naltrindole and binaltorphimine

Previously, we reported that central administration of bombesin, a stress-related peptide, elevated plasma levels of catecholamines (noradrenaline and adrenaline) in the rat. The sympatho-adrenomedullary system, which is an important component of stress responses, can be regulated by the central opioid system. In the present study, therefore, we examined the roles of brain opioid receptor subtypes (µ, δ, and κ) and nociceptin receptors, originally identified as opioid-like orphan receptors, in the bombesin-induced activation of central sympatho-adrenomedullary outflow using anesthetized male Wistar rats. Intracerebroventricularly (i.c.v.) administered bombesin-(1 nmol/animal) induced elevation of plasma catecholamines was significantly potentiated by pretreatment with naloxone (300 and 1000 µg/animal, i.c.v.), a non-selective antagonist for µ-, δ-, and κ-opioid receptors. Pretreatment with cyprodime (100 µg/animal, i.c.v.), a selective antagonist for µ-opioid receptors, also potentiated the bombesin-induced responses. In contrast, pretreatment with naltrindole (100 µg/animal, i.c.v.) or nor-binaltorphimine (100 µg/animal, i.c.v.), a selective antagonist for δ- or κ-opioid receptors, significantly reduced the elevation of bombesin-induced catecholamines. In addition, pretreatment with JTC-801 (30 and 100 µg/animal, i.c.v.) or J-113397 (100 µg/animal, i.c.v.), which are selective antagonists for nociceptin receptors, also reduced the bombesin-induced responses. These results suggest that brain µ-opioid receptors play a suppressive role and that brain δ-, κ-opioid, and nociceptin receptors play a facilitative role in the bombesin-induced elevation of plasma catecholamines in the rat. Thus, in the brain, these receptors could play differential roles in regulating the activation of central sympatho-adrenomedullary outflow.

Topics: Adrenal Medulla; Animals; Bombesin; Brain; Catecholamines; Morphinans; Naloxone; Naltrexone; Nociceptin Receptor; Rats; Receptors, Opioid; Sympathetic Nervous System

Melanin-concentrating hormone (MCH) exerts an orexigenic effect that resembles that of opioids, suggesting that the MCH and opioid systems could interact in controlling the food intake behavior. Three series of experiments were conducted in male Wistar rats: 1) to test the ability of the κ-, μ-, and δ-opioid receptor antagonists binaltorphimine (nor-BNI-κ), β-funaltrexamine (β-FNA-μ), and naltrindole (NTI-δ), respectively, to block the stimulating effects of MCH on food intake; 2) to verify the ability of MCH to induce a positive hedonic response to a sweet stimulus when injected into the nucleus accumbens shell (NAcSh) or right lateral ventricle (LV) of the brain; and 3) to assess the ability of nor-BNI, β-FNA, and NTI to block the effects of MCH on the hedonic response to a sweet stimulus. Nor-BNI, NTI (0, 10 and 40 nmol), and β-FNA (0, 10 and 50 nmol) were administered into the LV prior to injecting MCH (2.0 nmol). To assess the hedonic response, rats were implanted with an intraoral cannula allowing for the infusion of a sweet solution into the oral cavity. Food intake was assessed in sated rats during the first 3 h following the MCH or vehicle (i.e., artificial cerebrospinal fluid) injection. The hedonic response to a sweet stimulus was assessed by examining facial mimics, following the intraoral administration of a sucrose solution. Blockade of each of the three opioid receptors by selective antagonists prevented MCH-induced feeding. Furthermore, MCH-injections into the NAcSh and right LV resulted in enhanced hedonic responses. Finally, antagonism of the three opioid receptors blunted the LV-injected, MCH-induced, facial-liking expressions in response to an intraoral sweet stimulus. Overall, the present study provides evidence to link the MCH and opioid systems in the food intake behavior.

Topics: Analgesics, Opioid; Animals; Behavior, Animal; Eating; Hypothalamic Hormones; Injections, Intraventricular; Male; Melanins; Models, Animal; Naltrexone; Narcotic Antagonists; Pituitary Hormones; Rats; Rats, Wistar; Receptors, Opioid; Sucrose; Taste

1. A novel selective nociceptin/orphanin FQ (N/OFQ) peptide receptor antagonist, 1-[(3R,4R)-1-cyclooctylmethyl]-3-hydroxymethyl-4-piperidyl)-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one (CompB), inhibited specific binding of [(3)H]N/OFQ to crude membranes from the rat brain and spinal cord in a concentration-dependent manner and their K(i) values were 7.11 and 4.02 nM, respectively. Rosenthal analysis indicated that there was a significant increase in the K(d) value for [(3)H]N/OFQ binding in the brain and spinal cord in the presence of CompB (10 nM). 2. There was a dose-dependent increase in K(d) values for [(3)H]N/OFQ binding in the brain and spinal cord following i.v. injection of CompB at relatively low doses (0.69-6.88 micro mol kg(-1)), compared with the control values. In the spinal cord, enhancement with each dose was constantly greater and the duration of enhancement (6.88 micro mol kg(-1)) was significantly longer. 3. The degree of increase in K(d) values for [(3)H]N/OFQ binding after i.v. injection of CompB (6.88 micro mol kg(-1)) was significantly larger in the lumbar region of the spinal cord compared to other regions. 4. CompB (0.1, 0.3 micro M) shifted the concentration-effect curves of N/OFQ-stimulated [(35)S]GTPgammaS binding in the brain and spinal cord to the right. 5. The i.v. injection of CompB (6.88 micro mol kg(-1)) significantly suppressed the N/OFQ-stimulated [(35)S]GTPgammaS binding in the rat spinal cord and shifted the concentration-effect curve to the right, while it produced little inhibitory effect in the brain. The present study has shown that CompB may exhibit pharmacological effects through a predominant blockade of N/OFQ peptide receptors in the spinal cord under in vivo conditions.

Topics: Animals; Benzimidazoles; Binding, Competitive; Brain; Dose-Response Relationship, Drug; Guanosine Triphosphate; Injections, Intravenous; Male; Naltrexone; Narcotic Antagonists; Nociceptin Receptor; Opioid Peptides; Peptide Fragments; Piperidines; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, Opioid; Spinal Cord

In a model of self-sustaining status epilepticus induced in rats by 30 min intermittent stimulation of the perforant path through chronically implanted electrodes, a decrease in dynorphin-like immunoreactivity in the dentate gyrus and CA3 was observed 3 h and 24 h after the induction of status epilepticus. Enkephalin-like immunoreactivity decreased 3 h but not 24 h after perforant path stimulation. Injection into the hilus of the dentate gyrus 10 min prior to stimulation of the kappa-receptor agonist dynorphin-A(1-13), the delta-receptor antagonists ICI-174864 and naltrindole, as well as i.p. injection of naloxone prevented the development of status epilepticus. Perihilar administration of the delta-agonist [D-Ser2]Leu-enkephalin-Thr6 or the kappa-antagonist nor-Binaltorphimine, but not of the mu-agonist [D-Ala2,N-Me-Phe4,Gly-ol5]-Enkephalin, facilitated the establishment of self-sustaining status epilepticus. Injection into the hilus of dynorphin-A(1-13) after the end of perforant path stimulation, stopped established status epilepticus, while administration of naloxone, naltrindole and ICI-174864 were ineffective. We conclude that kappa-opioids in the hippocampus counteract initiation and maintenance of status epilepticus, while delta-opioids promote initiation, but not maintenance of seizure activity. These data are important for the understanding the mechanisms which underlie initiation and maintenance of status epilepticus and for the development of new approaches for its effective management.

Topics: Action Potentials; Analgesics; Analgesics, Opioid; Animals; Disease Models, Animal; Dynorphins; Electric Stimulation; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, Leucine; Enkephalins; Immunohistochemistry; Male; Naloxone; Naltrexone; Narcotic Antagonists; Neurons; Opioid Peptides; Peptide Fragments; Perforant Pathway; Rats; Rats, Wistar; Receptors, Opioid, delta; Receptors, Opioid, kappa; Status Epilepticus

The head kidney is the main lymphopoietic organ of teleost fish. It is the source of leukocytes inhabiting the peritoneal cavity during an experimental peritoneal inflammation (Gruca et al., Folia Biol.-Kraków, 1997, 44, 137-142). The number of elicited peritoneal leukocytes is significantly lower in the goldfish with concomitant morphine injection than in their counterparts injected with the irritant only. Morphine may act directly on the head kidney leukocytes, as they are equipped with the selective naloxone-binding sites (Chadzińska et al., Arch. Immunol. Ther. Exp., 1997, in press). Further characterization of these opioid receptors (by radioligand binding techniques) indicates that the goldfish head kidney leukocytes possess at least two different opiate-binding sites: the [3H]naloxone binding site with a KD = 87 +/- 2.1 nM and Bmax = 298 +/- 15 fmol/mg protein; and the second, the [3H]naltrindole binding site with a KD = 37 +/- 5.5 nM and Bmax = 1,172 +/- 220 fmol/mg protein. The competition experiments with delta- (naltrindole), kappa- (nor-binaltorphimine) and mu- (cyprodime, naltrexone) selective ligands suggest that the naloxone-binding site is similar to mu 3 receptors described by Stefano et al. (Proc. Nat. Acad. Sci. USA, 1993, 90 11099-11103). Low affinity binding of selective ligands excludes the presence of neuronal-type mu- and delta-opioid receptors on goldfish leukocytes.

Topics: Animals; Binding Sites; Goldfish; Leukocytes; Morphinans; Morphine; Naloxone; Naltrexone; Narcotic Antagonists; Receptors, Opioid, delta; Receptors, Opioid, mu

We examined the effect of [Met5]enkephalin-Arg6-Phe7 (MEAP) on the capsaicin-induced cough reflex in mice. Intracerebroventricular administration of MEAP significantly decreased the number of coughs in a dose-dependent manner. The antitussive effect of MEAP was blocked by nor-binaltorphimine, a selective kappa-opioid receptor antagonist. However, beta-funaltrexamine, a mu-opioid receptor antagonist, had no effect on the antitussive effect of MEAP. On the other hand, the antinociceptive effect of MEAP, as determined in the tail-flick test, was blocked by both nor-binaltorphimine and beta-funaltrexamine. Naltrindole, a delta-opioid receptor antagonist, had no effect on either the antitussive effect or the antinociceptive effect of MEAP. These data suggest that MEAP exerts its antitussive effect in mice through the stimulation of kappa-opioid receptors, whereas the antinociceptive effect of MEAP is mediated through the simulation of both kappa- and mu-opioid receptors.

Topics: Animals; Antitussive Agents; Capsaicin; Cough; Dose-Response Relationship, Drug; Enkephalin, Methionine; Injections, Intraventricular; Male; Mice; Naltrexone; Narcotic Antagonists; Receptors, Opioid, kappa; Receptors, Opioid, mu

Tail-pinch feeding (TPF) in rats is decreased following general (naltrexone, NTX) and mu (Cys2-Tyr3-Orn5-Pen7-amide, CTOP) opioid antagonists, but not following kappa (nor-binaltorphamine. Nor-BNI) or delta (naltrindole, NTI) opioid antagonists. Because multiple mu (mu1 and mu2) and delta (delta 1 and delta 2) opioid receptor subtypes have been characterized, the present study evaluated whether TPF was differentially altered following ICV administration of general (NTX), mu (beta-funaltrexamine, B-FNA), mu1 (naloxonazine, NAZ), kappa (Nor-BNI), delta 1 ([D-Ala2, Leu5, Cys6]-enkephalin, DALCE) and delta 2 (NTI) opioid antagonists. Like the reversible mu antagonist CTOP, the irreversible mu antagonist B-FNA significantly and dose-dependently (1-20 micrograms) reduced TPF by up to 28%. In contrast, whereas NAZ (50 micrograms) reduced TPF by 32%, this effect was highly variable and failed to achieve significance. Neither NTX (5-10 mg/kg, SC), Nor-BNI (20 micrograms), DALCE (40 micrograms) nor NTI (20 micrograms) significantly altered TPF, suggesting that kappa, delta 1 and delta 2 opioid receptor subtypes were not involved. Because no antagonist altered the duration of food contact during tail pinch, it appears that the opioid effect modulates ingestive rather than activational mechanisms. The reliable inhibition of TPF by B-FNA (mu1 and mu2), together with the variable effect of naloxonazine (mu1), appears to implicate both mu binding sites in this response.

Topics: Animals; Arousal; Enkephalin, Leucine-2-Alanine; Feeding Behavior; Indoles; Male; Morphinans; Naloxone; Naltrexone; Narcotic Antagonists; Nociceptors; Rats; Rats, Sprague-Dawley; Receptors, Opioid, mu

Previous work has demonstrated that 3 pharmacologically and neuroanatomically distinct analgesia systems can be sequentially activated by increasing numbers of transcutaneous tail-shock. To date, the categorization of the early (after 2 tail-shocks) and late (after 80-100 tail-shocks) analgesias as opiate-mediated has been based on the ability of systemic naltrexone and morphine tolerance to block these effects. In contrast, the analgesia observed after 5-40 tail-shocks is unaffected by these manipulations, leading to its categorization as non-opiate. The preceding companion paper and the present work were aimed at identifying the neuroanatomical loci at which opiates exert their analgesic effects in this tail-shock paradigm and, further, to identify which opiate receptor subtypes are involved. The 8 experiments included in the present paper examined the effect of microinjecting either naltrexone (a relatively non-selective opiate receptor antagonist), binaltorphimine (kappa receptor antagonist), Cys2-Tyr3-Orn5-Pen7-amide (CTOP) (mu receptor antagonist), or naltrindole (delta receptor antagonist) either into the third ventricle or over the frontal cortex. Taken together, these experiments demonstrate that the late (80-100 shock) opiate analgesia is mediated by delta opiate receptors located within subcortical structures rostral to the 4th ventricle. No evidence for supraspinal opiate involvement in the early (2 shock) opiate analgesia was found.

Topics: Analysis of Variance; Animals; Cerebral Ventricles; Dose-Response Relationship, Drug; Electroshock; Indoles; Injections, Intraventricular; Injections, Spinal; Male; Morphinans; Naltrexone; Narcotic Antagonists; Pain; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, delta; Spinal Cord

Previous work has demonstrated that 3 pharmacologically and neuroanatomically distinct analgesia systems can be sequentially activated by increasing numbers of transcutaneous tail-shock. To date, the categorization of the early (after 2 tail-shocks) and late (after 80-100 tail-shocks) analgesias as opiate-mediated has been based on the ability of systemic naltrexone and morphine tolerance to block these effects. In contrast, the analgesia observed after 5-40 tail-shocks is unaffected by these manipulations, leading to its categorization as non-opiate. The present work and the following companion paper were aimed at identifying the neuroanatomical loci at which endogenous opiates exert their analgesic effects in this tail-shock paradigm and, further, to identify which opiate receptor subtypes are involved. The 3 experiments included in the present paper focus on the role of spinal opiates in tail-shock induced analgesia. The first experiment demonstrates that the tail-shock parameters used do not directly activate pain suppressive circuitry within the spinal cord, but rather activate centrifugal pain modulation circuitry originating within the brain. The last two experiments examine the effect of intrathecal microinjection of either naltrexone (a relatively non-selective opiate receptor antagonist), binaltorphimine (kappa receptor antagonist), Cys2-Tyr3-Orn5-Pen7-amide (CTOP) (mu receptor antagonist), or naltrindole (delta receptor antagonist). Taken together, these latter 2 experiments demonstrate that both the early (after 2 shocks) and late (after 80-100 shocks) opiate analgesias are mediated by kappa opiate receptors within the spinal cord.

Topics: Analysis of Variance; Animals; Dose-Response Relationship, Drug; Electroshock; Indoles; Injections, Spinal; Male; Morphinans; Naltrexone; Narcotic Antagonists; Pain; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, kappa; Somatostatin; Spinal Cord

We assessed the effects of antagonists selective for mu (mu), delta (delta) or kappa (kappa) opioid receptors on the induction of long-term potentiation (LTP) and short-term potentiation (STP) at the rat hippocampal mossy fiber-CA3 synapse in vivo. The mu opioid receptor-selective antagonist Cys2,Tyr3,Orn5,Pen7 amide (CTOP, 1 or 3 nmol) did not alter either mossy fiber-CA3 responses evoked at low frequencies or previously potentiated mossy fiber-CA3 responses, but it attenuated the induction of mossy fiber LTP in a dose-dependent manner. By contrast, LTP of CA3 responses evoked by stimulation of commissural afferents to the CA3 region was unaffected by CTOP. Neither the delta opioid receptor-selective antagonist naltrindole hydrochloride (0.3-10 nmol) or the kappa opioid receptor-selective antagonist nor-binaltorphimine hydrochloride (3-10 nmol) altered the induction of mossy fiber LTP. Thus, a role for delta or kappa opioid receptors in the induction of mossy fiber LTP could not be demonstrated. CTOP, in quantities that attenuated mossy fiber LTP induction, also attenuated the magnitude of mossy fiber STP measured 5 sec after delivery of conditioning trains. Further examination of the component of STP corresponding to post-tetanic potentiation (PTP) revealed that CTOP selectively attenuated the estimated magnitude and time constant of decay of mossy fiber PTP. These results suggest that the frequency-dependent activation of mu opioid receptors by endogenous opioid peptides is required for the induction of LTP at hippocampal mossy fiber synapses.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Evoked Potentials; Hippocampus; Indoles; Male; Morphinans; Naltrexone; Rats; Rats, Sprague-Dawley; Receptors, Opioid, mu; Somatostatin; Synapses; Time Factors

The modulatory effects of intrathecally (i.t.) administered dynorphin A(1-17) and dynorphin A(1-13) on morphine antinociception have been studied previously in rats by other investigators. However, both potentiating and attenuating effects have been reported. In this study, the modulatory effects of i.t. administered dynorphin A(1-17) as well as the smaller fragment, dynorphin A(1-8), were studied in mice. In addition, nor-binaltorphimine (nor-BNI), a highly selective kappa opioid receptor antagonist, and naltrindole (NTI), a highly selective delta opioid receptor antagonist, were used to characterize the possible involvement of spinal kappa and delta opioid receptors in the modulatory effects of the dynorphins. Dynorphin A(1-17) and dynorphin A(1-8) administered i.t. at doses that did not alter tail-flick latencies, were both able to antagonize in a dose-dependent manner, the antinociceptive action of s.c. administered morphine sulfate. The antinociceptive ED50 of morphine sulfate was increased 3.9- and 5.3-fold by 0.4 nmol/mouse of dynorphin A(1-17) and dynorphin A(1-8), respectively. Injections of 0.4 and 0.8 nmol/mouse of nor-BNI i.t., but not its inactive enantiomer (+)-1-nor-BNI, inhibited dose-dependently the antagonistic effects of the dynorphins. These doses of nor-BNI alone did not affect the antinociceptive action of morphine sulfate. Intrathecal administration of 5 nmol/mouse of NTI also did not affect the modulatory effects of dynorphins. These observations that dynorphins exert their antagonistic effects on morphine-induced antinociception stereoselectively through spinal kappa opioid receptors may suggest a coupling between spinal kappa and mu opioid receptors.

Topics: Animals; Dynorphins; Indoles; Male; Mice; Morphinans; Morphine; Naltrexone; Pain; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, kappa; Spine; Stereoisomerism

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