naltrindole-benzofuran and phenylalanyl-cyclo(cysteinyltyrosyl-tryptophyl-ornithyl-threonyl-penicillamine)threoninamide

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

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

In view of the co-localization of spinal delta- and kappa-opioid receptors, we have investigated the interaction of selective opioid receptor agonists and antagonists in the spinal cord of mice in order to determine if these receptors are organized as heteromers. The finding that norbinaltorphimine (kappa) antagonized [D-Pen(2,5)]enkephalin (delta(1)), but not deltorphin II (delta(2)), strongly suggests that the putative delta(1)-subtype is a delta-kappa heteromer. Studies with selective opioid receptor (ant)agonists support this conclusion.

Topics: Animals; Benzylidene Compounds; Dynorphins; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, D-Penicillamine (2,5)-; Immune Sera; Mice; Naltrexone; Oligopeptides; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Somatostatin; Spinal Cord

Intracerebroventricularly (i.c.v.)-administered [D-Ala2]deltorphin II (20 micrograms) produced a marked locomotor hyperactivity in male ICR mice. The locomotor hyperactivity induced in response to i.c.v. [D-Ala2]deltorphin II (20 micrograms) was suppressed by pretreatment with naltriben (NTB, 10 micrograms) but not 7-benzylidene naltrexone (BNTX, 1 microgram) and D-Phe-Cys-Tyr-D-Try-Orn-Thr-Phe-Thr-NH2 (CTOP, 100 ng). The influence of antisense oligodeoxynucleotide to delta-opioid receptor mRNA (delta-AS oligo) or a mismatch oligodeoxynucleotide (MM oligo) on the locomotor hyperactivity induced by [D-Ala2]deltorphin II was determined. Groups of mice pretreated i.c.v. with delta-AS oligo (1 microgram), MM oligo (1 microgram) or saline (4 microliters) once a day for 3 days, were injected i.c.v. [D-Ala2]deltorphin II (10 or 20 micrograms) and the locomotor response to [D-Ala2]deltorphin II was measured. The locomotor hyperactivity of i.c.v. [D-Ala2]deltorphin II (10 or 20 micrograms) were significantly suppressed by i.c.v. pretreatment with delta-AS oligo but not MM oligo. The present results indicate that pretreatment with delta-AS oligo suppresses mouse locomotor hyperactivity produced by stimulation of delta 2-opioid receptors in the brain.

Topics: Amino Acid Sequence; Analysis of Variance; Animals; Base Sequence; Benzylidene Compounds; Cerebral Ventricles; Injections, Intraventricular; Male; Mice; Mice, Inbred ICR; Molecular Sequence Data; Motor Activity; Naltrexone; Narcotic Antagonists; Oligonucleotides, Antisense; Oligopeptides; Receptors, Opioid, delta; Somatostatin; Thionucleotides

The antinociception induced by beta-endorphin given supraspinally has been previously demonstrated to be mediated by the release of [Met5]enkephalin acting on delta-opioid receptors in the spinal cord. The present study was designed to determine what type of opioid receptors in the spinal cord is involved in beta-endorphin-induced antinociception in the rat. Antinociception was induced by beta-endorphin (0.6 nmol) given into nucleus raphe obscurus and was assessed by the tail-flick test in pentobarbital-anesthesized rats. Naltriben (0.6-6.0 nmol), a selective delta 2-opioid receptor antagonist, given intrathecally dose-dependently attenuated beta-endorphin-induced inhibition of the tail-flick response. On the other hand, 7-benzylidene naltrexone (2.1-64.3 nmol), CTOP (D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2, 0.09-2.8 nmol), or nor-binaltorphimine (1.4-40.8 nmol), selective delta 1-, mu-, and kappa-opioid receptor antagonists, respectively, did not block beta-endorphin-induced antinociception. The results of present study in rats are consistent with previous experiments in mice indicating that spinal delta 2-, but not delta 1-, mu- or kappa-opioid receptors are involved in beta-endorphin-induced inhibition of the tail-flick response.

Topics: Amino Acid Sequence; Analgesia; Animals; Benzylidene Compounds; beta-Endorphin; Dose-Response Relationship, Drug; Enkephalin, Methionine; Injections, Intraventricular; Injections, Spinal; Male; Molecular Sequence Data; Naltrexone; Narcotic Antagonists; Pentobarbital; Raphe Nuclei; Rats; Rats, Sprague-Dawley; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Somatostatin; Spinal Cord; Tail