stimulation and under neuropathic conditions.In vas deferens from wild-type and OP(4)-knockout mice, DAMGO (mu/OP(3) agonist), deltorphine II (delta/OP(1) agonist) and (-)-U-50488 (kappa/OP(2) agonist) induced similar concentration-dependent inhibition of electrically-evoked contractions. Naloxone and naltrindole (delta/OP(1) antagonists) shifted the curves of DAMGO (pA(2)=8.6) and deltorphine II (pA(2)=10.2) to the right, in each group. In the hot-plate assay, N/OFQ (10 nmol per mouse, i.t.) increased baseline latencies two-fold in wild-type mice while morphine (10mg/kg, s.c.), deltorphine II (10 nmol per mouse, i.c.v.) and dynorphin A (20 nmol per mouse, i.c.v.) increased hot-plate latencies by about four- to five-fold with no difference observed between wild-type and knockout mice. Furthermore, no change was evident in the development of the neuropathic condition due to chronic constriction injury (CCI) of the sciatic nerve, after both thermal and mechanical stimulation. Altogether these results suggest that the presence of OP(4) receptor is not crucial for (1) the development of either acute or neuropathic nociceptive responses, and for (2) the regulation of full receptor-mediated responses to opioid agonists, even though compensatory mechanisms could not be excluded. Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics, Non-Narcotic; Analgesics, Opioid; Animals; Dose-Response Relationship, Drug; Dynorphins; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Female; Male; Mice; Mice, Knockout; Morphine; Naloxone; Naltrexone; Narcotic Antagonists; Nociceptin; Nociceptin Receptor; Oligopeptides; Opioid Peptides; Pain; Receptors, Opioid; Time Factors; Vas Deferens | 2002 |
Delta opioid inhibition of light-induced phase advances in hamster circadian activity rhythms.
A master neuronal pacemaker located within the suprachiasmatic nucleus in the ventral hypothalamus generates circadian activity rhythms in hamsters. The circadian pacemaker receives afferent input from many brain regions, one of which is the intergeniculate leaflet of the thalamus. This thalamic input to the suprachiasmatic nucleus in hamsters contains enkephalins, neuropeptide Y, neurotensin, and GABA. The role of enkephalins in modulating light-induced phase shifts of hamster activity rhythms has not been reported. Therefore, in this study, we examined the ability of enkephalin-mimetic and other opioid compounds to modulate light-induced phase advances in hamster circadian activity rhythms. The delta opioid agonists SNC 80 and BW373U86 both inhibited light-induced phase advances of hamster circadian activity rhythms. Neither the mu opioid agonist morphine, nor the kappa opioid agonist U50488H had any effect on light-induced phase shifts. The antagonists naltrindole, naltrexone, and nor-binaltorphimine, selective for delta, mu, and kappa opioids respectively, were also without effect on light-induced phase advances. Therefore, we found that only delta opioid agonists modulate light-induced phase advances in hamster circadian activity rhythms. These results imply that enkephalins released from the intergeniculate leaflet onto components of the suprachiasmatic pacemaker may be capable of inhibiting the responsiveness of the pacemaker to photic input arriving from the retina. The inability of antagonists to modulate light-induced phase advances suggests that endogenous opiate systems are not tonically active in generating circadian activity rhythms, but rather that enkephalins are probably used by the circadian system to modulate responses only under certain conditions or time of day. Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Benzamides; Biological Clocks; Circadian Rhythm; Cricetinae; Enkephalins; Light; Male; Mesocricetus; Morphine; Motor Activity; Naltrexone; Narcotic Antagonists; Nerve Tissue Proteins; Opioid Peptides; Piperazines; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Suprachiasmatic Nucleus | 2002 |
Naloxone fails to produce conditioned place aversion in mu-opioid receptor knock-out mice.
There is growing evidence that tonic activity of the opioid system may be important in the modulation of affective state. Naloxone produces a conditioned place aversion in rodents, an effect that is centrally mediated. Previous pharmacological data using antagonists with preferential actions at mu-, delta-, and kappa-opioid receptors indicate the importance of the mu-opioid receptor in mediating this effect. We sought to test the mu-opioid receptor selectivity of naloxone aversion using mu-opioid receptor knock-out mice. mu-Opioid receptor knock-out and wild-type mice were tested for naloxone (10 mg/kg, s.c.) aversion using a place conditioning paradigm. As a positive control for associative learning, knock-out mice were tested for conditioned place aversion to a kappa agonist, U50,488H (2 mg/kg, s.c.). Naloxone produced a significant place aversion in wild-type mice, but failed to have any effect in mu-opioid receptor knock-out mice. On the other hand, both knock-out and wild-type mice treated with U50,488H spent significantly less time in the drug-paired chamber compared to their respective vehicle controls. We conclude that the mu-opioid receptor is crucial for the acquisition of naloxone-induced conditioned place aversion. Furthermore, in a separate experiment using C57BL/6 mice, the delta-selective antagonist naltrindole (10 or 30 mg/kg, s.c.) failed to produce conditioned place aversion.Taken together, these data further support the notion that naloxone produces aversion by antagonizing tonic opioid activity at the mu-opioid receptor. Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics, Non-Narcotic; Animals; Avoidance Learning; Brain; Conditioning, Psychological; Dose-Response Relationship, Drug; Habituation, Psychophysiologic; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Motor Activity; Naloxone; Naltrexone; Narcotic Antagonists; Neurons; Opioid Peptides; Phenotype; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Synaptic Transmission | 2001 |
Altered opioid-mediated control of the spinal release of dynorphin and met-enkephalin in polyarthritic rats.
Previous studies showed that spinal opioidergic neurotransmission is markedly altered in the polyarthritic rat, a model of chronic inflammatory pain. Present investigations aimed at assessing possible changes in opioid-mediated control of the spinal outflow of met-enkephalin (ME) and dynorphin (DYN) in these animals. Intrathecal (i.t.) perfusion under halothane anesthesia showed that polyarthritis was associated with both a 40% decrease in the spinal outflow of ME-like material (MELM) and a 90% increase in that of DYNLM. Local treatment with the mu-opioid agonist DAGO (10 microM i.t.) inhibited equally (-30%) the MELM outflow in polyarthritic and control rats, whereas the delta agonist DTLET (10 microM i.t.) also reduced the peptide outflow in controls (-27%) but enhanced it in polyarthritic animals (+56%). On the other hand, both DAGO (10 microM i.t.) and DTLET (10 microM i.t.) decreased (-40 and -49%) DYNLM outflow in polyarthritic rats, but were inactive in controls. Finally, neither MELM outflow nor that of DYNLM were affected by the kappa-agonist U50488H (10 microM i.t.) in both groups of rats. In all cases, the changes due to active agonists could be prevented by specific antagonists which were inactive on their own except the kappa antagonist nor-binaltorphimine (10 microM i.t.) that decreased (-38%) DYNLM outflow in polyarthritic rats. These data indicate that functional changes in spinal opioid receptors may promote enkephalinergic neurotransmission and reduce dynorphinergic neurotransmission in polyarthritic rats, thereby contributing to the analgesic efficacy of opioids in inflammatory pain. Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics, Non-Narcotic; Analgesics, Opioid; Anesthesia; Animals; Arthritis; Dynorphins; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, Methionine; Iodine Radioisotopes; Ligands; Male; Naloxone; Naltrexone; Narcotic Antagonists; Oligopeptides; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Spinal Cord | 2000 |
delta-, but not mu- and kappa-, opioid receptor activation protects neocortical neurons from glutamate-induced excitotoxic injury.
Recent observations from our laboratory have led us to hypothesize that delta-opioid receptors may play a role in neuronal protection against hypoxic/ischemic or glutamate excitotocity. To test our hypothesis in this work, we used two independent methods, i.e., "same field quantification" of morphologic criteria and a biochemical assay of lactate dehydrogenase (LDH) release (an index of cellular injury). We used neuronal cultures from rat neocortex and studied whether (1) glutamate induces neuronal injury as a function of age and (2) activation of opioid receptors (delta, mu and kappa subtypes) protects neurons from glutamate-induced injury. Our results show that glutamate induced neuronal injury and cell death and this was dependent on glutamate concentration, exposure period and days in culture. At 4 days, glutamate (up to 10 mM, 4 h-exposure) did not cause apparent injury. After 8-10 days in culture, neurons exposed to a much lower dose of glutamate (100 microM, 4 h) showed substantial neuronal injury as assessed by morphologic criteria (>65%, n=23, P<0.01) and LDH release (n=16, P<0. 001). Activation of delta-opioid receptors with 10 microM DADLE reduced glutamate-induced injury by almost half as assessed by the same criteria (morphologic criteria, n=21, P<0.01; LDH release, n=16, P<0.01). Naltrindole (10 microM), a delta-opioid receptor antagonist, completely blocked the DADLE protective effect. Administration of mu- and kappa-opioid receptor agonists (DAMGO and U50488H respectively, 5-10 microM) did not induce appreciable neuroprotection. Also, mu- or kappa-opioid receptor antagonists had no appreciable effect on the glutamate-induced injury. This study demonstrates that activation of neuronal delta-opioid receptors, but not mu- and kappa-opioid receptors, protect neocortical neurons from glutamate excitotoxicity. Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics, Non-Narcotic; Analgesics, Opioid; Animals; Cells, Cultured; Cytoprotection; Embryo, Mammalian; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, Leucine-2-Alanine; Excitatory Amino Acid Agonists; Female; Glutamic Acid; L-Lactate Dehydrogenase; Naltrexone; Narcotic Antagonists; Neocortex; Neurons; Pregnancy; Rats; Rats, Sprague-Dawley; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu | 2000 |
Different roles of mu-, delta- and kappa-opioid receptors in ethanol-associated place preference in rats exposed to conditioned fear stress.
The present study was designed to investigate the role of the endogenous opioid system in the development of ethanol-induced place preference in rats exposed to conditioned fear stress (exposure to an environment paired previously with electric foot shock), using the conditioned place preference paradigm. The administration of ethanol (300 mg/kg, i.p.) with conditioned fear stress induced significant place preference. Naloxone (1 and 3 mg/kg, s.c.), a non-selective opioid receptor antagonist, significantly attenuated this ethanol-induced place preference. Moreover, the selective mu-opioid receptor antagonist beta-funaltrexamine (3 and 10 mg/kg, i.p.) and the selective delta-opioid receptor antagonist naltrindole (1 and 3 mg/kg, s.c.) significantly attenuated ethanol-induced place preference. In contrast, the selective kappa-opioid receptor antagonist nor-binaltorphimine (3 mg/kg, i.p.) significantly enhanced ethanol-induced place preference. Furthermore, 75 mg/kg ethanol (which tended to produce place preference) combined with the mu-opioid receptor agonist morphine (0.1 mg/kg, s.c.) or the selective delta-opioid receptor agonist 2-methyl-4aalpha-(3-hydroxyphenyl)-1,2,3,4,4a,5,12,12aalpha- octahydroquinolino [2,3,3,-g] isoquinoline (TAN-67; 20 mg/kg, s.c.), at doses which alone did not produce place preference, produced significant place preference. However, co-administration of the selective kappa-opioid receptor agonist trans-3,4-dichloro-N-(2-(1-pyrrolidinyl)cyclohexyl)benzenacetamide methanesulfonate (U50,488H; 0.3 and 1 mg/kg, s.c.) with ethanol (300 mg/kg, i.p.) dose dependently attenuated ethanol-induced place preference. Moreover, conditioned fear stress shifted the response curve for the aversive effect of U50,488H to the left. These results suggest that mu- and delta-opioid receptors may play critical roles in the rewarding mechanism of ethanol, and that kappa-opioid receptors may modulate the development of the rewarding effect of ethanol under psychological stress. Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Behavior, Animal; Central Nervous System Depressants; Conditioning, Psychological; Ethanol; Fear; Male; Morphine; Naloxone; Naltrexone; Narcotic Antagonists; Quinolines; Rats; Rats, Sprague-Dawley; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Stress, Psychological | 1999 |
Analgesia-producing mechanism of processed Aconiti tuber: role of dynorphin, an endogenous kappa-opioid ligand, in the rodent spinal cord.
The analgesia-producing mechanism of processed Aconiti tuber was examined using rodents whose nociceptive threshold was decreased by loading repeated cold stress (RCS). The antinociceptive effect of processed Aconiti tuber (0.3 g/kg, p.o.) in RCS-loaded mice was antagonized by pretreatment with a kappa-opioid antagonist, nor-binaltorphimine (10 mg/kg, s.c.), and was abolished by an intrathecal injection of anti-dynorphin antiserum (5 microg). The Aconiti tuber-induced antinociception was inhibited by both dexamethasone (0.4 mg/kg, i.p.) and a dopamine D2 antagonist, sulpiride (10 mg/kg, i.p.), in RCS-loaded mice, and it was eliminated by both an electric lesion of the hypothalamic arcuate nucleus (HARN) and a highly selective dopamine D2 antagonist, eticlopride (0.05 microg), administered into the HARN in RCS-loaded rats. These results suggest that the analgesic effect of processed Aconiti tuber was produced via the stimulation of kappa-opioid receptors by dynorphin released in the spinal cord. It was also shown that dopamine D2 receptors in the HARN were involved in the expression of the analgesic activity of processed Aconiti tuber. Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Administration, Topical; Analgesics; Animals; Arcuate Nucleus of Hypothalamus; Cold Temperature; Dexamethasone; Dopamine Antagonists; Drugs, Chinese Herbal; Dynorphins; Glucocorticoids; Hypothalamus; Immune Sera; Ligands; Male; Mice; Naltrexone; Narcotic Antagonists; Nociceptors; Pain; Pain Threshold; Rats; Rats, Sprague-Dawley; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Salicylamides; Spinal Cord; Sulpiride | 1999 |
Identification of the G-protein-coupled ORL1 receptor in the mouse spinal cord by [35S]-GTPgammaS binding and immunohistochemistry.
1 Although the ORL1 receptor is clearly located within the spinal cord, the functional signalling mechanism of the ORL1 receptor in the spinal cord has not been clearly documented. The present study was then to investigate the guanine nucleotide binding protein (G-protein) activation mediated through by the ORL1 receptor in the mouse spinal cord, measuring the modulation of guanosine-5'-o-(3-[35S]-thio) triphosphate ([35S]-GTPgammaS) binding by the putative endogenous ligand nociceptin, also referred as orphanin FQ. We also studied the anatomical distribution of nociceptin-like immunoreactivity and nociceptin-stimulated [35S]-GTPgammaS autoradiography in the spinal cord. 2 Immunohistochemical staining of mouse spinal cord sections revealed a dense plexus of nociceptin-like immunoreactive fibres in the superficial layers of the dorsal horn throughout the entire length of the spinal cord. In addition, networks of fibres were seen projecting from the lateral border of the dorsal horn to the lateral grey matter and around the central canal. 3 In vitro [35S]-GTPgammaS autoradiography showed high levels of nociceptin-stimulated [35S]-GTPgammaS binding in the superficial layers of the mouse dorsal horn and around the central canal, corresponding to the areas where nociceptin-like immunoreactive fibres were concentrated. 4 In [35S]-GTPgammaS membrane assay, nociceptin increased [35S]-GTPgammaS binding of mouse spinal cord membranes in a concentration-dependent and saturable manner, affording maximal stimulation of 64.1+/-2.4%. This effect was markedly inhibited by the specific ORL1 receptor antagonist [Phe1Psi (CH2-NH) Gly2] nociceptin (1 - 13) NH2. None of the mu-, delta-, and kappa-opioid and other G-protein-coupled receptor antagonists had a significant effect on basal or nociceptin-stimulated [35S]-GTPgammaS binding. 5 These findings suggest that nociceptin-containing fibres terminate in the superficial layers of the dorsal horn and the central canal and that nociceptin released in these areas may selectively stimulate the ORL1 receptor to activate G-protein. Furthermore, the unique pattern of G-protein activation in the present study provide additional evidence that nociceptin is distinct from the mu-, delta- or kappa-opioid system. Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Atropine; Autoradiography; Baclofen; Binding, Competitive; Dose-Response Relationship, Drug; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, D-Penicillamine (2,5)-; GTP-Binding Proteins; Guanosine 5'-O-(3-Thiotriphosphate); Guanosine Diphosphate; Haloperidol; Immunohistochemistry; In Vitro Techniques; Male; Membranes; Mice; Mice, Inbred ICR; Naltrexone; Narcotic Antagonists; Nociceptin; Nociceptin Receptor; Opioid Peptides; Peptide Fragments; Propranolol; Receptors, Opioid; Somatostatin; Spinal Cord; Sulfur Radioisotopes; Yohimbine | 1999 |
Involvement of mu- and delta-opioid receptors in the ethanol-associated place preference in rats exposed to foot shock stress.
The purpose of this study was to establish the ethanol-induced place preference in rats exposed to foot shock stress using the conditioned place preference paradigm. We also investigated the role of the endogenous opioid system in the development of the ethanol-induced place preference. The administration of ethanol (300 mg/kg, i.p.) with foot shock stress, but not without such stress, induced a marked and significant place preference. Naloxone (1 and 3 mg/kg, s.c.), a non-selective opioid receptor antagonist, significantly attenuated the ethanol-induced place preference. Moreover, the selective mu-opioid receptor antagonist beta-funaltrexamine (3 and 10 mg/kg, i.p.) and selective delta-opioid receptor antagonist naltrindole (1 and 3 mg/kg, s.c.), but not the selective kappa-opioid receptor antagonist nor-binaltorphimine (1 and 3 mg/kg, i.p.), significantly attenuated the ethanol-induced place preference. Furthermore, 150 mg/kg ethanol (which tended to produce a place preference, although not significantly) combined with each dose (that did not produce a place preference) of the mu-opioid receptor agonist morphine (0.1 mg/kg, s.c.) or selective delta-opioid receptor agonist 2-methyl-4aalpha-(3-hydroxyphenyl)-1,2,3,4,4a,5,12, 12aalpha-octahydroquinolino [2,3,3-g] isoquinoline (TAN-67; 20 mg/kg, s.c.), but not the selective kappa-opioid receptor agonist trans-3, 4-dichloro-N-(2-(1-pyrrolidinyl)cyclohexyl)benzenacetamide methanesulfonate (U50,488H; 1 mg/kg, s.c.), produced a significant place preference. These data indicate that stress may be important for development of the rewarding effect of ethanol, and that mu- and delta-opioid receptors may be involved in the rewarding mechanism of ethanol under stressful conditions. Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Behavior, Animal; Dose-Response Relationship, Drug; Electric Stimulation; Ethanol; Exploratory Behavior; Foot; Injections, Intraperitoneal; Injections, Subcutaneous; Male; Morphine; Naloxone; Naltrexone; Narcotics; Quinolines; Rats; Rats, Sprague-Dawley; Receptors, Opioid, delta; Receptors, Opioid, mu | 1998 |
Renal excretory responses produced by the delta opioid agonist, BW373U86, in conscious rats.
Studies were performed in conscious Sprague-Dawley rats to characterize the changes in renal excretory function produced by activation of delta opioid systems. The intravenous infusion of 50 microgram/kg/min, BW373U86 (BW), a nonpeptide delta opioid receptor agonist, produced a significant increase in urine flow rate and urinary sodium excretion. The infusion of BW at a dose of 30 microgram/kg/min produced diuresis without affecting urinary sodium excretion. In contrast, BW did not alter either renal excretory parameter at a dose of 10 microgram/kg/min. The renal responses produced by BW occurred without changes in heart rate or mean arterial blood pressure. The diuretic and natriuretic responses produced by the i.v. infusion of BW (50 microgram/kg/min) were prevented by pretreatment of animals with the selective delta opioid receptor antagonist, naltrindole (1 mg/kg, i.v.). When administered alone, naltrindole (1 mg/kg, i.v.) failed to change any systemic cardiovascular or renal excretory parameter. In other groups of animals, the peripheral administration of the delta opioid receptor agonist, SNC80, also evoked a profound diuretic and natriuretic response (naltrindole sensitive) similar to that produced by BW. In contrast to these findings, the diuretic and natriuretic response produced by BW infusion (30 or 50 microgram/kg/min, i.v.) was abolished in rats having undergone chronic bilateral renal denervation. Together, these results demonstrate that the peripheral administration of BW373U86 or SNC80 produce marked diuretic and natriuretic responses in conscious Sprague-Dawley rats via a delta opioid receptor pathway and that intact renal nerves are required for mediating these responses. Although endogenous delta opioid systems do not appear to exert a tonic influence under basal conditions, these findings suggest that delta opioid pathways may evoke significant changes in renal excretory function under conditions in which these systems are activated. Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Benzamides; Denervation; Infusions, Intravenous; Kidney; Male; Naltrexone; Oligopeptides; Opioid Peptides; Piperazines; Rats; Rats, Sprague-Dawley; Receptors, Opioid, delta | 1998 |
Butorphanol-mediated antinociception in mice: partial agonist effects and mu receptor involvement.
In the present experiments, we characterized the agonist and antagonist effects of butorphanol in mice. In the mouse radiant-heat tail-flick test, the mu agonists morphine and fentanyl and the kappa agonist U50,488H were fully effective as analgesics, whereas butorphanol was partially effective (producing 82% of maximal possible analgesic effect). Naltrexone was approximately equipotent in antagonizing the effects of morphine, fentanyl and butorphanol; in vivo apparent pA2 values for these naltrexone/agonist interactions were 7.5 (unconstrained). Naltrexone was approximately 10 times less potent in antagonizing the effect of U50,488H (average apparent pK(B) = 6.7). The selective mu antagonist beta-funaltrexamine (0.1-1.0 mg/kg) antagonized the effects of butorphanol in a dose-dependent insurmountable manner. Pretreatment with nor-binaltorphimine (32 mg/kg), a kappa-selective antagonist, did not reliably antagonize butorphanol, and naltrindole (20 and 32 mg/kg), a delta-selective antagonist, failed to antagonize the effects of butorphanol. Low doses of butorphanol (1.0, 1.8 or 3.2 mg/kg) caused parallel, rightward shifts in the dose-effect curve for morphine and parallel leftward shifts in the dose-effect curve for U50,488H. Taken together, the results of the present study suggest that butorphanol is a partial agonist in the mouse radiant-heat tail-flick test and that activity at mu receptors accounts for the majority of its antinociceptive effects. Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics, Opioid; Animals; Butorphanol; Male; Mice; Morphine; Naltrexone; Pyrrolidines; Receptors, Opioid, mu | 1997 |
Anatomical distribution of mu, delta, and kappa opioid- and nociceptin/orphanin FQ-stimulated [35S]guanylyl-5'-O-(gamma-thio)-triphosphate binding in guinea pig brain.
An in vitro autoradiographic technique has recently been developed to visualize receptor-activated G-proteins by using agonist-stimulated [35S]guanylyl-5'-O-(gamma-thio)-triphosphate ([35S]GTPgammaS) binding in the presence of excess guanosine 5'-diphosphate. This technique was used to localize opioid-activated G-proteins in guinea pig brain, a species that contains the three major types of opioid receptors. This study used selective mu, delta, and kappa opioid agonists as well as nociceptin or orphanin FQ (N/OFQ) peptide, an endogenous ligand for an orphan opioid receptor-like (ORL1) receptor, to stimulate [35S]GTPgammaS binding in guinea pig brain sections. Opioid receptor specificity was confirmed by blocking agonist-stimulated [35S] GTPgammaS binding with the appropriate antagonists. In general, the distribution of agonist-stimulated [35S]GTPgammaS binding correlated with previous reports of receptor binding autoradiography, although quantitative differences suggest regional variations in receptor coupling efficiency. Mu, delta, and kappa opioid-stimulated [35S]GTPgammaS binding was found in the caudate-putamen, nucleus accumbens, amygdala, and hypothalamus. Mu-stimulated [35S]GTPgammaS binding predominated in the hypothalamus, amygdala, and brainstem, whereas kappa-stimulated [35S]GTPgammaS binding was particularly high in the substantia nigra and cortex and was moderate in the cerebellum. N/OFQ-stimulated [35S] GTPgammaS binding was highest in the cortex, hippocampus, and hypothalamus and exhibited a unique anatomical distribution compared with opioid-stimulated [35S]GTPgammaS binding. The present study extends previous reports on opioid and ORL1 receptor localization by anatomically demonstrating functional activity produced by mu, delta, and kappa opioid and ORL1 receptor activation of G-proteins. Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Analgesics, Non-Narcotic; Animals; Autoradiography; Brain Chemistry; Cerebellum; Diencephalon; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, Leucine; Enkephalins; Guanosine 5'-O-(3-Thiotriphosphate); Guinea Pigs; Male; Medulla Oblongata; Mesencephalon; Naloxone; Naltrexone; Narcotic Antagonists; Nociceptin; Opioid Peptides; Pons; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Sulfur Radioisotopes; Telencephalon | 1997 |
Opioid receptor-mediated control of acetylcholine release in human neocortex tissue.
The effects of various opioid receptor agonists and antagonists on evoked acetylcholine release were studied in slices of human neocortex prelabelled with [3H]-choline, superfused and depolarized electrically (2 min, 3 Hz, 2 ms, 24 mA) or by K+ (20 mM). The delta-opioid receptor agonist DPDPE and the kappa-opioid receptor agonist U50488 reduced the evoked [3H]-overflow (acetylcholine release) in a concentration-dependent fashion; the delta-opioid receptor antagonist naltrindole and the kappa-opioid receptor antagonist norbinaltorphimine, respectively, antagonized these effects. Application of the mu-opioid receptor agonist DAGO also resulted in an inhibition of acetylcholine release; however, both delta- and kappa-opioid receptor antagonists were able to block this effect. The mu-opioid receptor agonists morphine and (+)-nortilidine had no effect. These results indicate that acetylcholine release in human neocortex is inhibited through delta- and kappa-opioid receptors, but not through mu-opioid receptors. Acetylcholine release was significantly increased by the delta-opioid receptor antagonist naltrindole in the presence of a mixture of peptidase inhibitors providing evidence for a delta-opioid receptor-mediated inhibition of acetylcholine release by endogenous enkephalin. K(+)-evoked acetylcholine release in the presence of TTX was inhibited by U50488, but not by DPDPE, suggesting the presence of kappa-opioid receptors on cholinergic terminals and the localization of delta-receptors on cortical interneurons. Therefore, the potent effect of DPDPE on acetylcholine release is likely to be indirect, by modulation of intrinsic cortical neurons. These interneurons probably do not use GABA as neurotransmitter since both GABAA and GABAB receptor agonists (muscimol and baclofen, respectively) were without effect on acetylcholine release. Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Acetylcholine; Adolescent; Adult; Aged; Analgesics; Analysis of Variance; Baclofen; Cerebral Cortex; Dose-Response Relationship, Drug; Electric Stimulation; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, D-Penicillamine (2,5)-; Enkephalins; Female; GABA Agonists; Humans; Male; Middle Aged; Muscimol; Naloxone; Naltrexone; Narcotic Antagonists; Pyrrolidines; Receptors, Opioid, delta; Tetrodotoxin | 1996 |
Characterization of the opioid receptor subtypes mediating the negative inotropic effects of DAMGO, DPDPE and U-50, 488H in isolated human right atria strips.
The present investigation was aimed at elucidating if mu-, delta- and kappa-opioid receptors are involved in the effects of DAMGO (selective mu-agonist), DPDPE (selective delta-agonist) and U-50,488H (selective kappa-agonist) in isolated electrically driven human right atria strips. The negative inotropic effects induced by the opioid agonists used in this study were not antagonized in presence of naloxone (preferentially mu-antagonist), naltrindole (selective delta-antagonist) and norbinaltorphimine (selective kappa-antagonist). These data suggest that the opioid receptors are not involved in the cardiac depressant effects induced by mu-, delta- and kappa-opioid agonists. Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Adult; Aged; Analgesics; Dose-Response Relationship, Drug; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, D-Penicillamine (2,5)-; Enkephalins; Female; Heart Atria; Humans; Male; Middle Aged; Myocardial Contraction; Naloxone; Naltrexone; Narcotic Antagonists; Narcotics; Pyrrolidines; Receptors, Opioid | 1995 |
Inhibition of luteinizing hormone-releasing hormone secretion by delta-opioid agonists in GT1-1 neuronal cells.
The endogenous opioids play a major role in regulation of the secretion of hypothalamic LHRH. However, it is not clear whether opioids exert a direct effect on LHRH neurons or interfere with other neuronal systems impinging on the cells synthesizing LHRH. The neuronal LHRH-producing cell line GT1 provides a new model to evaluate which signals may directly modify LHRH release. In a previous paper it has been reported that opioid-binding sites of the delta-type are present in a clone of the GT1 cells (GT1-1). In the present study, the possible effects of opioids on the release of LHRH were studied in GT1-1 cells. The results obtained show that only the addition of opioid agonists that bind to delta-receptors brings about a significant inhibition of forskolin- or prostaglandin E2-stimulated LHRH release in GT1-1 cells. The effect of the delta-opioid agonist [D-Pen2,D-Pen5]enkephalin is dose dependent and is reversed by the universal opioid antagonist naltrexone and the delta-specific antagonist naltrindole. No effect of opioid agonists or antagonists was observed in unstimulated cells. These results suggest that opioids may control the release of LHRH also, acting directly on LHRH-producing neurons. Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Alprostadil; Amino Acid Sequence; Cell Line; Colforsin; Culture Media, Conditioned; Dinoprostone; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, D-Penicillamine (2,5)-; Enkephalins; Gonadotropin-Releasing Hormone; Molecular Sequence Data; Naltrexone; Narcotic Antagonists; Neurons; Pyrrolidines; Receptors, Opioid, delta | 1995 |
Repeated acquisition of behavioral chains in squirrel monkeys: comparisons of a mu, kappa and delta opioid agonist.
Responding by squirrel monkeys was maintained by food presentation under a repeated acquisition of behavioral chains procedure. Monkeys acquired a different three-response chain each session. Sequence completions were reinforced under a fixed-ratio 5 schedule, whereas errors produced a brief time out. Morphine (0.1-3.2 mg/kg) produced dose-related decreases in response rate at doses that had little or no effect on errors. U50488H ([trans]3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)- cyclohexyl]benzeneacetamide methane sulfonate hydrate) (0.018-0.56 mg/kg) yielded a steep dose-effect curve, decreasing response rate only at high doses that also had little or no effect on errors. The delta opioid agonist BW373U86 (+/-)-4-((alpha-R*)-alpha-((2S*,5R*)-4-allyl-2,5-dimethyl-1- piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide dihydrochloride (0.0056-0.32 mg/kg) produced dose-related decreases in response rate and increased errors. The delta opioid receptor antagonist naltrindole (0.056-18 mg/kg) alone had no effect on either the rate of responding or percent errors. The rate-decreasing and error-increasing effects produced by BW373U86 were antagonized by naltrindole. BW373U86 alone at doses of > or = 0.56 mg/kg produced brief tonic-clonic convulsions in all monkeys. Naltrindole (1 mg/kg) also antagonized the convulsant effects of BW373U86. At doses at which naltrindole was an effective antagonist of BW373U86, it failed to antagonize either morphine or U50488H. These results demonstrate that the delta opioid agonist BW373U86 produces effects on acquisition that differ dramatically from prototypical mu and kappa opioid agonists.(ABSTRACT TRUNCATED AT 250 WORDS) Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Benzamides; Conditioning, Operant; Dose-Response Relationship, Drug; Female; Morphine; Naltrexone; Piperazines; Pyrrolidines; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Saimiri | 1995 |
The kappa agonist fedotozine modulates colonic distention-induced inhibition of gastric motility and emptying in dogs.
Gastric motor disturbances, associated with a delay in gastric emptying, occur in patients with the irritable bowel syndrome. The influence of fedotozine and kappa agonists on the cologastric reflex produced by nonpainful colonic distention was evaluated in conscious dogs.. Colonic distention was applied in dogs fitted with either strain gauges or gastric cannula to assess its influence on gastrointestinal motility and gastric emptying, respectively.. Colonic distention delayed the occurrence of gastric migrating motor complex by 141%, an effect blocked by intravenous fedotozine, U 50,488 (25 and 50 micrograms/kg), and hexamethonium (0.5 mg/kg) but not by D-Ala2, N-methyl, Phe4, Gly5-ol enkephalin (1, 5, and 10 micrograms/kg), granisetron (50 and 100 micrograms/kg), or bretylium tosylate (5 mg/kg). Nor-binaltorphimine hydrochloride (1 mg/kg intravenously) eliminated the suppressive action of fedotozine. Colonic distention reduced the 1-hour gastric emptying of solids by 40.1%, an effect blocked by fedotozine and U 50,488 (50 and 100 micrograms/kg); nor-binaltorphimine hydrochloride (1 mg/kg) antagonized the blocking effect of fedotozine.. Fedotozine acts through kappa receptors to block the colonic distention-induced delay on gastric motility and emptying. The cologastric reflex involves nicotinic ganglionic receptors but not adrenergic pathway and 5-hydroxytryptamine 3 receptors. Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Benzyl Compounds; Bretylium Compounds; Catheterization; Colon; Dogs; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalins; Gastric Emptying; Gastrointestinal Motility; Granisetron; Hexamethonium; Male; Naltrexone; Narcotic Antagonists; Propylamines; Pyrrolidines; Receptors, Opioid, kappa; Receptors, Opioid, mu; Reflex; Stomach | 1994 |
Morphine reduces the release of met-enkephalin-like material from the rat spinal cord in vivo by acting at delta opioid receptors.
The modulation by morphine of the spinal release of met-enkephalin-like material (MELM) was investigated in anaesthetized rats whose intrathecal space was perfused with an artificial CSF (ACSF). Morphine (10 microM in the ACSF), as well as a mu- (DAGO, 10 microM) or delta opioid receptor agonist (DTLET, 10 microM), significantly decreased the outflow of MELM. The effects of morphine and DTLET were prevented by the delta antagonist, naltrindole (10 microM), but not by naloxone (10 microM). Conversely, naloxone, but not naltrindole, prevented the inhibitory effect of DAGO. Although neither the kappa 1 agonist, U 50488H (10 microM), nor the kappa 1 antagonist, norbinaltorphimine (10 microM), exerted on their own any significant effect, norbinaltorphimine enhanced the inhibitory action of morphine. In contrast to the inhibition induced by morphine (with or without naloxone) which was preventable by 10 microM naltrindole, the inhibition of MELM release by morphine plus norbinaltorphimine was only partly reduced by naltrindole. Thus, concomitant stimulation of mu, delta and kappa 1 receptors might account for the apparent delta opioid receptor-dependent inhibition of MELM release by morphine. Indeed, its potential inhibitory effect through the stimulation of mu receptors (normally prevented by the concomitant stimulation of kappa 1 receptors) becomes efficient only when kappa 1 receptors are blocked. Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, Methionine; Enkephalins; Injections, Spinal; Male; Morphine; Naloxone; Naltrexone; Narcotic Antagonists; Oligopeptides; Pyrrolidines; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Receptors, Opioid, delta; Spinal Cord | 1994 |
Agonists and antagonists bind to different domains of the cloned kappa opioid receptor.
Opium and its derivatives are potent analgesics that can also induce severe side effects, including respiratory depression and addiction. Opioids exert their diverse physiological effects through specific membrane-bound receptors. Three major types of opioid receptors have been described, termed delta, kappa, and mu. The recent molecular cloning of these receptor types opens up the possibility to identify the ligand-binding domains of these receptors. To identify the ligand-binding domains of the kappa and delta receptors, we have expressed in COS-7 cells the cloned mouse delta and kappa receptors and chimeric delta/kappa and kappa/delta receptors in which the NH2 termini have been exchanged. The opioid antagonist naloxone binds potently to wild-type kappa receptor but not to wild-type delta receptor. The kappa/delta chimera bound [3H]naloxone with high affinity. In contrast, the kappa-specific agonist [3H]U-69,593 did not bind to the kappa/delta chimera. These findings indicate that selective agonists and antagonists interact with different recognition sites in the kappa receptor and localize the antagonist-binding domain to the NH2 terminus. Consistent with the results of radioligand-binding studies, the kappa/delta chimera did not mediate kappa-agonist inhibition of cAMP formation. In contrast, the delta/kappa chimera did mediate kappa-agonist inhibition of cAMP formation, but this effect was not blocked by naloxone. Furthermore, a truncated kappa receptor lacking its NH2 terminus was able to mediate agonist inhibition of cAMP accumulation in a naloxone-insensitive manner. This result further indicates that the NH2 terminus of the kappa receptor contains the selective antagonist-binding domain. The ability to dissociate agonist- and antagonist-binding sites will facilitate the development of more specific kappa agonists, which could have analgesic properties devoid of side effects. Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Base Sequence; Benzeneacetamides; Binding Sites; Cell Line; Chlorocebus aethiops; Cloning, Molecular; Colforsin; Cyclic AMP; Enkephalin, Leucine; Kinetics; Mice; Molecular Sequence Data; Mutagenesis, Site-Directed; Naloxone; Naltrexone; Oligodeoxyribonucleotides; Protein Structure, Secondary; Pyrrolidines; Radioligand Assay; Receptors, Opioid, delta; Receptors, Opioid, kappa; Recombinant Fusion Proteins; Recombinant Proteins; Transfection | 1994 |
Differential involvement of ventral tegmental mu, delta and kappa opioid receptors in modulation of basal mesolimbic dopamine release: in vivo microdialysis studies.
In vivo microdialysis was used to assess the involvement of ventral tegmental area (VTA) mu, delta, and kappa opioid receptors in modulation of basal extracellular ventral striatal dopamine (DA) and DA-metabolite concentrations. Independent groups of chloral hydrate-anesthetized rats were given VTA microinjections of selective opioid agonists, and extracellular ventral striatal DA and DA-metabolite concentrations were assayed using HPLC. VTA microinjections of [D-Ala2, N-Me-Phe4-Gly5-ol]-enkephalin (DAMGO; a mu agonist) and [D-Pen2, D-Pen5]-enkephalin (DDDPE; a delta agonist) each caused dose-orderly increases in ventral striatal DA and DA-metabolite concentrations. The effective concentrations of DPDPE were 100- to 1000-fold higher than the effective concentrations of DAMGO. VTA microinjections of (trans-(dl)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclo-hexyl]- benzeneacetamide) methane sulfonate hydrate (U-50,488H); a kappa agonist) failed to alter ventral striatal DA concentrations at any dose tested, but subsequent systemic injections significantly decreased DA and DA-metabolite concentrations. Pretreatment with VTA microinjections of 17-cyclopropylmethyl-6,7-dehydro-4,5-epoxy-3,14-dihydroxy-6,7,2',3'- indolmorphinan hydrochloride (naltrindole; a delta antagonist) (delta antagonist) antagonized VTA DPDPE-mediated increases in ventral striatal DA and DA-metabolite concentrations but failed to antagonize VTA DAMGO-mediated increases. Pretreatment with D-Pen-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP; a mu antagonist) antagonized VTA DAMGO-mediated increases but failed to antagonize VTA DPDPE-mediated increases. Thus both mu and delta receptor agonist appear capable of increasing ventral striatal DA and DA-metabolite concentrations through selective actions on their preferred class of opioid receptors in the VTA. The increases in ventral striatal DA and DA-metabolite concentrations that are seen after systemic treatment with kappa opioid agonists appear not to involve VTA opioid receptors. Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; 3,4-Dihydroxyphenylacetic Acid; Amino Acid Sequence; Analgesics; Animals; Chromatography, High Pressure Liquid; Corpus Striatum; Dialysis; Dopamine; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, D-Penicillamine (2,5)-; Enkephalins; Homovanillic Acid; Hydroxyindoleacetic Acid; Limbic System; Male; Microinjections; Molecular Sequence Data; Naltrexone; Narcotic Antagonists; Pyrrolidines; Rats; Rats, Inbred Strains; Receptors, Opioid; Tegmentum Mesencephali | 1993 |
Antagonism of the morphine-induced Straub tail reaction by kappa-opioid receptor activation in mice.
The Straub tail reaction (STR) induced by intracerebroventricular injection (ICV) of morphine was significantly antagonized by beta-funaltrexamine (beta-FNA, mu antagonist), given intracerebroventricularly (ICV), but not naltrindole given ICV (NTI, delta antagonist) or SC norbinaltorphimine given subcutaneously (SC) (nor-BNI, kappa antagonist). When given either SC or ICV the kappa-agonist, U-50,488 H markedly suppressed the STR elicited by ICV morphine; these effects were reversed by nor-BNI. These results suggest that the activation of supraspinal kappa receptors can inhibit the ICV morphine-induced STR which results from activation of supraspinal mu receptors. Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Dose-Response Relationship, Drug; Injections, Intraventricular; Male; Mice; Mice, Inbred Strains; Morphine; Naltrexone; Narcotic Antagonists; Pain Measurement; Pyrrolidines; Receptors, Opioid, kappa | 1993 |
The use of specific opioid agonists and antagonists to delineate the vagally mediated antinociceptive and cardiovascular effects of intravenous morphine.
Intravenous (i.v.) administration of morphine produces a dose-dependent inhibition of the tail-flick (TF) reflex, depressor response, and bradycardia in the rat. Some of these effects depend on interactions of i.v. morphine with peripheral opioid receptors and the integrity of cervical vagal afferents. The present studies used the relatively specific mu, delta, and kappa opioid receptor agonists (DAGO, DPDPE or U-50,488H) and the relatively specific mu, delta, and kappa opioid receptor antagonists (beta-FNA, naloxonazine, naltrindole or nor-BNI) in either intact rats or rats with bilateral cervical vagotomy (CVAG) to delineate the vagal afferent/opioid-mediated components of these effects. I.v. administration of DAGO in intact rats produced a dose-dependent inhibition of the TF reflex, depressor response, and bradycardia virtually identical to those produced by i.v. morphine. All of these effects of either i.v. DAGO or i.v. morphine were significantly attenuated by either bilateral CVAG or pre-treatment with the mu 2 opioid receptor antagonist beta-FNA. Pre-treatment with the mu 1 opioid receptor antagonist naloxonazine affected i.v. DAGO-induced inhibition of the TF reflex and bradycardia, but had no significant effects on i.v. morphine-produced responses. I.v. administration of DPDPE produced a dose-dependent pressor response, but had no marked effects on the either the TF reflex or heart rate (HR). The pressor response was unaffected by either bilateral CVAG or pre-treatment with naltrindole, naloxone, hexamethonium, or bertylium. i.v. administration of U-50,488H produced a depressor response and bradycardia, but had no significant effect on the TF reflex. The depressor response and bradycardia produced by i.v. U-50,488H were unaffected by bilateral CVAG, but could be antagonized by pre-treatment with either nor-BNI or naloxone. These studies suggest that the vagal afferent-mediated antinociceptive and cardiovascular effects of i.v. morphine are primarily mediated by interactions with low affinity mu 2 opioid receptors. Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analysis of Variance; Animals; Blood Pressure; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, D-Penicillamine (2,5)-; Enkephalins; Heart Rate; Hexamethonium; Hexamethonium Compounds; Indoles; Injections, Intravenous; Male; Morphinans; Morphine; Naloxone; Naltrexone; Narcotic Antagonists; Narcotics; Pain; Pyrrolidines; Rats; Rats, Sprague-Dawley; Reference Values; Time Factors; Vagotomy; Vagus Nerve | 1993 |
Effect of diabetes on the antinociceptive effect of beta-endorphin.
We examined whether streptozotocin-induced diabetes can modulate beta-endorphin-induced antinociception in mice. While beta-endorphin administered i.c.v. produced a dose-dependent inhibition of the tail-flick response in both diabetic and non-diabetic mice, the antinociceptive response was greater in diabetic mice than in non-diabetic mice. The ED50 value of beta-endorphin administered i.c.v. in diabetic mice was significantly lower than that in non-diabetic mice. The antinociceptive effects of beta-endorphin administered i.c.v. in both diabetic and non-diabetic mice were significantly antagonized by s.c. administration of naltrindole, a selective delta-opioid receptor antagonist. beta-Endorphin administered i.t. also produced a dose-dependent antinociception in both diabetic and non-diabetic mice. However, the ED50 value of kappa-opioid receptor antagonist. On the other hand, the antinociceptive potency of DPDPE, a selective delta-opioid agonist, administered i.t. is significantly increased in diabetic mice, as compared with non-diabetic mice, whereas, the antinociceptive potency of U-50,488H, a kappa-opioid receptor agonist, administered i.t. is significantly less than in non-diabetic mice. These results suggest that diabetes may modulate beta-endorphin-induced antinociception differently at the spinal and supraspinal levels. Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; beta-Endorphin; Cerebral Ventricles; Diabetes Mellitus, Experimental; Dose-Response Relationship, Drug; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, D-Penicillamine (2,5)-; Enkephalins; Injections, Intraventricular; Male; Mice; Mice, Inbred ICR; Naltrexone; Narcotic Antagonists; Pain; Pyrrolidines; Reference Values | 1993 |
Spinal delta 2 but not delta 1 opioid receptors are involved in intracerebroventricular beta-endorphin-induced antinociception in the mouse.
The antinociception induced by beta-endorphin given intracerebroventricularly (i.c.v.) has been previously demonstrated to be mediated by the release of Met-enkephalin and subsequent stimulation of delta receptors in the spinal cord for antinociception. The present study was designed to determine what type of opioid receptor, delta 1 or delta 2, in the spinal cord is involved in i.c.v. beta-endorphin-induced antinociception. Antinociception was assessed by the tail-flick test in male ICR mice. NTB (0.2-20 nmol) and NTI (0.22-2.2 nmol), selective delta 2 receptor antagonists, given intrathecally (i.t.) dose-dependently attenuated i.c.v. beta-endorphin-induced inhibition of the tail-flick response. On the other hand, BNTX (0.02-2.2 nmol), a selective delta 1 receptor antagonist, given i.t., did not block i.c.v. beta-endorphin-induced antinociception. The tail-flick inhibition induced by DAMGO, a mu receptor agonist, or U50,488H, a kappa receptor agonist, was not blocked by i.t. BNTX, NTB or NTI. It is concluded that delta 2 but not delta 1 receptors in the spinal cord are involved in i.c.v. beta-endorphin-induced antinociception. Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Benzylidene Compounds; beta-Endorphin; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalins; Injections, Intraventricular; Injections, Spinal; Male; Mice; Mice, Inbred ICR; Naltrexone; Narcotic Antagonists; Nociceptors; Pain Measurement; Pyrrolidines; Receptors, Opioid, delta; Spinal Cord | 1993 |
Opioid control of the release of calcitonin gene-related peptide-like material from the rat spinal cord in vivo.
The possible control by opioids of the spinal release of calcitonin gene-related peptide-like material (CGRPLM) was investigated in halothane-anaesthetized rats whose intrathecal space was perfused with an artificial cerebrospinal fluid. Morphine (20 mg/kg i.v.; or at 10-100 microM added to the perfusing fluid), the mu selective agonist DAGO (10 microM) and the kappa selective agonist U 50488 H (10 microM) did not affect the spontaneous outflow of the CGRPLM. In contrast, the selective delta agonist DTLET (10 microM) significantly increased CGRPLM release. The latter effect could be prevented by the selective delta antagonist naltrindole (10 microM) as expected from the involvement of this class of opioid receptors. However, the addition of naltrindole alone to the perfusing fluid did not modify CGRPLM outflow, indicating that endogenous opioids do not exert a tonic control of CGRP-containing fibers through the stimulation of delta receptors. In contrast, intrathecal perfusion with naloxone (10 microM) or nor-binaltorphimine (10 microM), a selective antagonist of kappa receptors, produced a marked increase in spinal CGRPLM release, suggesting that endogenous opioids acting at mu and kappa receptors, respectively, exert a tonic inhibitory control of CGRP-containing fibers. Indeed, a significant decrease in the spinal release of CGRPLM release could be evoked by the combined addition of U 50488 H (10 microM) plus DAGO (10 microM) to the perfusing medium, indicating that the simultaneous stimulation of both kappa and mu receptors is required for this negative control to occur. This could notably be achieved with morphine (10 microM) in the presence of naltrindole (10 microM) which also produced a significant reduction in the spinal release of CGRPLM. In conclusion, morphine per se did not change CGRPLM release because this drug triggers opposite positive (through the stimulation of delta receptors) and negative (through the concomitant stimulation of both kappa and mu receptors) control mechanisms within the rat spinal cord. Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Calcitonin Gene-Related Peptide; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalins; Injections, Spinal; Iodine Radioisotopes; Male; Morphine; Naloxone; Naltrexone; Narcotic Antagonists; Oligopeptides; Pyrrolidines; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Spinal Cord | 1993 |
Antitussive effects of mu- and kappa-agonists in diabetic rats.
We evaluated the antitussive effect of morphine and U-50,488 in diabetic and non-diabetic rats. The antitussive potency of morphine (0.3 mg/kg, i.p.) in diabetic rats was significantly reduced as compared to the results in non-diabetic rats. The antitussive effect of U-50,488, a kappa-agonist, was also significantly lower in diabetic rats than in non-diabetic rats. When naltrindole (0.03 mg/kg, i.p.), a delta-antagonist, was administered 15 min before morphine or U-50,488, there was no difference between the antitussive potencies of these two opioid agonists in non-diabetic rats and in diabetic rats. Furthermore, naltrindole produces a reduction of the number of coughs in diabetic rats, but not in non-diabetic rats. It is possible that the enhancement of the antitussive potency of morphine and U-50,488 in naltrindole-treated diabetic rats is the result of the antitussive synergy produced by these opioid agonists and naltrindole. It seems likely, therefore, that delta-receptor-mediated endogenous inhibitory systems in mu- and kappa-receptor-mediated antitussive processes may be activated under diabetic conditions. Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Antitussive Agents; Diabetes Mellitus, Experimental; Male; Morphine; Naltrexone; Narcotic Antagonists; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Receptors, Opioid, mu | 1993 |
Kappa-opioid receptor stimulation abolishes mu- but not delta-mediated inhibitory control of spinal Met-enkephalin release.
The possible opioid control through delta, mu and kappa receptors of the spinal release of Met-enkephalin-like material (MELM) was investigated in halothane-anaesthetized rats. The intrathecal perfusion of the delta agonist DTLET (10 microM) or the mu agonist DAGO (10 microM) resulted in a marked inhibition of MELM release, which could be prevented by the selective antagonists naltrindole and naloxone, respectively. Although the kappa agonist U 50488 H (10 microM) was inactive per se, it completely suppressed the inhibitory effect of DAGO, without affecting that of DTLET. As the selective kappa antagonist norbinaltorphimine blocked the action of U 50488 H, it can be concluded that kappa receptors modulate the mu- (but not the delta-) mediated feed back control of spinal enkephalinergic neurones. Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, Methionine; Enkephalins; Indoles; Injections, Spinal; Male; Morphinans; Naloxone; Naltrexone; Neurons; Oligopeptides; Pyrrolidines; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Spinal Cord | 1992 |
Modulation of kappa-mediated antitussive activity in rats by a delta-agonist.
When co-administered intracisternally, the selective delta-opioid agonist [D-Pen2,5]enkephalin (DPDPE), which had no significant effect on the cough reflex, consistently and significantly decreased the antitussive potencies of kappa-receptor agonists, U-50,488H and U-62,066E. The decrease in the antitussive effects of these kappa-receptor agonists caused by DPDPE were prevented by selective delta receptor antagonist, naltrindole. These results suggest that delta receptors may play an inhibitory role in antitussive processes that are mediated by the kappa-receptors. Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Antitussive Agents; Cough; Enkephalin, D-Penicillamine (2,5)-; Enkephalins; Indoles; Male; Morphinans; Naltrexone; Narcotic Antagonists; Pyrrolidines; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, kappa; Reflex | 1992 |
Pentazocine-induced biphasic analgesia in mice.
Pentazocine (PZ) is well known to act as an opioid mixed agonist-antagonist analgesic. In the present study, we selected the mouse warm plate test condition of 51 +/- 0.5 degrees C instead of 55 +/- 0.5 degrees C to determine the analgesic action of PZ. As a result, i.c.v. PZ produced a biphasic antinociceptive response, while U-50,488H (U-50) and morphine (MRP) showed a monophasic response. Pretreatment with i.c.v. beta-FNA (mu antagonist) antagonized the initial response, whereas the delayed one was antagonized by pretreatment with nor-BNI (kappa antagonist). In addition, pretreatment with NTI (delta antagonist) significantly attenuated the initial response but not the delayed one. These results suggest that the initial and delayed responses may be mediated mainly by mu/delta and kappa receptors, respectively. With regards to the interaction between MRP and PZ, a low dose of PZ antagonized the analgesic action of MRP, while a high dose PZ plus MRP showed the additive effect. Furthermore, tolerance developed almost equally to both initial and delayed responses, indicating that tolerance to the kappa component of PZ may be developed as well as the mu component of action of PZ. Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesia; Analgesics; Animals; Drug Administration Schedule; Drug Interactions; Drug Tolerance; Indoles; Injections, Intraventricular; Male; Mice; Morphinans; Morphine; Naltrexone; Narcotic Antagonists; Pentazocine; Pyrrolidines; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Time Factors | 1991 |
Further evidence for the implication of a kappa-opioid receptor mechanism in the production of psychological stress-induced analgesia.
The analgesic effect induced by exposure to psychological stress, using a communication box (psychological stress-induced analgesia, PSY-SIA), was completely antagonized by 10 min pretreatment with 0.5, 1 and 2 mg/kg of nor-binaltorphimine and with 0.5 and 1 mg/kg of Mr2266, selective kappa-opioid receptor antagonists, in the tail pinch method. Neither footshock (FS)- nor forced swimming (SW)-SIA was affected by these antagonists. The selective delta-opioid receptor antagonist naltrindole, at doses up to 20 mg/kg, had no appreciable effect on PSY-SIA. Daily morphine treatment, 10 mg/kg, s.c., resulted in tolerance to the analgesic effect, and concurrent exposure to PSY-stress suppressed the development of morphine tolerance. The substitution of treatment with U-50,488H for PSY-stress still resulted in analgesia on the initial day; and likewise, the suppression by U-50,488H of the development of morphine tolerance was replicated by PSY-stress. Pretreatment with nor-binaltorphimine antagonized the suppressive effect of PSY-stress on the development of morphine tolerance without affecting the analgesic effect of morphine per se. These results provide further evidence that PSY-SIA involves the mediation by kappa-opioid receptor mechanisms. Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesia; Analgesics; Animals; Benzomorphans; Drug Tolerance; Electroshock; Indoles; Male; Mice; Mice, Inbred Strains; Morphinans; Morphine; Naltrexone; Narcotic Antagonists; Pyrrolidines; Receptors, Opioid; Receptors, Opioid, kappa; Stress, Psychological; Swimming | 1990 |