ici-154129 and beta-funaltrexamine

An overactive endogenous opioid peptide system (EOP) in the hypothalamus of the obese rats could contribute to a subnormal metabolic response to cold stress. Specific mu, delta, kappa opioid receptor antagonists and naloxone were infused into cannulaes aimed at the paraventricular nucleus (PVN) of awake freely moving obese (LA/N-cp corpulent) and lean littermate rats. Metabolic responses were measured by indirect calorimetry during thermoneutrality (30 degrees C) and at 10 degrees C for 60 minutes each. When expressed relative to metabolic body size (kg(-.75)) obese rats had lower values (obese = 21.1 +/- 1.9 vs. lean = 27.9 +/- 2.7 ml x kg(-.75) x min, mean +/- s.d., p < 0.05) at 10 degrees C during saline infusion. EOP antagonist infusions at 30 degrees C had no effect on metabolic rate for either lean or obese animals. Mu (23.5 +/- 3.4 ml x kg x (-75) x min) and delta (23.0 +/- 2.0) antagonism and naloxone (25.0 +/- 2.3) significantly increased the metabolic response to cold in obese but not lean rats. These data suggest that certain subtypes of EOP receptors in or near PVN are overactive in obese rats. This overactive state may inappropriately inhibit the thermogenic response to cold stress in obesity.

Topics: Animals; Cold Temperature; Enkephalin, Leucine; Male; Naloxone; Naltrexone; Narcotic Antagonists; Obesity; Opioid Peptides; Oxygen Consumption; Paraventricular Hypothalamic Nucleus; Rats; Rats, Sprague-Dawley; Stress, Physiological; Thermogenesis

The growth hormone (GH) secretory response to beta-endorphin and the involvement of opiate receptor subtypes in this response were determined in diestrous female rats. The involvement of the mu (mu), delta (delta) and/or kappa (kappa) site was determined by administering specific antagonists for each of these sites prior to beta-endorphin. beta-Funaltrexamine (1 or 5 micrograms) was administered to block mu sites, ICI 154,129 (5 or 25 micrograms) blocked delta sites and nor-binaltorphimine (8 micrograms) blocked kappa sites. The ability of these antagonists to block GH secretion following intravenous morphine administration was also determined. The opiate antagonists and beta-endorphin were administered into the lateral ventricle. A dose-response study for beta-endorphin indicated that 0.5 micrograms beta-endorphin was the minimum stimulatory dose for GH release, producing an approximately 4-fold increase in circulating levels of GH; lower doses of beta-endorphin did not stimulate secretion. All three antagonists were capable of blocking the stimulatory effects of beta-endorphin. These results provide evidence that all three opiate receptor subtypes are involved in the stimulatory effect of beta-endorphin on GH release.

Topics: Animals; beta-Endorphin; Diestrus; Enkephalin, Leucine; Female; Growth Hormone; Kinetics; Naltrexone; Rats; Rats, Sprague-Dawley; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu

The prolactin secretory response to beta-endorphin and the involvement of opiate receptor subtypes in this response was determined in both diestrous and postpartum, lactating female rats. The involvement of the mu-, delta- and/or kappa-site was determined by administering specific antagonists for each of these sites prior to beta-endorphin. beta-Funaltrexamine (beta-FNA, 1 or 5 micrograms) was administered to block mu-sites, ICI 154,129 (5, 10 or 25 micrograms) blocked delta-sites and nor-binaltorphimine (norBNI, 8 micrograms) blocked kappa-sites. The ability of beta-FNA and ICI 154,129 to block prolactin secretion following morphine administration was also determined. A dose response study for beta-endorphin indicated that beta-endorphin, at doses as low as 25 ng, was a potent stimulus for prolactin release producing an increase in prolactin that mimicked the suckling-induced prolactin increase. In addition, all three antagonists were capable of antagonizing the stimulatory effect of beta-endorphin in both diestrous and postpartum female rats. These results indicate that beta-endorphin is a potent stimulus for prolactin secretion and that these three opiate receptor subtypes interact to produce its stimulatory effect on prolactin release.

Topics: Animals; beta-Endorphin; Diestrus; Dose-Response Relationship, Drug; Enkephalin, Leucine; Female; Lactation; Male; Naltrexone; Narcotic Antagonists; Prolactin; Rats; Rats, Sprague-Dawley; Receptors, Opioid

The present studies were designed to determine what type of opioid receptor, mu or delta, in the spinal cord was involved in beta-endorphin-induced antinociception. The tail-flick response was used as an antinociceptive test. Intrathecal (i.t.) injection of ICI-174,864 [(Allyl)2-Tyr-Aib-Aib-Phe-Leu-OH] (10 micrograms) or ICI-154,129 [(N,N-Bisallyl)-Tyr-Gly-Gly-psi-(CH2S)-Phe-Leu-OH] (20 micrograms), delta-opioid receptor antagonists, but not beta-funaltrexamine (0.025 microgram), a mu-opioid receptor antagonist, antagonized inhibition of the tail-flick response induced by beta-endorphin given i.c.v. However, i.t. injection of the same dose of ICI-174,864, ICI-154,129 or beta-funaltrexamine did not affect inhibition of the tail-flick response induced by morphine given i.c.v. Mice were pretreated i.c.v. with either beta-endorphin (2 micrograms), morphine (2 micrograms) or saline (5 microliters) for 2, 3 or 4 hr (which were times that the tail-flick response was no longer inhibited) and were injected i.t. with various doses of D-Ala2-NMePhe4-Gly-ol-enkephalin (a selective mu-opioid receptor agonist), D-Ala2-D-Leu5-enkephalin (a mu- and delta-opioid receptor agonist) or D-Pen2-D-Pen5-enkephalin (a delta-opioid receptor agonists). The tail-flick response was performed 10 min after i.t. injection. A single i.c.v. pretreatment with beta-endorphin for 2 and 3 hr, but not 4 hr, reduced markedly the inhibition of the tail-flick response induced by D-Pen2-D-Pen5-enkephalin and D-Ala2-DLeu5-enkephalin, but not D-Ala2-NMePhe4-Gly-ol-enkephalin, injected i.t.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Analgesia; Animals; beta-Endorphin; Enkephalin, Leucine; Injections, Intraventricular; Male; Mice; Mice, Inbred ICR; Morphine; Naltrexone; Narcotic Antagonists; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, mu; Spinal Cord

In a previous study, electrically induced contractions of the gastrocnemius muscle in conscious spontaneously hypertensive rats were shown to induce a blood pressure reduction of 15-20 mmHg lasting several hours. We showed in that study that endogenous opioid systems were involved. In this study, drugs with selective affinity for different opioid receptors were used to analyse further the involvement of endogenous opioid systems in the post-stimulatory drop in blood pressure in spontaneously hypertensive rats. Prestimulatory intracerebroventricular administration of beta-FNA (a mu-receptor antagonist) did not significantly influence the response at all, nor did a lower intravenous dose of naloxone reverse the post-stimulatory drop in blood pressure. High-dose naloxone (15 mg kg-1) increased post-stimulatory blood pressure by around 10 mmHg. About 50% of the drop thus remained after this treatment. A similar, partial reversal of the decreased blood pressure was seen after intravenous administration of a delta-receptor antagonist, ICI 154,129. However, the depressor response was completely reversed by a low intravenous dose of MR 2266 BS (a kappa-receptor antagonist). These results suggest that the reduction in blood pressure after muscle stimulation is mainly mediated by the opioid kappa-receptor. A certain involvement of the delta-receptor is also indicated.

Topics: Animals; Benzomorphans; Blood Pressure; Electric Stimulation; Enkephalin, Leucine; Heart Rate; Hindlimb; Male; Naloxone; Naltrexone; Physical Conditioning, Animal; Rats; Rats, Inbred SHR; Receptors, Opioid; Regional Blood Flow

Exposure to either cold or warm stress increased the thermal nociceptive thresholds of the terrestrial snail, Cepaea nemoralis. The warm stress-induced 'analgesia' was blocked by the prototypic opiate antagonist, naloxone, and the delta-opiate antagonist, ICI 154,129, and was suppressed by a 24-h pretreatment with the irreversible opiate antagonist, beta-funaltrexamine (B-FNA). In contrast, cold stress-induced analgesia was unaffected by either naloxone, ICI 154,129 or B-FNA. These results indicate that this mollusc displays both opioid and non-opioid forms of stress-induced analgesia in a manner analogous to that reported for mammals. These findings suggest an early evolutionary development and phylogenetic continuity of opioid and non-opioid mediated stress responses to aversive environmental stimuli.

Topics: Animals; Cold Temperature; Endorphins; Enkephalin, Leucine; Hot Temperature; Naloxone; Naltrexone; Pain; Reaction Time; Snails; Stress, Physiological

Administration of opioid receptor antagonists was utilized to determine the opioid receptor type involved in the suppression of LH release by beta-endorphin (beta-END). Long-term (three to four weeks) ovariectomized rats with chronic third ventricular cannulae were fitted with jugular catheters and received treatment with vehicle or one of three opioid antagonists. The delta antagonist ICI 154, 129, but not the mu1 or mu antagonists naloxazone or beta-funaltrexamine, respectively, blocked the suppressive effect of beta-END on plasma LH levels and transiently but significantly increased LH levels above preinfusion value. None of the antagonists significantly reduced the beta-END-induced release of PRL. These results provide evidence that the inhibitory effect of beta-END on LH release may be mediated by delta receptors.

Topics: Animals; beta-Endorphin; Castration; Endorphins; Enkephalin, Leucine; Female; Kinetics; Luteinizing Hormone; Naloxone; Naltrexone; Narcotic Antagonists; Prolactin; Rats; Rats, Inbred Strains; Receptors, Opioid

Dose-response comparisons of the ability of the selective delta antagonist ICI 154,129 (12.5-50 nmol), the nonselective antagonist naloxone (29-290 nmol), and the irreversible selective mu antagonist beta-fNA (1.3-21 nmol) to alter the threshold response to DADLE or etorphine was studied in the rat flurothyl seizure test. DADLE (35 nmol, i.c.v.) and etorphine (122 nmol/kg, s.c.) both caused increases in seizure threshold which were differentially antagonized by pretreatment (i.c.v.) with the respective antagonists. For DADLE, only ICI 154,129 and naloxone produced a dose-related blockade of the increase in seizure threshold, with ICI 154,129 being more potent than naloxone. In contrast, the anticonvulsant action of etorphine was not antagonized by ICI 154,129 (50 nmol), but was blocked by a low dose of naloxone (29 nmol) or beta-fNA (21 nmol). In addition, prior occupancy of mu-sites with beta-fNA (21 nmol) significantly diminished the abilities of either ICI 154, 129 (50 nmol) or naloxone (290 nmol) to antagonize the anticonvulsant action of DADLE. The results of this study demonstrated that the effects of DADLE to increase seizure threshold in the rat were primarily mediated by activation of a delta-opioid receptor system. Furthermore, evidence has been provided for a functional interaction between delta and mu receptors in the opioid regulation of seizure threshold.

Topics: Animals; Anticonvulsants; Cerebral Ventricles; Enkephalin, Leucine; Enkephalin, Leucine-2-Alanine; Etorphine; Male; Naloxone; Naltrexone; Narcotic Antagonists; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, mu; Seizures

Topics: Animals; Disease Models, Animal; Enkephalin, Leucine; Enkephalin, Leucine-2-Alanine; Male; Naloxone; Naltrexone; Narcotic Antagonists; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, mu; Seizures

Acute i.c.v. administration of ICI 154,129 (100-600 micrograms), a delta-opioid receptor antagonist, raised the seizure threshold in a dose-related manner in rats exposed to flurothyl, a volatile convulsant. Pretreatment with naloxone or beta-funaltrexamine (beta-FNA) antagonized this effect. Lower doses of ICI 154,129 (12.5-50 micrograms), which did not influence seizure threshold, selectively antagonized the anticonvulsant action of [D-Ala2,D-Leu5]enkephalin (DADLE) in the same procedure. Consequently, it may be inferred that ICI 154,129 at high doses has mu-agonist and at low doses delta-antagonist properties in the rat flurothyl test.

Topics: Animals; Enkephalin, Leucine; Enkephalin, Leucine-2-Alanine; Male; Naloxone; Naltrexone; Narcotic Antagonists; Rats; Rats, Inbred Strains; Receptors, Opioid; Seizures

The use of selective delta and mu opioid antagonists has provided evidence that delta opioid receptors within the brain mediate the endogenous opioid component of endotoxic shock hypotension. The selectivity of these delta and mu antagonists was demonstrated by their differing effects upon morphine analgesia and endotoxic hypotension. The mu antagonist beta-funaltrexamine, at doses that antagonized morphine analgesia, failed to alter shock, whereas the delta antagonist M 154,129: [N,N-bisallyl-Tyr-Gly-Gly-psi-(CH2S)-Phe-Leu-OH] (ICI) reversed shock at doses that failed to block morphine analgesia. Therefore, selective delta antagonists may have therapeutic value in reversing circulatory shock without altering the analgesic actions of endogenous or exogenous opioids. Additional data revealed that prior occupancy of mu binding sites by irreversible opioid antagonists may allosterically attenuate the actions of antagonists with selectivity for delta binding sites. For endogenous opioid systems, this observation provides an opportunity to link in vivo physiological responses with receptor-level biochemical interactions.

Topics: Allosteric Regulation; Animals; Blood Pressure; Enkephalin, Leucine; Macromolecular Substances; Male; Naltrexone; Rats; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, mu; Shock, Septic

Administration of naloxazone (50 mg/kg i.v.), an irreversible, selective and long acting antagonist of the mu 1 subclass of the opioid receptors, strongly reduced stimulation of PRL secretion by morphine (5.0 mg/kg i.v.) injected 24 hours later into conscious, unrestrained rats. In contrast, the effect of morphine on PRL release was unimpaired in rats treated 24 hours beforehand with either the reversible opioid antagonist naloxone (50 mg/kg i.v.), or the vehicle for naloxazone. A complete suppression of the PRL response to morphine (3.0 mg/kg i.v.) was observed in animals given intraventricular (IVT) injection of beta- funaltrexamine (beta-FNA, 2.5 micrograms), another selective, irreversible and long acting antagonist of the mu receptors, 24 hours beforehand. Neither naloxazone nor beta-FNA had any effect on the activation of GH secretion by morphine, which, however, was conspicuously reduced by ICI 154, 129, a preferential delta receptor antagonist, injected IVT (50 micrograms) 5 minutes before morphine. ICI 154, 129 had no effect on the PRL response to morphine. It is concluded that the PRL stimulating effect of morphine is mediated by the mu receptors, whereas activation of GH probably involves the delta sites.

Topics: Animals; Drug Interactions; Enkephalin, Leucine; Growth Hormone; Injections, Intraventricular; Male; Morphine; Naloxone; Naltrexone; Prolactin; Rats; Rats, Inbred Strains; Receptors, Opioid

Studies were conducted with the putative delta-opioid receptor antagonist lCl 154,129 (lCl) and the putative mu-receptor antagonist beta-funaltrexamine (beta-FNA) to investigate their ability to block the acute opioid-like effects of a single electroconvulsive shock (ECS). lCl, but not beta-FNA, attenuated the increase in hot-plate escape latencies seen following ECS. From these data, we conclude that ECS activates endogenous opioids which act upon delta rather than mu receptors to result in an increase in hot-plate escape latencies.

Topics: Animals; Electroshock; Enkephalin, Leucine; Escape Reaction; Hot Temperature; Male; Naloxone; Naltrexone; Narcotic Antagonists; Nociceptors; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, delta

Using antagonists with selectivity for the delta (ICI 154,129) and mu (beta-funaltrexamine) binding sites, evidence was obtained to indicate that delta receptors within the brain mediate the endogenous opioid component of endotoxic hypotension. The therapeutic actions of intravenous ICI 154,129 were dose related, with effective doses between 15-60 mg/kg. Evidence for a functional interaction between mu and delta binding sites was obtained: prior occupancy of the mu binding site by beta-funaltrexamine prevented the usual therapeutic response to the delta antagonist ICI 154,129 in endotoxemic rats. These data indicate that mu and delta binding sites may be a part of the same macromolecular complex which interact through allosteric coupling.

Topics: Animals; Blood Pressure; Enkephalin, Leucine; Heart Rate; Male; Naloxone; Naltrexone; Narcotic Antagonists; Pulse; Rats; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, mu; Shock, Septic