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PubMed1982

Stereoisomers of N-allylnormetazocine: phencyclidine-like behavioral effects in squirrel monkeys and rats.

(+/-)-N-Allylnormetazocine is a benzomorphan opioid with psychotomimetic effects. The pure stereoisomers of this compound, as well as the racemic mixture, were compared to phencyclidine for their behavioral effects on squirrel monkeys and rats trained to discriminate phencyclidine from saline. Dose-response determinations were made for responses to phencyclidine, to a racemic mixture of N-allylnormetazocine, and to the pure levo and dextro isomers of N-allylnormetazocine. In both rats and monkeys, the dextro isomer and the racemic mixture produced dose-dependent responses appropriate for phencyclidine; the levo isomer did not produce the responses appropriate for phencyclidine at any of the doses tested. In both species, the levo isomer was more potent than the dextro isomer in decreasing the rate of responding. Thus racemic N-allylnormetazocine is a mixture of compounds that produce different behavioral effects.

Animals↗
PubMed1984

Opioid receptors in bovine adrenal medulla.

Using prototypic ligands for each type of opioid receptors (mu, delta, kappa, and sigma) as well as compounds derived from each class of endogenous opioid peptides (beta-endorphin, enkephalins, and dynorphins), we have undertaken the characterization of adrenomedullary opioid binding sites. The specific binding of [3H]etorphine ([3H]ET) to a membrane preparation of bovine adrenal medulla was greatly increased when the incubation temperature was raised from 22 to 37 degrees C. Characterization of the opioid binding sites was obtained at 37 degrees C with [3H]ET (nonspecific opioid ligand), [3H]ethylketocyclazocine ([3H]EKC; kappa), [3H]dihydromorphine ([3H]DHM; mu), [3H]-[D-Ala2,D-Leu5]enkephalin ([3H]DADLE: delta), and N-[3H]allylnormetazocine ([3H]SKF-10047; sigma) in the absence or presence of blocking agents for cross-reacting receptors. [3H]ET had a high affinity binding site (KD = 0.98 nM) with a Bmax of 119 pmol/g protein. All the other opioid compounds showed biphasic saturation curves with KD ranging from 0.6 to 1.29 nM for the high affinity binding site and from 2.49 to 12.1 nM for the low affinity binding site. The opioid mu-receptor was characterized by the high affinity binding site for [3H]DHM (KD = 1.29 nM; Bmax = 38 pmol/g protein). Blockade of the cross-reacting receptor sites for [3H]EKC, [3H]DADLE, and [3H]SKF-10047 revealed the presence of kappa (KD = 0.66 nM; Bmax = 12 pmol/g protein), kappa 2 (benzomorphan site; KD = 11.1 nM; Bmax = 56 pmol/g protein), delta (KD = 0.67 nM; Bmax = 4.7 pmol/g protein), and sigma (KD = 4.54 nM; Bmax = 32 pmol/g protein) opioid receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Medulla↗
PubMed1988

Effect of morphine on the electroencephalogram and other physiological and other physiological and behavioral parameters.

A double-blind, crossover, placebo-controlled study was carried out in 10 healthy male volunteers to investigate the effects of subcutaneously administered single doses of 4 and 8 mg morphine and 2.5 and 5 mg of a new centrally acting analgesic with a benzomorphane structure. After an adaptation session, each subject received all five treatments in a random sequence at intervals of 1 week. Quantified EEG, cardiovascular and behavioral parameters, quantitative respiratory measurements, body temperature, symptom reports, pain threshold estimates, and blood drug assays were used to assess the effects of the drugs. The measurement battery was completed before injection and after 30, 60, 120, 240 and 360 min. In addition, EEG, blood samples and respiratory signals were also taken during/after the first 5, 10, 15, 20 and 25 min. As the new compound did not show any obvious advantages over morphine, only the results with the latter substance are reported here. As the main effects of morphine on the EEG a dose-dependent slowing and monorhythmization of alpha and an increase of the average frequency of fast beta activity were observed. Slow EEG waves tended to decrease. Heart rate and body temperature decreased, whereas there was no discernible effect on blood pressure. Subjects reported feelings of drowsiness, muzziness, lethargy and mental slowness. The pain threshold increased. All these effects had a maximum between min 120 and 240, although the highest blood levels of the parent drug were measured 10-25 min after drug administration. An explanation for this delay might be that the pharmacological effects are due not to free morphine but to one of its metabolites.

Adult↗
PubMed1992

Neuroprotective mechanism of (+)SKF 10,047 in vitro and in gerbil global brain ischemia.

BACKGROUND AND PURPOSE: The N-methyl-D-aspartate receptor is believed to mediate part of the ischemic neuronal damage caused by the excitatory amino acid glutamate. (+)SKF 10,047, the prototypic sigma-agonist, interacts with the N-methyl-D-aspartate receptor. Therefore, we studied the neuroprotective effect of (+)SKF 10,047 on cultured rat cerebellar neurons and on CA1 hippocampal neurons of gerbils exposed to brain ischemia. METHODS: Mechanisms of neuroprotection were studied in vitro by measuring calcium influx into cultured rat cerebellar granule cells loaded with fura 2-AM. In vivo neuroprotection of gerbil CA1 hippocampal neurons was studied in a posttreatment regimen following 5 minutes of bilateral carotid artery occlusion and 7 days of reperfusion. RESULTS: In primary cultured rat cerebellar granule cell neurons, (+)SKF 10,047 in a dose-dependent manner diminished intracellular calcium levels of N-methyl-D-aspartate-stimulated neurons by a maximum of 87% (n = 8), with a 50% inhibitory concentration of 0.8 microM. (+)SKF 10,047 did not prevent subsequent calcium influx stimulated by kainic acid or KCl, nor did it interfere with modulation of the kainate response by quisqualic acid. Neuroprotection of 64% (p = 0.006, n = 15) of gerbil CA1 hippocampal neurons was achieved by posttreatment injection followed by minipump infusion. CONCLUSIONS: Neuroprotection by (+)SKF 10,047 most likely involves interaction at the N-methyl-D-aspartate receptor. These results suggest that the benzomorphan class of sigma-agonists may provide neuroprotection in cerebral ischemia and stroke.

Animals↗
PubMed1983

Mu-receptors mediate opioid cardiovascular effects at anterior hypothalamic sites through sympatho-adrenomedullary and parasympathetic pathways.

Intracerebroventricular injections of selective opioid agonists were used to investigate the role of opiate receptor subtypes in cardiovascular function in awake rats. The mu-agonist (D-Ala2,MePhe4,Gly5-ol)enkephalin (1 nmol) caused a prolonged increase in blood pressure and an initial decrease followed by a delayed increase in heart rate. These effects were antagonized by the selective mu-antagonist beta-funaltrexamine. A selective delta-agonist (dimeric tetrapeptide enkephalin) was devoid of cardiovascular effects at 10 nmol, whereas a benzomorphan kappa-agonist MRZ caused a pressor response which was not antagonized by beta-funaltrexamine. The mechanisms by which opioids elicit cardiovascular effects were analyzed in detail by using microinjections into the anterior hypothalamic area. Low doses of enkephalin produced increases in heart rate and blood pressure. Associated elevations of plasma norepinephrine and epinephrine, but not vasopressin, suggested a stimulation of sympatho-adrenomedullary pathways. Higher doses caused increases in blood pressure but decreases in heart rate. Peripheral vagal blockade with atropine methyl nitrate caused a large sudden rise in heart rate, indicating that an increased vagal outflow counteracted the sympathetic activation. Adrenal demedullated rats displayed no tachycardia after anterior hypothalamic injection of low doses of enkephalin, whereas high dose caused pronounced bradycardia. Additional treatment of demedullated rats with the sympathetic blocker bretylium led to severe hypotension in addition to bradycardia. These data provide evidence that mu-opiate receptors primarily mediate cardiovascular effects of opiates in awake rats. At low doses, a sympathetic adrenomedullary activation occurs, whereas higher doses additionally activate parasympathetic efferents, both possibly from anterior hypothalamic sites.

Adrenal Medulla↗
PubMed1993

Multiplicity of [3H]1,3-di-o-tolylguanidine binding sites with low affinity for haloperidol in rat brain.

Specific binding of [3H]1,3-di-o-tolylguanidine (DTG) was found not only in synaptic membrane fractions but also in subcellular fractions enriched of microsomes, nuclei and mitochondria/myelins, with different sensitivities to displacement by the antipsychotic haloperidol. The highest binding was detected in microsomal fractions followed by, in order of decreasing binding, fractions enriched in nuclei, synaptic membranes, mitochondria/myelins and homogenates. [3H]DTG binding was completely abolished by prior treatment of the synaptic membranes with a low concentration of Triton X-100. [3H]DTG binding reached a plateau within 30 min of the incubation at 2 degree C, whereas raising the incubation temperature to 30 degrees C resulted in marked shortening of the time required to attain equilibrium, without altering the binding at equilibrium. The binding was inhibited by haloperidol in a concentration-dependent manner over a concentration range of 1 nM to 0.1 mM but with a potency more than 100 times weaker than the value reported in the literature, irrespective of the termination method employed and the external proton concentrations. [3H]DTG binding was markedly displaced by a variety of compounds including sigma ligands, benzomorphan opiates and noncompetitive antagonists at the N-methyl-D-aspartate (NMDA) receptor in synaptic membranes of the cortex, hippocampus and cerebellum. However, sigma ligands such as haloperidol, DTG and (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine were more potent in displacing [3H]DTG binding in cortical membranes than in hippocampal and cerebellar membranes, while the potencies of the NMDA antagonists were not significantly different from each other among these 3 different central structures.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Synthesis and analgetic activity of sulfur-containing morphinans and related compounds.

3-Acylthiomorphinans, 3-carbamoylthio-3-deoxydihydromorphine and 3-benzoylthio-9-aza-17-carbamorphinan were synthesized by Newman-Kwart rearrangement of the corresponding O-thiocarbamates. The analgetic activities were lower than that of pentazocine, and the opioid receptor binding affinities were very weak. These acylthiomorphinans showed low antinociceptive activity compared with corresponding sulfur-containing benzomorphans. 3-Carbamoylthio-deoxydihydromorphine had no significant analgetic activity.

Analgesics↗
PubMed1994

[Sigma-ligands for new therapeutic drugs].

Compounds that show their pharmacological actions via specific receptors are considered potential candidates for new drugs. Recently, several compounds that have specific binding sites and show certain pharmacological actions have been identified, but neither their binding sites, their endogenous substances, nor the functional role of the binding sites have been clarified. Regardless of the exact role of the binding sites of the compounds, research into the sites has opened up new areas of receptor investigation, and also new strategies for developing drugs. The sigma-ligand is one such kind of compound, and the existence of a binding site for the ligand was first postulated to account for the psychotomimetic effects of N-allylnormetazocine and related racemic benzomorphans. The binding site of the sigma-ligand is widely distributed in the central nervous system and peripheral systems. However, it still remain to be established whether sigma-ligand binding sites are to be referred to as "receptors". The classification of the ligands as agonists or antagonists at the sites and the heterogeneity and the functional role of the binding sites have not yet been clarified. Furthermore, the therapeutic targets have not been clearly determined. However, the sigma-ligands have high potential for developing new drugs. One of the possible targets of the sigma-ligands as new forms of drugs is schizophrenia. Recently, we identified two potent and highly selective sigma-ligands, FH-510 and NE-100. Together with the data on the binding properties and pharmacological actions of these compounds, the possibilities of the sigma-ligand as a new therapeutic drug were discussed.

Animals↗
PubMed2003

Kappa-receptor selective binding of opioid ligands with a heterocyclic bicyclo[3.3.1]nonan-9-one structure.

Previous pharmacological results have suggested that members of the heterocyclic bicyclo[3.3.1]nonan-9-one-like compounds are potent kappa-opioid receptor specific agonists. One lead molecule of this series. called compound 1 (dimethyl 7-methyl-2,4-di-2-pyridyl-3.7-diazabicyclo[3.3.1]nonan-9-one-1,5-dicarboxylate) exhibited high affinity for [3H]ethylketocyclazocine and [3H]U-69.593 binding sites in guinea pig cerebellar membranes which known to be a good source for kappa1 receptors. It was shown by molecular modelling that heterocyclic bicyclo[3.3.1]nonan-9-ones fit very well with the structure of ketazocine, a prototypic kappa-selective benzomorphan compound; when compared to the arylacetamide structure of U-69.593, a specific kappa1-receptor agonist, a similar geometry was found with a slightly different distribution of the charges. It is postulated, that the essential structural skeleton involved in the opioid activity is an aryl-propyl-amine element distributed along the N7-C6-C5-C4-aryl bonds.

Animals↗
PubMed1981

Pharmacological studies of 3-(3-methyl-3-butenyl)-1,2,3,4,5,6-hexahydro-6,11-dimethyl-8-hydroxy-2,6-methano-3-benzazocine.

3-(3-methyl-3-butenyl)-1,2,3,4,5,6-hexahydro-6, 11-dimethyl-8-hydroxy-2,6-methano-3-benzazocine (KF-1820) is a derivative of benzomorphan and is different from pentazocine only in the site of the double bond. KF-1820 showed potent analgesic activity in all tests performed. KF-1820 was 6 to 12 times and 30 to 40 times more potent than morphine and pentazocine, respectively, when administered subcutaneously. KF-1820 had little or no narcotic antagonist property. Physical dependence liability tests indicated that KF-1820 may be a little less, or as liable as, pentazocine to produce physical dependence. ID50 values of KF-1820, pentazocine and morphine for depression of contractions of isolated guinea pig ileum to coaxial stimulation correlated well with their analgesic activities in the rodent. The dissociation equilibrium constant of KP-1820 confirmed the in vivo finding that KF-1820 had little or no narcotic antagonist property.

Analgesics↗
PubMed2004

Sigma-1 receptor ligands: potential in the treatment of neuropsychiatric disorders.

The sigma receptor was originally proposed to be a subtype of the opioid receptor. However, it is now clear that sigma receptors are unique non-opioid, non-phencyclidine brain proteins. Two types of sigma receptor exist, the sigma-1 receptor and the sigma-2 receptor. sigma-1 receptors have been cloned and their distribution, physiological functions and roles in signal transduction were recently characterised. Certain sex hormones in the brain (neurosteroids) are known to interact with sigma-1 receptors. sigma-1 receptors regulate glutamate NMDA receptor function and the release of neurotransmitters such as dopamine. They are thus proposed to be involved in learning and memory as well as in certain neuropsychiatric disorders. Selective sigma-1 receptor ligands have been suggested to represent a new class of therapeutic agents for neuropsychiatric disorders, although none have yet been introduced into therapeutic use. Early studies showed that psychotomimetic benzomorphans, as well as several antipsychotics, can bind to sigma-1 receptors. As a result of these findings, sigma-1 receptor ligands have been proposed as being of potential use in the treatment of schizophrenia. Nevertheless, the relationship of sigma-1 receptors to the underlying pathogenesis of schizophrenia is still unclear. sigma-1 receptor ligands have failed to improve acute psychotic symptoms of schizophrenia in clinical trials, but, interestingly, a few studies have shown an improvement in negative symptoms in schizophrenic patients. A number of preclinical studies have shown that selective agonists of sigma-1 receptors affect higher-ordered brain functions such as learning and memory, cognition and mood. These studies indicate that sigma-1 receptor agonists may exert therapeutic effects in depression and senile dementia. Indeed, the sigma-1 receptor agonist igmesine, has been shown to improve depression in a clinical trial. The most distinctive feature of the action of sigma-1 receptor ligands is their "modulatory" role. In behavioural studies of depression and memory, they exert beneficial effects only when brain functions are perturbed. Given the recently accumulated preclinical and clinical data, it is time to reconstruct the concept of sigma-1 receptors and the associated pathophysiological conditions that ligands of these receptors target. This would allow clinical trials to be performed more efficiently, and the results may confirm a long-speculated possibility that sigma-1 receptor ligands represent a new class of therapeutic agents for neuropsychiatric disorders.

Animals↗
PubMed2003

Understanding the molecular mechanism of sigma-1 receptors: towards a hypothesis that sigma-1 receptors are intracellular amplifiers for signal transduction.

Although sigma receptors were discovered in 1982, the biochemical and physiological roles of sigma receptors have just begun to unveil. Sigma receptors are non-opioid, non-phencyclidine receptors that contain two subtypes: sigma-1 and sigma-2 receptors. The sigma-1 receptor has been cloned and its sequence does not resemble that of any mammalian protein. Sigma-2 receptors have not been cloned. The focus of this review will be on sigma-1 receptors. Sigma-1 receptors contain 223 amino acids and reside primarily at the endoplasmic reticulum. Sigma-1 receptors exist mainly in the central nervous system, but also in the periphery. Sigma-1 receptor ligands include cocaine, (+)-benzomorphans like (+)-pentazocine and (+)N-allyl-normetazocine (or (+)-SKF-10047), and endogenous neurosteroids like progesterone and pregnenolone sulfate. Many pharmacological and physiological actions have been attributed to sigma-1 receptors. These include the regulation of IP3 receptors and calcium signaling at the endoplasmic reticulum, mobilization of cytoskeletal adaptor proteins, modulation of nerve growth factor-induced neurite sprouting, modulation of neurotransmitter release and neuronal firing, modulation of potassium channels as a regulatory subunit, alteration of psychostimulant-induced gene expression, and blockade of spreading depression. Behaviorally, sigma-1 receptors are involved in learning and memory, psychostimulant-induced sensitization, cocaine-induced conditioned place preference, and pain perception. Notably, in almost all the aforementioned biochemical and behavioral tests, sigma-1 agonists, while having no effects by themselves, caused the amplification of signal transductions incurred upon the stimulation of the glutamatergic, dopaminergic, IP3-related metabotropic, or nerve growth factor-related systems. Thus, it is hypothesized that sigma-1 receptors, at least in part, are intracellular amplifiers creating a supersensitized state for signal transduction in the biological system.

Animals↗
PubMed2000

Modulation of cellular calcium by sigma-2 receptors: release from intracellular stores in human SK-N-SH neuroblastoma cells.

Human SK-N-SH neuroblastoma cells expressed sigma-1 and sigma-2 receptors with similar pharmacological profiles to those of rodent-derived tissues, although sigma-2 receptors exhibited some affinity differences that might suggest heterogeneity or species differences. Structurally diverse sigma ligands produced two types of increases in intracellular (cytosolic) Ca(2+) concentration ([Ca(2+)](i)) in these cells. CB-64D, CB-64L, JL-II-147, BD737, LR172, BD1008, haloperidol, reduced haloperidol, and ibogaine all produced an immediate, dose-dependent, and transient rise in [Ca(2+)](i). Sigma-inactive compounds structurally similar to the most active sigma ligands and ligands for several neurotransmitter receptors produced little or no effect. The high activity of CB-64D and ibogaine (sigma-2-selective ligands) compared with the low activity of (+)-pentazocine and other (+)-benzomorphans (sigma-1-selective ligands), in addition to enantioselectivity for CB-64D over CB-64L, strongly indicated mediation by sigma-2 receptors. The effect of CB-64D and BD737 was blocked by the sigma antagonists BD1047 and BD1063, further confirming specificity as a receptor-mediated event. The transient rise in [Ca(2+)](i) occurred in the absence of extracellular Ca(2+) and was completely eliminated by pretreatment of cells with thapsigargin. Thus, sigma-2 receptors stimulate a transient release of Ca(2+) from the endoplasmic reticulum. Prolonged exposure of cells to sigma-receptor ligands resulted in a latent and sustained rise in [Ca(2+)](i), with a pharmacological profile identical to that of the transient rise. This sustained rise in [Ca(2+)](i) was affected by neither the removal of extracellular Ca(2+) nor thapsigargin pretreatment, suggesting latent sigma-2 receptor-induced release from thapsigargin-insensitive intracellular Ca(2+) stores. Sigma-2 receptors may use Ca(2+) signals in producing cellular effects.

Calcium↗
PubMed2000

Ca(2+) signaling via sigma(1)-receptors: novel regulatory mechanism affecting intracellular Ca(2+) concentration.

The sigma(1)-receptor is a one-transmembrane endoplasmic reticulum protein that binds neurosteroids and dextrorotatory benzomorphans. The roles of sigma(1)-receptors in regulating intracellular Ca(2+) in NG108 cells were examined in this study. sigma(1)-Ligands pregnenolone sulfate, (+)-pentazocine, and 2-(4-morpholino)ethyl-1-phenylcyclohexane-1-carboxylate hydrochloride modulate Ca(2+) signaling in NG108 cells via two modes of action. First, nanomolar concentrations of the ligands, without effect by themselves, potentiated the bradykinin-induced increase of the cytosolic free Ca(2+) concentration in a bell-shaped manner. This effect of sigma(1)-ligands was unaffected by depletion of Ca(2+) from perfusion buffer and was blocked by a 21-mer antisense oligodeoxynucleotide against the cloned sigma(1)-receptors. Second, after the cells were depleted of the endoplasmic reticulum Ca(2+) stores, the depolarization (75 mM KCl)-induced increase in cytosolic free Ca(2+) was potentiated by 2-(4-morpholino)ethyl-1-phenylcyclohexane-1-carboxylate hydrochloride, whereas it was inhibited by pregnenolone sulfate and (+)-pentazocine. These effects, albeit opposite in direction, were blocked by both the 21-mer antisense oligodeoxynucleotide and pertussis toxin. Western blotting indicates that sigma(1)-receptors are increased on the plasma membrane and the nuclear membrane in the presence of sigma(1)-ligand. These results suggest that Ca(2+) signaling via sigma(1)-receptors may represent a novel mechanism that affects intracellular Ca(2+) concentrations.

Animals↗
PubMed1991

Effects of drugs that bind to PCP and sigma receptors on punished responding.

Several arylcyclohexylamines and opioid benzomorphans that bind to phencyclidine (PCP) receptors were studied for their effects on punished and unpunished responding maintained under fixed-interval schedules of food presentation. All of these drugs increased both punished and unpunished responding, although higher doses decreased responding. The order of potency for increasing punished responding was MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzoa(a,d)-cyclohepten-5,1 0-imine] greater than [1-[1-(2-thienyl)cyclohexyl]piperidine] = PCP greater than (+)-N-allylnormetazocine = (-)-N-allynormetazocine. There was a high correlation (0.95) between the relative potency of these drugs in increasing punished responding and their relative affinity for PCP receptors. Because some of these drugs also bind to sigma receptors, drugs with a high affinity for sigma receptors, such as haloperidol, BD 737 [1S,2R-(-)-cis-N-[2-(3,4-dichlorophenyl)ethyl]-N- methyl-2-(1-pyrrolidinyl) cyclohexylamine] and (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine, were also studied for their effects on punished and unpunished responding. These drugs produced only rate-decreasing effects. The correlation between the relative potency of drugs in increasing punished responding and their relative affinity for sigma receptors was low (-0.19). These data suggest that the PCP receptor is involved in some drug-induced increases in punished responding.

Animals↗
PubMed1991

[Interaction of tetrahydroisoquinolines and 3-aminotetralines with opioid mu-receptors].

The interaction of the tetrahydroisoquinoline (THIQ) and 3-aminotetraline (3-AT derivatives with opioid mu-receptors has been studied. It is shown that THIQ and 3-AT derivatives bind to a site on the mu-receptor which these compounds are likely to share with "classical" opiates, whose structure also includes the 3-AT group. The binding site for nonpeptide substances is in a strong allosteric interaction with the binding site for enkephalins. Some biological effects of THIQ and 3-AT derivatives can be explained in terms of their interaction with opioid receptors. One may speculate that the evolution of the endogenous opioid receptor ligands proceeded from simple 3-AT derivatives towards morphinans and, probably, benzomorphans.

Animals↗
PubMed1977

Affinities of opiate agonists and antagonists for the enkephalin receptors of rat brain.

The binding of 3H-enkephalin (methionine-enkephalin) to membranes of rat brain is inhibited by enkephalin and levorphanol with IC50 values of 5 and 1.6 nM, respectively. Dextrorphan, the optical isomer of levorphanol, is over 6,000 times less effective. Opiate agonists, morphine, dihydromorphine and l-methadone and opiate antagonists, naltrexone and naloxone are less effective inhibitors of 3H-enkephalin than in 3H-dihydromorphine and 3H-naloxone binding. However, opiates without the oxygen bridge as in the structure of morphine, such as levorphanol and the benzomorphans show affinities for the receptors of 3H-enkephalin equal or greater than their affinities for the receptors of 3H-opiates.

Animals↗
PubMed1990

Regulatory role of enteric mu and kappa opioid receptors in the release of acetylcholine and norepinephrine from guinea pig ileum.

We examined the role of opioid receptor subtypes in the contraction and release of acetylcholine (ACh) and norepinephrine in longitudinal muscle-myenteric plexus preparations of the guinea pig ileum. [D-Ala2, N-Me-Phe4, Gly5-ol]enkephalin (DAMGO) (10(-8) to 10(-5) M) inhibited the contraction and the release of ACh evoked by 0.2 and 1 Hz of electrical stimulation (ES), whereas the response to 5 Hz was enhanced by low concentrations of DAMGO (10(-9) to 10(-8) M) and inhibited by high concentrations (10(-7) to 10(-5) M); naloxone antagonized these effects. In preparations treated with yohimbine, DAMGO inhibited the ES (5 Hz)-evoked contraction and ACh release, but failed to enhance either effect. Dynorphin-A inhibited the contraction and ACh release evoked by 0.2, 1 and 5 Hz of ES, and the effect of dynorphin-A was mimicked by U-69593 [5 alpha,7 alpha,8 beta-(-)-N-methyl-N-[7- (pyrrolinyl)-1-ozaspiro(4,5)dec-8-yl]-benzene] and antagonized by MR 2266 [(-)-alpha-5,9-diethyl-2-(3-furylmethyl)-2'-hydroxy-6,7-benzomorphan]. The release of norepinephrine evoked by 5 Hz of ES was inhibited by DAMGO (10(-10) to 10(-6) M), but not by U-69593, and the effect of DAMGO was antagonized by naloxone. Thus, it would appear that mu-opioid receptors are present on both cholinergic and adrenergic neurons, whereas kappa-opioid receptors are present on cholinergic neurons. The affinity of DAMGO was 30 times higher for the mu-opioid receptors on the adrenergic than on the cholinergic neurons.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗