The sigma1 receptor interacts with N-alkyl amines and endogenous sphingolipids.

The sigma1 receptor is distinguished for its ability to bind various pharmacological agents including drugs of abuse such as cocaine and methamphetamine. Some endogenous ligands have been identified as putative sigma1 receptor regulators. High affinity ligands for the sigma1 receptor contain a nitrogen atom connected to long alkyl chains. We found that long alkyl chain primary amines including endogenous amines belonging to the sphingolipid family such as D-erythro-sphingosine and sphinganine bind with considerable affinity to the sigma1 receptor but not to the sigma2 receptor. The binding of D-erythro-sphingosine to the sigma1 receptor appears to be competitive in nature as assessed against the radioligand [3H]-(+)-pentazocine. Interestingly, the well studied sphingolipid mediator sphingosine-1 phosphate did not bind to the sigma1 or the sigma2 receptor. Sphingosine is converted to sphingosine-1 phosphate by a family of sphingosine kinases that regulate the relative levels of these two bioactive lipids in the cell. The selective binding of sphingosine but not sphingosine-1 phosphate to the sigma1 receptor suggests a mechanism for regulation of sigma1 receptor activity by the sphingosine kinase. We have successfully reconstituted this hypothetical model in HEK-293 cells overexpressing both the sigma1 receptor and sphingosine kinase-1. The data presented here strongly supports sphingosine as an endogenous modulator of the sigma1 receptor.

In vivo evidence for the efflux transport of pentazocine from the brain across the blood-brain barrier using the brain efflux index method.

The efflux transport of pentazocine (PTZ) from the brain across the blood-brain barrier (BBB) was investigated using the Brain Efflux Index method. PTZ was eliminated with the apparent elimination half-life of 13.0 min after microinjection into the parietal cortex area 2 region of the rat brain. The apparent efflux clearance of PTZ across the BBB was 137 microl/min/g brain, which was calculated from the elimination rate constant (5.35 x 10(-2) min(-1) and the distribution volume in the brain (2.56 ml/g brain). The efflux transport of PTZ was decreased in the presence of unlabeled PTZ, suggesting that PTZ is eliminated by a carrier-mediated transport system across the BBB. To characterize the efflux transport of PTZ from the brain in vivo, the effects of several compounds on the efflux transport of PTZ were investigated. P-glycoprotein (P-gp) inhibitors (verapamil and quinidine) reduced the PTZ efflux transport. In addition, the efflux transport of PTZ was inhibited by organic cations such as l-carnitine and tetraethylammonium (TEA), whereas organic anions such as p-aminohippuric acid, probenecid and taurocholate did not affect the PTZ efflux transport. The present results suggest that PTZ is transported from the brain across the BBB via l-carnitine/TEA-sensitive carrier-mediated efflux transport system(s) in addition to P-gp.

[Possible role of sigma-receptors in the regulation of cough reflex, gastrointestinal and retinal function].

This paper provides an overview of our current understanding of the role of sigma-receptors in the regulation of cough, gastrointestinal and retinal function. Systemic administration of N-(+)-allylnormetazocine ((+)SKF-10,047), 1,2-di-(2-toyl)guanidine (DTG) or pentazocine markedly reduced the number of coughs in a dose-dependent manner. The antitussive effect of these sigma-receptor ligands was significantly reduced by pretreatment with haloperidol or rimcazol, a specific antagonist of sigma-receptors. Antitussive effects of dextromethorphan and noscapine were significantly and dose-dependently reduced by pretreatment with rimcazole. However, rimcazole did not have a significant effect on the antitussive effect of morphine. These results suggest that haloperidol-sensitive sigma-receptors may be involved in the antitussive mechanism of non-narcotic antitussive drugs. Selective sigma-receptor ligands such as (+)SKF-10,047, DTG and (+)pentazocine elicit a potent protection against gastric and duodenal ulcers. Ulcerprotective activity of sigma-receptor ligands may be related to their stimulating effect on bicarbonate secretion through interaction with sigma-receptors in the gastrointestinal mucosa. Activation of sigma-receptors in retina protect retinal cells against glutamate-induced neurotoxicity. It is possible that sigma-receptor ligands may be useful as therapeutic drugs against retinal disease with ischemia-induced neuronal cell death such as retinal artery occlusion, diabetes mellitus or glaucoma.

Effects of morphine, nalbuphine and pentazocine on gastric emptying of indigestible solids.

The effects of morphine (CAS 57-27-2), nalbuphine (CAS 20594-83-6) and pentazocine (CAS 359-83-1) on gastric emptying of indigestible solids were studied. In rats, which were fasted for 24 h, either morphine, nalbuphine, pentazocine or saline was injected intraperitoneally, and ten steel balls (1.0 mm in diameter) were inserted into the stomach. At 3 h, the number of balls which had passed into the small intestine was counted. If these drugs inhibited gastric emptying, naloxone was injected concurrently to study the mechanisms of the inhibitory effect. Morphine, nalbuphine and pentazocine significantly inhibited gastric emptying (ED50:0.041 [95% confidence interval: 0.0078-0.14] mg kg-1, 0.0012 [0.00037-0.0081] mg kg-1 and 0.81 [0.41-1.30] mg kg-1, respectively). Naloxone 0.3 mg kg-1 antagonized the inhibitory effect of both morphine 1.3 mg kg-1 (ED75) and nalbuphine 0.005 mg kg-1 (ED75). In contrast, naloxone 0.3 or 1.0 mg kg-1 did not antagonize the effect of pentazocine 1.9 mg kg-1 (ED75), but a higher dose of naloxone (3.0 mg kg-1) did so. Therefore, in the rat, morphine, nalbuphine and pentazocine inhibit gastric emptying of indigestible solids, and it is likely that morphine and nalbuphine inhibit the emptying through the same opioid receptor, whereas pentazocine does so through a different receptor interaction.

Regulation of [3H]norepinephrine release from guinea pig hippocampus by sigma2 receptors.

The binding profile of the sigma2 receptor ligand endo-N-(8-methyl-8-azabicyclo[3.2.1.]oct-3-yl)-2,3-dihydro-(1-methyl)eth yl-2-oxo-1H-benzimidazole-1-carboxamidehydrochloride (BIMU-8) had previously been determined, but its agonist/antagonist status at sigma2 receptors had not been identified. We therefore investigated the effects of BIMU-8 for its ability to regulate the stimulated release of [3H]norepinephrine from slices of guinea pig hippocampus. BIMU-8 alone, at a concentration chosen to occupy 50% of sigma2 receptors, had no significant effect on N-methyl-D-aspartate (NMDA)-stimulated release of [3H]norepinephrine. We have shown previously that the sigma receptor agonist (+)-pentazocine inhibits NMDA-stimulated release in a concentration-dependent manner, producing a biphasic inhibition curve. Similarly, the sigma receptor agonist 1S,2R-(-)-cis-N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl )cyclohexylamine (BD737) produced a broad inhibition curve. The inhibition by low concentrations of (+)-pentazocine or BD737 that selectively activated sigma1 receptors was reversed by the sigma1-selective receptor antagonist (1-(cyclopropylmethyl)-4-2'-oxoethyl)piperidine HBr (DuP 734). In the current study, when the sigma1 component of inhibition by (+)-pentazocine was blocked by DuP 734, the remaining component of inhibition mediated by sigma2 receptors was reversed by BIMU-8. Our results suggest that (1) BIMU-8 is an antagonist at sigma2 receptors and that (2) sigma2 receptors contribute to regulation of norepinephrine release in guinea pig hippocampus.

Stereoselective inhibition of natural killer activity by the sigma ligand (+)-pentazocine.

The effect of sigma (sigma) receptor ligands on natural killer (NK) activity was examined both in vivo and in vitro. Following injection of mice with sigma receptor ligands such as (+)-pentazocine, (-)-pentazocine, BD 1073, BD 1165 and BD 737, NK activity was measured in poly-I.C.-stimulated mouse splenocytes. (+)-Pentazocine reduced NK cell activity in a dose-dependent fashion, while the (-) enantiomer was inactive in this measure. For example, at a dose of 50 mg/kg, (+)-pentazocine suppressed NK activity (using effector to target cell ratios of 200:1, 100:1 and 50:1) by > 70%, 24 h after injection while (-)-pentazocine was inactive. The other sigma ligands examined either slightly enhanced or had no effect on NK activity. Nonetheless, parenteral administration of the sigma receptor ligand BD 1165 blocked (+)-pentazocine-induced suppression of NK activity, while the opiate receptor antagonist naltrexone was ineffective. Addition of sigma receptor ligands (10(-11)-10(-5) M) to splenocyte cultures for 24 h did not affect NK activity. These findings indicate that while sigma receptor ligands are capable of modulating NK activity, this effect is not the result of an action on splenocyte sigma receptors, but may be mediated via sigma receptors either in the central or peripheral nervous systems.

Binding properties of SA4503, a novel and selective sigma 1 receptor agonist.

The binding profiles of SA4503 (1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride), a novel sigma receptor ligand, to sigma 1 and sigma 2 receptor subtypes in guinea pig and rat brain membranes were evaluated. SA4503 showed a high affinity for the sigma 1 receptor subtype labeled by (+)-[3H]pentazocine (IC50 = 17.4 +/- 1.9 nM), while it had about 100-fold less affinity for the sigma 2 receptor subtype labeled by [3H]1,3-di(2-tolyl)guanidine ([3H]DTG) in the presence of 200 nM (+)-pentazocine. SA4503 showed little affinity for 36 other receptors, ion channels and second messenger systems. The inhibition curves of SA4503 for (+)-[3H]pentazocine binding were shifted to the right in the presence of guanosine 5'-o-(3-thiotriphosphate) (GTP gamma S), as similar to those of (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ((+)-3-PPP) and (+)-pentazocine, sigma 1 receptor agonists. SA4503 significantly increased the KD value, but did not affect the Bmax value for specific (+)-[3H]pentazocine binding. These results indicated that SA4503 is a potent and selective agonist for the sigma 1 receptor subtype in the brain. In addition, SA4503 inhibited specific (+)-[3H]pentazocine binding in a competitive manner.

The effects of sigma ligands and of neuropeptide Y on N-methyl-D-aspartate-induced neuronal activation of CA3 dorsal hippocampus neurones are differentially affected by pertussin toxin.

1. The in vivo effects of the high affinity sigma ligands 1,3-di(2-tolyl)guanidine (DTG), (+)-N-cyclopropylmethyl-N-methyl-1,4-diphenyl-1- ethyl-but-3-en-1-ylamine hydrochloride (JO-1784), (+)-pentazocine and haloperidol, as well as of those of neuropeptide Y (NPY), on N-methyl-D-aspartate (NMDA)- and quisqualate (Quis)-induced neuronal activations of CA3 pyramidal neurones were assessed, using extracellular unitary recording, in control rats and in rats pretreated with a local injection of pertussis toxin (PTX), to evaluate the possible involvement of Gi/o proteins in mediating the potentiation of the neuronal response to NMDA by the activation of sigma receptors in the dorsal hippocampus. 2. Microiontophoretic applications as well as intravenous injections of (+)-pentazocine potentiated selectively the NMDA response in control rats as well as in PTX-pretreated animals. In contrast, the PTX pretreatment abolished the potentiation of the NMDA response by DTG, JO-1784 and NPY. Moreover, microiontophoretic applications of DTG induced a reduction of NMDA-induced neuronal activation. Neither in control nor in PTX-treated rats, did the sigma ligands and NPY have any effect on Quis-induced neuronal response. 3. In PTX-treated rats, the potentiation of the NMDA response induced by (+)-pentazocine was suppressed by haloperidol, whereas the reduction of the NMDA response by DTG was not affected by haloperidol. 4. This study provides the first in vivo functional evidence that sigma ligands and NPY modulate the NMDA response by acting on distinct receptors, differentiated by their PTX sensitivity.

Differential naltrexone antagonism of hydromorphone and pentazocine effects in human volunteers.

Naltrexone is more potent in blocking mu receptor activity than kappa receptor activity. This study examined the interactions of naltrexone with the mu agonist, hydromorphone, and with the mixed agonist-antagonist, pentazocine, to assess the apparent receptor mechanisms of their effects. After oral, 2-hr pretreatment with placebo or naltrexone (12.5 or 25 mg), a within-session cumulative dosing procedure (four intramuscular injections at 1-hr intervals) was used to assess the effects of hydromorphone (0, 0.75, 1.5 and 3 mg) and pentazocine (0, 15, 30 and 60 mg) vs. saline placebo. Subjective, physiological and behavioral effects were studied in six substance abusers. Hydromorphone significantly increased ratings on subjective measures typical of mu agonists, increased blood pressure and heart rate and decreased pupil diameter and respiratory rate; pretreatment with naltrexone (12.5 and 25 mg) blocked these effects. Pentazocine produced mu-like subjective effects, miosis and increases in blood pressure and heart rate. Naltrexone (12.5 mg) pretreatment decreased the mu-like subjective effects and miosis produced by pentazocine but increased kappa-like effects such as ratings of bad effects and Addiction Research Center Inventory LSD scale scores. Naltrexone (25 mg) blocked both the mu-like and kappa-like subjective effects of pentazocine. There was incomplete blockade of the cardiovascular effects of pentazocine. Thus, differential blockade of mu-like and kappa-like opioid effects by naltrexone was demonstrated in human subjects. Furthermore, the results suggest that mu agonist activity may suppress kappa-like effects such a dysphoria.

[The influence of piracetam on the effects of narcotic analgesics]. / Vliianie piratsetama na éffekty narkoticheskikh anal'getikov.

In experiments on white male mice there was studied the influence of piracetam (250-300 mg/kg) on the analgesic effect of ligands of different types of opioid receptors (morphine, 7.5 mg/kg, DADLE, 7.5 mg/kg, pentazocine, 15 mg/kg) and also on the action of morphine concerning the cardiovascular system and respiration. Piracetam was shown to possess the antagonistic properties with respect to some effects of morphine, however they are not of the universal character and do not depend on the interaction with a certain type of opioid receptors.

Interactions between pentazocine and tripelennamine on autonomic and nociceptive measures in the dog.

Pentazocine and tripelennamine, which have been abused in combination by humans, were evaluated for pharmacologic interactions on autonomic, behavioral, and antinociceptive measures in chronic spinal dogs. Pentazocine (0.31-5 mg/kg, IV) produced miosis, hypothermia and antinociception which was mediated by spinal and supraspinal reflexes; these effects were antagonized by naltrexone. Tripelennamine (0.63-2.5 mg/kg, IV) elicited mydriasis, hyperthermia and antinociception; these effects were not blocked by naltrexone. Tripelennamine produced antinociception only on the supraspinally-mediated skin twitch reflex. Interactions between pentazocine and tripelennamine varied depending on the response measured. Effects of both drugs on pupils were additive. Temperature effects were infra-additive, with the hyperthermic effects of tripelennamine predominating over the pentazocine hypothermia, resulting in a complete physiologic antagonism of pentazocine hypothermia. Antinociception, measured by flexor reflex depression, represented only the effect of pentazocine, whereas skin twitch reflex antinociception reflected either infra-additive or additive properties. The coadministration of nonconvulsive doses of pentazocine and tripelennamine produced seizures indicating a potentiated adverse interaction. In summary, the patterns of the pentazocine-triplennamine interactions were complex and the effects of tripelennamine could not be attributed to opioid activity.

Effects of pentazocine and other opioids on the potassium-evoked release of [3H]noradrenaline from guinea pig cortical slices.

Noradrenaline release and its modulation via presynaptic opioid receptors were examined in guinea pig cortical slices. Slices preloaded with [3H]noradrenaline were superfused in the presence of desipramine (1 microM) and were stimulated by 16 mM K+. 1-Pentazocine inhibited the K+-evoked release of [3H]noradrenaline in a dose-dependent manner (3 x 10(-7)-10(-5) M), while d-pentazocine did not inhibit. This inhibitory effect of 1-pentazocine was antagonized by Mr 2266 (10(-6) M) but not by naloxone (10(-6) M). Among other opioids, dynorphin A-(1-13) and ethylketocyclazocine (kappa agonists) decreased the K+-evoked release of [3H]noradrenaline. Tyr-D-Ala-Gly-NMe-Phe-Gly-ol (DAGO, mu agonist) also inhibited [3H]noradrenaline release but was less potent than the kappa agonists. [D-Pen2,D-Pen5]enkephalin (DPDPE, delta agonist) and phencyclidine (sigma agonist) had no effects on the stimulated release of [3H]noradrenaline. Thus, it was shown that kappa receptors are the major subtype of opioid receptor involved in modulation of noradrenaline release in guinea pig cortex, and that 1-pentazocine inhibits the K+-evoked release of noradrenaline through activation of these receptors.

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.

Possible role of dopamine in the growth inhibitory effect of pentazocine.

Growth inhibitory effect of pentazocine was studied in young rats for a duration of 4 weeks. The animals were subjected to various drug treatments, namely (1) distilled water 0.5 ml/kg s.c.; (2) pentazocine 10 mg/kg s.c.; (3) pentazocine 10 mg/kg s.c. plus metoclopramide 10 mg/kg s.c., and (4) pentazocine 10 mg/kg s.c. plus l-dopa 100 mg/kg s.c. Body weight was taken as a measure for the assessment of growth rate. The results of group 2 were compared with group 1 and that of groups 3 and 4 were compared with group 2. Pentazocine alone markedly inhibited the growth from the second to fourth weeks of treatment. Dopamine antagonist metoclopramide has almost completely prevented the growth inhibitory effect of pentazocine. Combination of l-dopa with pentazocine produced a significant growth inhibition in the first week but subsequently this effect was significantly less marked as compared to that of pentazocine alone. The growth inhibitory effect of pentazocine may possibly be mediated through alterations in dopaminergic mechanisms which are known to exert controlling influence on the release of several of the pituitary hormones.

Antagonism of the analgesic effect of opioid and non-opioid agents by p-chlorophenylalanine (PCPA).

The ability of p-chlorophenylalanine (PCPA), an inhibitor of serotonin (5HT) biosynthesis to antagonize the antinociceptive effects of three classes of analgesics: opiates agonist (morphine), opiate agonist-antagonist (pentazocine) and non-steroid anti-inflammatory (aspirin and clonixin) were evaluated using the rat yeast paw test. The analgesic effect of equipotent doses of each of these drugs was abolished 48 h after PCPA (300 mg/kg i.p.) PCPA (150 mg/kg i.p.) reduced the relative potencies of morphine and aspirin to the same degree. The effect could not be attributed to a hyperalgesia or to an interaction with inflammatory mechanisms. PCPA did not alter the anti-edema activity of clonixin and it blocked morphine-induced increases in reaction times to pressure applied to the non-inflamed paw to the same extent as in the inflamed paw. The serotonin precursor 5-hydroxytryptophan (5HTP, 80 mg/kg i.p.) restored the antinociceptive activity of all four drugs. These results demonstrate serotonin can modulate sensitivity to analgesics with differing mechanisms of action.

Inhibition of growth in young mice treated with pentazocine: reversal by naltrexone.

One week old mice were injected subcutaneously once daily with d,1-methadone (5 mg/kg), pentazocine, naltrexone, naloxone, nalorphine or nalbuphine, each at 10 mg/kg. The remaining half of each litter was used as control. Only methadone and pentazocine groups showed reduced weight gain after 3 weeks of treatment (P < 0.01). Injection of pentazocine in dosages of 5-20 mg/kg inhibited weight gain and protein synthesis in a dose-related manner. The incorporation of labeled leucine was followed in brain, liver and muscles. Methadone and pentazocine groups showed a significant decrease in protein synthesis in all tissues studied. The nalbuphine, nalorphine, naloxone, and naltrexone-treated groups incorporated leucine normally, correlating with normal weight gain. These data suggest that pentazocine, unlike the other mixed agonist-antagonists and antagonists, adversely affects the growth of very young animals when administered chronically. A specific opioid effect is suggested by the fact that naltrexone given concomitantly with the pentazocine prevents development of the biochemical lesion.

Electroencephalographic study of pentazocine and buprenorphine.

Both pentazocine and buprenorphine are hypnoanalgetics of the agonistic-antagonist group. They suppress the inhibitory effect of fentanyl upon the central nervous system. They show also secondary their own inhibitory properties (fig. 8). The agonistic-antagonists can be further divided in excitants (like pentazocine) and non-excitants (buprenorphine).