cyprodime and norbinaltorphimine

Bone resorption associated to chronic diseases, such as arthritis and periodontitis, results from exacerbated immuno-inflammatory host response that leads to tissue breakdown. The significance of opioid pathways as endogenous modulators of inflammatory events has already been described. Thus, the aim of this work is to determine whether some of the main three opioid receptors are endogenously activated to prevent bone loss during experimentally-induced alveolar bone resorption.. This study used an experimental model of alveolar bone resorption induced by ligature in rats. A silk thread was placed around the 2nd maxillary molar of male Wistar rats. In the 3rd, 4th and 5th day after ligation the rats received a local injection of different concentrations of opioid antagonists Cyprodime, Naltrindole, or Nor-binaltorphimine, which specifically block mü, delta and kappa opioid receptors, respectively. In the 7th experimental day, rats were euthanized and their maxillae collected for evaluation of alveolar bone and fiber attachment loss, morphometric counting of osteoclasts and osteoblasts, as well as the levels of cytokines IL-1β, IFN-γ, and IL-6 by ELISA.. Selective antagonism of kappa opioid receptors, but not mü and delta, exacerbated alveolar bone resorption induced by ligature in rats. The increased bone loss associated with higher number of osteoclasts surrounding alveolar bone, although osteoblasts' counting remained unchanged. The concentrations of IL-1β and IL-6 in periodontal tissues were also significantly higher in the rats treated with the kappa antagonist.. Inhibiting kappa opioid receptors exacerbates alveolar bone resorption.

Topics: Alveolar Bone Loss; Animals; Bone Resorption; Cytokines; Disease Models, Animal; Male; Morphinans; Naltrexone; Narcotic Antagonists; Osteoblasts; Osteoclasts; Periodontitis; Rats; Rats, Wistar; Receptors, Opioid

Topics: Analgesics, Opioid; Animals; Bone Neoplasms; Cancer Pain; Cell Line, Tumor; Fentanyl; Hydrogen-Ion Concentration; Hyperalgesia; Ligands; Male; Melanoma, Experimental; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Morphinans; Naloxone; Naltrexone; Narcotic Antagonists; Piperidines; Receptors, Opioid, mu

Novelty- and sensation-seeking behaviors induce activity of the brain reward system and are associated with increased susceptibility to drug abuse. Endogenous opioids have been implicated in reward-related behavior; however, the involvement of specific opioid receptors in the mechanism of sensation seeking is unknown. Here, we show that selective inhibition of opioid receptors reduce operant sensation seeking in mice. Administration of naltrexone (a nonselective opioid antagonist) reduced instrumental responding for sensory stimuli at one of the tested doses (2 mg/kg). More robust effects were observed in the case of cyprodime, a selective μ opioid receptor antagonist, which reduced instrumental responses by ∼50% at doses of 0.5 mg/kg and larger. Conversely, selective δ and κ receptor antagonists (naltrindole and nor-binaltorphimine, respectively) had no effect on sensation-seeking behavior. Importantly, while naltrexone produces aversion in the conditioned place preference test, cyprodime had no such effect. Therefore, reduced instrumental responding was not correlated with aversive effects of the opioid antagonists. In conclusion, our results revealed a novel mechanism of action of selective opioid receptors antagonists, which may have relevance for their efficacy in the treatment of drug abuse.

Topics: Animals; Appetitive Behavior; Brain; Conditioning, Operant; Dose-Response Relationship, Drug; Exploratory Behavior; Male; Mice, Inbred C57BL; Morphinans; Motivation; Motor Activity; Naltrexone; Narcotic Antagonists; Random Allocation; Receptors, Opioid; Receptors, Opioid, mu; Reward

The use of regional and other opioid-sparing forms of anesthesia has been associated with a decrease in the recurrence of certain malignancies. Direct suppression of human natural killer cells by opioids has been postulated to explain this observation. However, the effect of different classes of opioids on suppression of natural killer cell cytotoxicity has not been systematically characterized.. After confirming that freshly isolated natural killer cells from peripheral human blood express opioid receptors, cells were incubated with increasing concentrations of clinically used or receptor-specific opioid agonists. We also evaluated the effect of pretreatment with receptor-specific antagonists or naloxone. Treated natural killer cells were then coincubated with a carboxyfluorescein succinimidyl ester-labeled target tumor cell line, K562. Annexin V staining was used to compare the percent of tumor cell apoptosis in the presence of opioid-pretreated and untreated natural killer cells. Treated samples were compared to untreated samples using Kruskal-Wallis tests with a post hoc Dunn correction.. Morphine, methadone, buprenorphine, loperamide, [D-Ala2, N-MePhe4, Gly-ol]-enkephalin, and U-50488 significantly decreased natural killer cell cytotoxicity. When natural killer cells were pretreated with naloxone, cyprodime, and nor-binaltorphimine before exposure to morphine, there was no difference in natural killer cytotoxicity, compared to the amount observed by untreated natural killer cells. Fentanyl, O-desmethyltramadol, and [D-Pen2,D-Pen5] enkephalin did not change natural killer cell cytotoxicity compare to untreated natural killer cells.. Incubation of isolated natural killer cells with certain opioids causes a decrease in activity that is not observed after naloxone pretreatment. Suppression of natural killer cell cytotoxicity was observed with μ- and κ-receptor agonists but not δ-receptor agonists. These data suggest that the effect is mediated by μ- and κ-receptor agonism and that suppression is similar with many clinically used opioids.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics, Opioid; Anesthesia; Buprenorphine; Enkephalin, D-Penicillamine (2,5)-; Fentanyl; Fluoresceins; Humans; Immunosuppression Therapy; K562 Cells; Killer Cells, Natural; Loperamide; Methadone; Morphinans; Morphine; Naloxone; Naltrexone; Succinimides; Toll-Like Receptor 4; Tramadol

In α-chloralose anesthetized cats, we examined the role of opioid receptor (OR) subtypes (µ, κ, and δ) in tibial nerve stimulation (TNS)-induced inhibition of bladder overactivity elicited by intravesical infusion of 0.25% acetic acid (AA). The sensitivity of TNS inhibition to cumulative i.v. doses of selective OR antagonists (cyprodime for µ, nor-binaltorphimine for κ, or naltrindole for δ ORs) was tested. Naloxone (1 mg/kg, i.v., an antagonist for µ, κ, and δ ORs) was administered at the end of each experiment. AA caused bladder overactivity and significantly (P < 0.01) reduced bladder capacity to 21.1% ± 2.6% of the saline control. TNS at 2 or 4 times threshold (T) intensity for inducing toe movement significantly (P < 0.01) restored bladder capacity to 52.9% ± 3.6% or 57.4% ± 4.6% of control, respectively. Cyprodime (0.3-1.0 mg/kg) completely removed TNS inhibition without changing AA control capacity. Nor-binaltorphimine (3-10 mg/kg) also completely reversed TNS inhibition and significantly (P < 0.05) increased AA control capacity. Naltrindole (1-10 mg/kg) reduced (P < 0.05) TNS inhibition but significantly (P < 0.05) increased AA control capacity. Naloxone (1 mg/kg) had no effect in cyprodime pretreated cats, but it reversed the nor-binaltorphimine-induced increase in bladder capacity and eliminated the TNS inhibition remaining in naltrindole pretreated cats. These results indicate a major role of µ and κ ORs in TNS inhibition, whereas δ ORs play a minor role. Meanwhile, κ and δ ORs also have an excitatory role in irritation-induced bladder overactivity.

Topics: Acetic Acid; Animals; Cats; Female; Male; Morphinans; Naloxone; Naltrexone; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Tibial Nerve; Transcutaneous Electric Nerve Stimulation; Urinary Bladder, Overactive

The objective of this study was to evaluate the antinociceptive effects of a lectin from Canavalia brasiliensis (ConBr) when administered orally to murine models of chemical and thermal nociception. ConBr up to 100 mg/kg produced significant and dose-dependent antinociceptive effects: 81% reduction in abdominal writhing induced by 0.6% acetic acid; 26 and 52% reduction in early- and late-stage paw licking, respectively, induced by 2.5% formalin; and 155% increase in reaction latency (heightened thermal pain threshold). In all models, the antinociceptive effect was reversed by the lectin-binding carbohydrate α-d-methyl-mannoside and by the nonselective opioid antagonist naloxone. The antinociceptive effect observed in the formalin test was inhibited by the δ-selective antagonist naltrindole and the κ-selective antagonist nor-binaltorphimine but not by the μ-selective antagonist cyprodime. In conclusion, when administered orally to Swiss mice, the ConBr lectin displayed antinociceptive activity, both peripheral and central, mediated by the opioid system and involving δ-and κ-receptors and the lectin domain.

Topics: Administration, Oral; Analgesics; Analgesics, Opioid; Animals; Canavalia; Mice; Morphinans; Naloxone; Naltrexone; Nociception; Pain Measurement; Plant Lectins; Receptors, Opioid, delta; Receptors, Opioid, kappa; Seeds

A chimeric opioid peptide (MCRT, YPFPFRTic-NH(2)) was here designed and synthesized. This peptide was based on morphiceptin (YPFP-NH(2)) and a neuropeptide FF (NPFF) derivative (PFRTic-NH(2)) sharing one proline. This peptide is intended to produce potent analgesia. MCRT was found to induce analgesic activity in a dose- and time-dependent manner, as indicated by a tail flick latency test in mice to which it had been intracerebroventricularly administered (5-60 min, 0.025-2.5 nmol/kg (0.5-50 pmol per mouse), ED(50)=1.49 nmol/kg). At 2.5nmol/kg, MCRT showed significantly higher levels of analgesic activity than morphiceptin or PFR(Tic)amide at 2500 nmol/kg. Naltrindole and cyprodime were found to partially but significantly inhibit this analgesic activity, but naloxone blocked it completely. The kappa opioid receptor antagonist nor-BNI was found to slightly inhibit MCRT and morphiceptin. Pre-injection of BIBP3226 and co-administration of NPFF and MCRT showed that NPFF receptors were involved in the analgesia of MCRT. BIBP3226 was found to weaken the analgesic effects of MCRT, but BIBP3226 could not block the analgesic effects of PFR(Tic)amide. Overall, MCRT was found to have stronger analgesic activity than morphiceptin or PFR(Tic)amide when interacting with mixed μ/δ opioid receptor interactions. MCRT also showed partial interaction with NPFF receptors.

Topics: Analgesia; Analgesics, Opioid; Animals; Arginine; Dose-Response Relationship, Drug; Endorphins; Guinea Pigs; Male; Mice; Morphinans; Naloxone; Naltrexone; Neuropeptides; Opioid Peptides; Proline; Receptors, Neuropeptide; Tetrahydroisoquinolines; Time Factors

7-Hydroxymitragynine is a potent opioid analgesic alkaloid isolated from the Thai medicinal herb Mitragyna speciosa. In the present study, we investigated the opioid receptor subtype responsible for the analgesic effect of this compound. In addition, we tested whether development of tolerance, cross-tolerance to morphine and naloxone-induced withdrawal signs were observed in chronically 7-hydroxymitragynine-treated mice. Subcutaneous (s.c.) administration of 7-hydroxymitragynine produced a potent antinociceptive effect mainly through activation of mu-opioid receptors. Tolerance to the antinociceptive effect of 7-hydroxymitragynine developed as occurs to morphine. Cross-tolerance to morphine was evident in mice rendered tolerant to 7-hydroxymitragynine and vice versa. Naloxone-induced withdrawal signs were elicited equally in mice chronically treated with 7-hydroxymitragynine or morphine. 7-Hydroxymitragynine exhibited a potent antinociceptive effect based on activation of mu-opioid receptors and its morphine-like pharmacological character, but 7-hydroxymitragynine is structurally different from morphine. These interesting characters of 7-hydroxymitragynine promote further investigation of it as a novel lead compound for opioid studies.

Topics: Analgesics; Analgesics, Opioid; Animals; Dose-Response Relationship, Drug; Drug Tolerance; Injections, Subcutaneous; Male; Mice; Mitragyna; Models, Molecular; Morphinans; Morphine; Naloxone; Naltrexone; Narcotic Antagonists; Pain Measurement; Reaction Time; Secologanin Tryptamine Alkaloids; Substance Withdrawal Syndrome; Thailand

The stimulation of peripheral opioid receptors yields analgesic responses in a model of bone cancer-induced pain in mice. In order to know the type(s) of peripheral opiate receptors involved, the paw thermal withdrawal latencies were measured in C3H/HeJ mice bearing a tibial osteosarcoma, after administering selective agonists of mu-,delta-and kappa-opiate receptors. The peritumoral administration of DAGO (0.6-6 microg) inhibited the osteosarcoma-induced hyperalgesia at doses ineffective in healthy animals, the highest one even increasing the withdrawal latencies over the control values. Naloxone-methiodide (2 mg/kg) and cyprodime (1 mg/kg), but not naltrindole (0.1 mg/kg) nor nor-binaltorphimine (10 mg/kg), antagonized DAGO-induced analgesic effects, these therefore probably being mediated through peripheral mu-opioid receptors. The peritumoral injection of DPDPE (100 microg) induced analgesia which was inhibited by naloxone-methiodide and naltrindole but not by nor-binaltorphimine. Cyprodime partially antagonized the analgesia induced by 100 microg of DPDPE, but did not modify the effect induced by 30 microg of this agonist-a dose that restores the hyperalgesic latencies up to the control values. The antihyperalgesic effect induced by the peritumoral administration of U-50,488H (1 microg) was antagonized by naloxone-methiodide and nor-binaltorphimine, but not by cyprodime nor naltrindole, thus suggesting the involvement of peripheral kappa-opioid receptors. In conclusion, the stimulation of peripheral mu-, delta- and kappa-opioid receptors is a pharmacological strategy useful for relieving this experimental type of bone cancer-induced pain, the greatest analgesic effect being achieved by stimulating peripheral mu-opioid receptors.

Topics: Analgesics, Opioid; Animals; Bone Neoplasms; Drug Interactions; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Hyperalgesia; Mice; Morphinans; Naltrexone; Narcotic Antagonists; Osteosarcoma; Receptors, Opioid

Long-term treatment of Parkinson's disease with levodopa is complicated by the emergence of involuntary movements, known as levodopa-induced dyskinesia. It has been hypothesized that increased opioid transmission in striatal output pathways may be responsible for the generation of dyskinesia. In this study, we have investigated the effect of blockade of opioid peptide transmission on levodopa-induced dyskinesia in a primate model of Parkinson's disease-the MPTP-lesioned marmoset. Coadministration of nonselective and mu- or delta-subtype-selective opioid receptor antagonists with levodopa resulted in a significant decrease in dyskinesia. There was no attenuation of the anti-parkinsonian actions of levodopa. These data suggest that specific mu- or delta-opioid receptor antagonists might be applicable clinically in the treatment of levodopa-induced dyskinesia in Parkinson's disease.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Callithrix; Disease Models, Animal; Drug Therapy, Combination; Dyskinesias; Female; Hypokinesia; Levodopa; Male; Morphinans; Motor Activity; Naltrexone; Narcotic Antagonists; Parkinsonian Disorders; Posture; Receptors, Opioid, delta; Receptors, Opioid, mu

1. Although cholecystokinin octapeptide sulphate (CCK-8) activates the opioid system of isolated guinea-pig ileum (GPI) whether it activates the mu- or kappa-system, or both, remains unclear. Neither is it known whether CCK-8 influences the withdrawal responses in GPI preparations briefly exposed to opioid agonists. This study was designed to clarify whether CCK-8 activates mu- or kappa-opioid systems or both; and to investigate its effect on the withdrawal contractures in GPI exposed to mu- or kappa-agonists and on the development of tolerance to the withdrawal response. 2. In GPI exposed to CCK-8, the selective kappa-antagonist nor-binaltorphimine elicited contractile responses that were concentration-related to CCK-8 whereas the selective mu-antagonist cyprodime did not. 3. In GPI preparations briefly exposed to the selective mu-agonist, dermorphin, or the selective kappa-agonist, U-50, 488H, and then challenged with naloxone, CCK-8 strongly enhanced the withdrawal contractures. 4. During repeated opioid agonist/CCK-8/opioid antagonist tests tolerance to opioid-induced withdrawal responses did not develop. 5. These results show that CCK-8 preferentially activates the GPI kappa-opioid system and antagonizes the mechanism(s) that control the expression of acute dependence in the GPI.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Guinea Pigs; Ileum; In Vitro Techniques; Male; Morphinans; Muscle Contraction; Naloxone; Naltrexone; Oligopeptides; Opioid Peptides; Receptor, Cholecystokinin A; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; Receptors, Opioid; Sincalide; Substance Withdrawal Syndrome

Relationship between activation of opioid receptors and muscarinic autoinhibition in acetylcholine (ACh) release from the myenteric plexus was studied in longitudinal muscle myenteric plexus (LMMP) preparations of guinea pig ileum. A mu-receptor agonist, [D-Ala2, N-Me-Phe4, Gly5-ol] enkephalin (DAMGO), at a concentration of 1 microM inhibited the ACh release evoked by electrical field stimulation (EFS) at 1 Hz but not at 10 Hz. After the muscarinic autoreceptors were blocked with atropine (1 microM), DAMGO inhibited EFS-evoked ACh release also at 10 Hz. After the autoreceptors were potently activated with muscarine (200 microM), the inhibitory effect of DAMGO at 1 Hz was abolished. A kappa-receptor agonist, U-50,488, at 1 microM inhibited the EFS-evoked ACh release both at 1 and 10 Hz. U-50,488 inhibited ACh release regardless of the presence of atropine or muscarine. A delta-agonist, enkephalin [D-PEN2.5] (PDPDE), did not show any significant effect. On the other hand, a selective mu-receptor antagonist, cyprodime, increased ACh release evoked by EFS at 1 Hz, but not at 10 Hz. After the autoreceptors were blocked, cyprodime increased EFS-evoked ACh release also at 10 Hz. The selective kappa-receptor antagonist, nor-binaltorphimine, did not affect ACh release in the absence or presence of atropine. The results suggest that endogenous opioid(s) inhibits ACh release by activating mu-, but not kappa- and delta-receptors in the LMMP of guinea pig ileum and that the inhibitory effect of endogenous opioid(s) in the ACh release is important when muscarinic autoinhibition mechanism does not fully work.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Acetylcholine; Analgesics, Non-Narcotic; Analgesics, Opioid; Animals; Atropine; Electric Stimulation; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalins; Guinea Pigs; Ileum; In Vitro Techniques; Male; Morphinans; Muscarine; Muscarinic Agonists; Muscarinic Antagonists; Muscle, Smooth; Myenteric Plexus; Naltrexone; Narcotic Antagonists; Opioid Peptides; Receptors, Muscarinic; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu

The type of opioid receptors involved in the conditioned enhancement of natural killer (NK) cell activity is identified in the present study. In our previous observations, we have demonstrated that the conditioned enhancement of NK cell activity was dependent on beta-endorphin and methionine-enkephalin, but not dynorphin. Based on the interaction of opioids with their homologous receptors, we concluded that mu- and delta-opioid receptors might be involved. To further classify the type(s) of opioid receptors involved in eliciting the conditioned NK cell activity, three opioid receptor antagonists, cyprodime hydrobromide, ICI-174864, and nor-binaltorphimine dihydrochloride, were used to block the conditioned NK cell activity in BALB/c mice. Blocking was conducted by intracisternal injection of the drugs. The results showed that the activation of mu-opioid receptors was required in the conditioned enhancement of NK cell activity, but not the delta- or kappa-type of receptors.

Topics: Animals; beta-Endorphin; Enkephalin, Leucine; Enkephalin, Methionine; Injections, Spinal; Killer Cells, Natural; Mice; Mice, Inbred BALB C; Morphinans; Naltrexone; Narcotic Antagonists; Receptors, Opioid, mu

We have studied the effects of mu- and kappa-opioid receptor blockade on endogenous acetylcholine and noradrenaline overflow from the myenteric plexus of the guinea-pig isolated colon. Cyprodime (putative mu-selective antagonist) and nor-binaltorphimine (kappa-selective antagonist) had a concentration-dependent facilitatory effect on both acetylcholine and noradrenaline overflow. Moreover, in colonic specimens obtained from sympathetically denervated animals, the effect of opioid antagonists on acetylcholine overflow was significantly higher with respect to normal preparations. Evidence is thus given in favour of an involvement of mu- and kappa-opioid receptor pathways in the tonic modulation of neurotransmitter release at the colonic level. Enhanced sensitivity to the effect of mu and kappa antagonists after chronic sympathetic denervation is strongly suggestive for the existence of a functional link between opioid and adrenergic pathways in this model.

Topics: Acetylcholine; Animals; Colon; Dose-Response Relationship, Drug; Guinea Pigs; Morphinans; Myenteric Plexus; Naltrexone; Narcotic Antagonists; Neurotransmitter Agents; Norepinephrine; Receptors, Opioid, kappa; Receptors, Opioid, mu; Sympathetic Nervous System

The effects of the selective opioid antagonists cyprodime (mu; 1, 3, 10, 30 mg/kg IP), norbinaltorphimine (kappa; 3, 10, 30 mg/kg IP) and naltrindole (delta; 0.3, 1, 3, 10 mg/kg IP) on electroshock seizure threshold in mice were compared with those of the universal opioid antagonist naloxone (0.3, 1, 10 mg/kg IP). Seizure threshold was increased by mu-receptor blocking doses of both cyprodime and naloxone, unaltered by norbinaltorphimine and decreased (in a dose-related manner) by all doses of naltrindole. The effects of naltrindole were similar to those of the established pro-convulsant agent bicuculline (1 mg/kg IP); however, naloxone and cyprodime produced relatively small increases in seizure threshold when compared with phenytoin (doses up to 30 mg/kg IP). The differential effects of mu-, kappa- and delta-receptor antagonists obtained in this study suggest that electroshock seizure threshold in mice may be controlled, at least in part, by a balance between endogenous opioids acting either pro-convulsantly through mu-receptors or anti-convulsantly via delta-receptors.

Topics: Animals; Anticonvulsants; Bicuculline; Dose-Response Relationship, Drug; Electroshock; gamma-Aminobutyric Acid; Indoles; Male; Mice; Mice, Inbred Strains; Morphinans; Naloxone; Naltrexone; Narcotic Antagonists; Phenytoin; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu