Phencyclidine and psychotomimetic sigma opiates: recent insights into their biochemical and physiological sites of action.
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Benzomorphans↗
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Involvement of mu-receptors in the opioid-induced generation of bursting discharges in hippocampal pyramidal cells.
Cultured hippocampal pyramidal cells responded to field stimulation with a short latency excitation followed by a long-lasting inhibition. This sequence was transformed into a bursting response by bath application of 10(-8) M FK 33-824, 10(-6) M (D-Ala)2(D-Leu)5-enkephalin and 10(-5) M bremazocine. Bremazocine and ethylketocyclazocine stereospecifically blocked the effects of FK 33-824. The results indicate that the excitatory responses were predominantly mediated by mu-receptors.
Animals↗
Dynorphin A (1-13) in the brain suppresses epinephrine-induced ventricular premature complexes and ventricular tachyarrhythmias.
The objectives of this study were to test the hypothesis that dynorphin in the central nervous system modulates epinephrine-induced cardiac arrhythmias and that central cholinergic mechanisms are operative in this action of dynorphin. Cardiac arrhythmias were produced by continuous intravenous infusion of epinephrine, in Wistar rats, previously instrumented with catheters in the lateral cerebral ventricle, femoral vein and femoral artery. Epinephrine produced ventricular premature complexes and later the development of fatal ventricular fibrillation. Dynorphin A (1-13), 5 or 20 micrograms (3 or 12 nM) administered into the lateral cerebral ventricle (ICV), significantly (P less than 0.05) increased the threshold for development of cardiac arrhythmias. Dynorphin A (1-13), 20 micrograms, increased the epinephrine dose at the occurrence of ventricular premature beats to 171 +/- 8 (mean +/- 1 S.E.M.) compared to 120 +/- 5 micrograms epinephrine/kg in the control group and increased the dose at the onset of fatal arrhythmias to 186 +/- 8 compared to 141 +/- 10 micrograms epinephrine/kg in the control group. The action of dynorphin was significantly (P less than 0.05) antagonized by the kappa opioid antagonist MR2266. Atropine sulfate, administered ICV or intravenously, produced a dose dependent antagonism of this action of dynorphin A (1-13). This was not due to the peripheral effects of atropine, as atropine methylnitrate, which does not cross the blood brain barrier, did not oppose the effects of dynorphin A (1-13). These data indicate (i) dynorphin A (1-13) increases the threshold for or suppresses the manifestations of epinephrine-induced ventricular arrhythmias, (ii) dynorphin's action on cardiac arrhythmias is mediated through central cholinergic rather than peripheral parasympathetic mechanisms (iii) dynorphin may play a role as an endogenous opioid within the brain that modulates cardiac arrhythmias in circumstances of elevated circulating epinephrine concentration.
Animals↗
Involvement of beta-endorphin in the modulation of paw inflammatory edema in the rat.
This study investigates the role of the opiod receptors and of the opioid peptide beta-endorphin in the development of yeast-induced inflammation in the rat paw. Pretreatment with the opioid receptor antagonist naltrexone (10 mg/kg i.p.) exacerbates the paw edema, while morphine pretreatment (5 and 10 mg/kg) reduces it. In addition, the intravenous injection of a specific anti-beta-endorphin antibody aggravates the yeast-induced inflammation. On the contrary, both the kappa-opioid receptor antagonist MR 1452 (2.5, 5 and 10 mg/kg i.p.) and the delta-opioid receptor antagonist ICI 174-864 (2.5, 5 and 10 mg/kg i.p.) do not interfere with the inflammatory process. After intraplantar injection, naltrexone, morphine and the anti-beta-endorphin antibody do not interfere with the yeast-induced inflammatory edema. Our data suggest that beta-endorphin exerts an inhibitory regulation on the inflammatory responses through the activation of mu-opioid receptors probably located on immune cells, rather than in the paw.
Animals↗
The opioid system and central cardiovascular control: analysis of controversies.
Opiates, like morphine, were long known to produce changes in blood pressure and cardiac functions. However, the nature of these changes are a subject of continuous controversy. The substantial differences in the opiate effects on the cardiovascular system is also apparent in more recent studies using enkephalins, beta-endorphin and dynorphins. The present review is aimed to indicate the source of the variations in the experimental data and analyze the relative contribution of different experimental factors to the observed effects of opiates and opioid peptides on the cardiovascular system. The major factors which contribute to the nature of the opioid effect on the cardiovascular system are: anesthesia, species, dose, site of action in the brain, respiratory changes and receptor specificity. However, the cardiovascular status per se is an important determinant of the opiates and opioid peptide effects on hemodynamic functions as indicated in states of hypertension and shock. A newly described factor is the plasticity of the opioid receptor system which changes its level and distribution pattern in different physiological and pathophysiological states. This review emphasizes the importance of utilization of highly specific ligands to opiate receptors administered to discrete brain areas in the conscious animal.
Anesthesia, General↗
Studies on the antinociceptive effect of intrathecal salmon calcitonin.
The involvement of spinal opioid receptors and spinal monoaminergic systems, in the antinociceptive effect of intrathecal (IT) salmon calcitonin, has been evaluated by means of the hot plate test, in the rat. Intrathecal pretreatment with 40 micrograms MR 1452 and 40 micrograms ICI 154,129, purported selective antagonists respectively for kappa and delta opioid receptors did not modify sCT-induced antinociception (2 micrograms IT). A delay in the development of IT sCT-induced antinociception was observed in rats selectively depleted of cord serotonin (25 mg/kg IP desipramine plus 100 micrograms IT 5,7-dihydroxytryptamine), whereas the administration of serotonergic antagonists, methysergide and ketanserin, 30 micrograms IT, did not influence sCT effect. Cord catecholamine depletion (6-OHDA pretreatment) reduced significantly sCT antinociception. A similar reduction was produced by the dopaminergic antagonist haloperidol (15 micrograms IT), but not by the alpha-blocker phentolamine (15 micrograms IT). Findings of this study rule out an involvement of opioid peptidergic system in sCT-induced increase of hot plate latencies at spinal level; a possible involvement of cord dopaminergic receptors is suggested.
Analgesics↗
ACTH-(1-24) and alpha-MSH antagonize feeding behavior stimulated by kappa opiate agonists.
ACTH-(1-24) and alpha-MSH, intracerebroventricularly (ICV) injected at the doses of 4 and 10 micrograms/animal, respectively, markedly inhibited spontaneous feeding in adult Sprague-Dawley rats, the effect remaining significant for 6-9 hours. At these same doses, ACTH-(1-24) and alpha-MSH abolished the feeding-stimulatory effect of the kappa opiate receptor agonist pentazocine, intraperitoneally (IP) injected at the dose of 10 mg/kg. The same antagonism was obtained by ICV injection of ACTH-(1-24) into rats IP treated with other kappa opiate agonists, bremazocine and tifluadom, at the doses of 1 and 5 mg/kg, respectively. These data suggest that melanocortin peptides play an inhibitory role in the complex regulation of food intake, and further support and extend the hypothesis of a melanocortin-opioid homeostatic system, its two neuropeptide components usually having opposite, mutually-balancing effects.
Adrenocorticotropic Hormone↗
Interaction of endogenous opioid peptides and other drugs with four kappa opioid binding sites in guinea pig brain.
Guinea pig brain membranes depleted of mu and delta receptors by pretreatment with the site-directed acylating agents, 2-(4-ethoxybenzyl)-1- diethylaminoethyl-5-isothiocyanatobenzimidazole.HCl (BIT) and N-phenyl-N-[1-(2-(4-isothiocyanato)phenethyl)-4- piperidinyl]-propanamide.HCl (FIT), were used in this study to test the hypothesis that guinea pig brain possesses subtypes of kappa receptors. Pretreatment of membranes with either (-)-(1S,2S)-U50,488 or the kappa selective acylating agent, (1S,2S)-trans-2-isothiocyanato-N-methyl-N-[2-(1- pyrrolidinyl)cyclohexyl]benzeneacetamide, caused a wash-resistant inhibition of kappa 1 binding sites labeled by [3H]U69,593 binding, but not kappa 2 binding sites labeled by [3H]bremazocine. Binding surface analysis of [3H]bremazocine binding resolved two binding sites, termed kappa 2 and kappa 2b, present at densities of 212 and 225 fmol/mg protein, which had low affinity for (-)-(1S,2S)-U50,488 and U69,593. The kappa 2b site had high affinity for beta-endorphin(1-31) (Kd = 5.5 nM) and [D-Ala2,D-Leu5]enkephalin (Kd = 14 nM), and lower affinity for [D-Ala2-MePhe4,Gly-ol5]enkephalin (Kd = 147 nM) and [Leu5]enkephalin (Kd = 46.0 nM). Binding surface analysis of [3H]U69,593 binding also resolved two binding sites, termed kappa 1a and kappa 1b, present at densities of 6.0 and 40.0 fmol/mg protein. The kappa 1a binding site was characterized by very high affinity for alpha-neoendorphin. Quantitative autoradiographic studies demonstrated that kappa 2a and kappa 2b binding sites are heterogeneously distributed in guinea pig brain, and that the anatomical distribution of kappa 1 binding sites reported in the literature is different from that observed in this study for the kappa 2 binding sites. Viewed collectively, these data provide evidence for four kappa receptor subtypes in guinea pig brain.
3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
Interaction of opioid peptides and other drugs with multiple kappa receptors in rat and human brain. Evidence for species differences.
Previous experiments resolved four kappa binding sites in guinea pig brain termed kappa 1a, kappa 1b, and kappa 2b. The present study was undertaken to examine the occurrence of kappa receptor subtypes in rat and human brain. [3H]U69,593 and [3H]bremazocine were used to label kappa 1 and kappa 2 binding sites, respectively, present in brain membranes depleted of mu and delta binding sites by pretreatment with the irreversible ligands, BIT and FIT. Low levels of [3H]U69,593 binding precluded a detailed quantitative study of kappa 1 binding sites in these species. Quantitative examination of [3H]bremazocine binding resolved two kappa 2 binding sites in both rat and human brain whose ligand selectivity patterns differed from that of the guinea pig. These observations suggest that there may be considerable variation in the ligand recognition site of kappa receptor subtypes among mammalian species.
3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
Oral administration of Tyr-MIF-1 stimulates gastric emptying and gastrointestinal motility in rodents.
The effects of orally administered Tyr-MIF-1, an agonist of an endogenous antiopiate system, were examined on gastric emptying in mice and gastrointestinal myoelectric activity in rats. Tyr-MIF-1 (5 mg/kg in mice, 20 mg/kg in rats) accelerated gastric emptying of a methylcellulose test meal, increased the frequency of antral spike bursts, and disrupted intestinal migrating myoelectric complexes. These effects were reproduced by a subcutaneous administration of Tyr-MIF-1 at the same dosage. They were blocked by naloxone (1 mg/kg) but not by the kappa receptor subtype antagonist MR 2266 (1 mg/kg). The GABAA antagonist bicuculline (0.5 mg/kg), but not the GABAB antagonist 2-hydroxysaclofen (4 mg/kg), also antagonized the effects of Tyr-MIF-1. These data demonstrate that oral Tyr-MIF-1 stimulates gastric emptying and gastrointestinal motility through a systemic or central action that involves opioid and GABA systems.
Administration, Cutaneous↗
Reversible suppression of spermiogenesis in beagle dogs following overdosage with the narcotic analgesic cogazocine lactate.
Acute single overdosage (1.0 mg/kg, i.m.) with the novel benzmorphan narcotic analgesic agent Cogazocine lactate lowered serum LH and testosterone concentrations of Beagle dogs. The effect was rapidly reversible and persisted for less than 24 h after drug administration. Repeated administration (1.0 mg/kg, i.m.) induced reversible suppression of spermatid maturation with subsequent effects on semen characteristics. Examination of circulating LH and testosterone concentrations, together with pituitary and prostate morphology, suggested that the changes were due to inhibition of LH release. It is probable that the underlying mechanism is an exaggerated pharmacological response to repeated overdosage, common to many potent narcotic analgesic agents.
Analgesics, Opioid↗
Multiplicity of opiate receptors in different species.
Three populations of opiate binding sites (mu, delta and kappa) could be distinguished by displacement studies with the mu-agonist (D)-Ala2-MePhe4-Glyol5-enkephalin and the kappa-agonist [3H](-)-bremazocine in brain membranes of different species. Whereas brain membranes from pig or guinea-pig and human cortical membranes had a proportion of approximately 35-50% kappa-, 29-40% mu-, and 21-30% delta-binding sites, rat membranes contained much less kappa-sites (12% kappa, 62% mu and 25% delta).
Aged↗
Relative effectiveness of naloxone and MR2266 in potentiating oestrogen-stimulated luteinizing hormone surges in ovariectomized female rats.
The oestrogen-stimulated surge of luteinizing hormone (LH) can be inhibited by opiates and potentiated when endogenous opiate pathways are blocked by naloxone. Experiments were undertaken to allow an assessment to be made of the opiate receptor category predominantly responsible for inhibiting LH secretion. Thus the effects of MR2266 (primarily a mu and kappa antagonist) and naloxone (primarily a mu and delta antagonist) on LH surges were compared. At a dose of 4.5 mg/kg, administered three times in the 6 h preceding the LH surge, naloxone significantly potentiated LH release whereas this dose of MR2266 was without effect. However at the lower dose of 0.5 mg/kg, administered three times also, the size of the LH surge was significantly increased by MR2266 but not by naloxone.
Animals↗
Human leumorphin is a potent, kappa opioid receptor agonist.
The opioid activity and opioid receptor type specificity of synthetic human leumorphin were studied in vitro. Human leumorphin inhibited the contraction of the myenteric plexus-longitudinal muscle preparation of the guinea pig ileum and was similar in opioid potency to porcine leumorphin. This action of human leumorphin was antagonized less effectively by naloxone than by the opiate antagonist Mr 2266. Human leumorphin also inhibited the contraction of the rabbit vas deferens which has only the kappa-type opioid receptor. It is concluded that human leumorphin has potent opioid activity and acts as an agonist at the kappa-type opioid receptor, like porcine leumorphin and other peptides derived from preproenkephalin B.
Animals↗
Different effects of dynorphin A on in vitro guinea pig hippocampal CA3 pyramidal cells with various degrees of paired-pulse facilitation.
We investigated the effects of dynorphin A (Dyn A), a heptadecapeptide, on the population spikes of the guinea pig hippocampal CA3 pyramidal neurons, in vitro, using paired-pulse stimulation of the mossy fibers. Dyn A produced facilitatory and inhibitory effects on the population spikes in the preparations with lower and higher degrees of paired-pulse facilitation, respectively. Morphine and D-Ala2, D-Leu5-en-kephalin, mu- and delta-agonist, respectively, predominantly potentiated the population spikes, while kappa-agonists such as U-50, 488H and bremazocine mainly caused an inhibition. These results suggest that Dyn A has two separate (excitatory and inhibitory) effects on the guinea pig hippocampal CA3 neurons through mu-(delta) and kappa-opioid receptors, respectively.
3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
Opioid binding sites in the nigrostriatal system of the guinea pig are not located on nigral dopaminergic neurons.
Unilateral 6-hydroxydopamine injection into the compact zone of the guinea pig substantia nigra was used to destroy nigral dopamine neurons. The glyoxylic acid method for monoamine fluorescence was employed to ascertain the loss of dopaminergic fibers in the striatum and substantia nigra. It could be shown that there was no change in the number of [3H](-)-bremazocine binding sites in the substantia nigra or the striatum on the lesioned side of these guinea pigs.
Animals↗
Presynaptic opioid kappa-receptor and regulation of the release of Met-enkephalin in the rat brainstem.
Opioid kappa-agonists had much more potent inhibitory effects on the high K+-evoked Met-enkephalin release from rat brain slices than did the mu- or delta-agonists. The opioid kappa- antagonist, MR2266 enhanced the evoked release of Met-enkephalin to a greater extent than did mu- or delta-antagonists in vitro and had a potent analgesia in mice in vivo. These findings suggest that the release of Met-enkephalin may be regulated in vitro and in vivo, mainly by presynaptic kappa-receptor-mediated mechanisms.
Action Potentials↗
Localisation and pharmacological characterisation of [3H]bremazocine binding in the bovine adrenal medulla.
[3H]Bremazocine (5 nM), in the presence of excess unlabelled mu and delta opioid ligands labelled two anatomically distinct populations of binding sites in the bovine adrenal medulla; a high density over the peripheral adrenaline-containing region of the medulla and a lower density over the central noradrenaline-containing region. This non-mu, non-delta opioid binding was specific (diprenorphine sensitive) but did not appear to involve classical kappa (kappa 1), sigma or PCP binding sites being insensitive to high concentrations of dynorphin (1-13), 3-PPP or MK-801. A significant proportion of the binding at both locations was however sensitive to competition by U50,488H or metorphamide. These data provide further evidence to support the existence of multiple opioid binding sites in the bovine adrenal medulla.
Adrenal Medulla↗