Safety and efficacy of a combination of pethidine and levallorphan for pain relief during labor: An observational study.

AIM: To evaluate the safety, effect on breastfeeding and efficacy of a combination of pethidine and levallorphan (Pethilorfan) for pain relief during labor. METHODS: We compared maternal or neonatal morbidities, suckling difficulties in newborns and breastfeeding rates between 177 women who received 50-200 mg (as pethidine) of Pethilorfan during labor (Pethilorfan group) and 354 women who delivered their infants without analgesic drugs immediately before or after each woman in the Pethilorfan group (control group) from January 1, 2005 to December 31, 2016. We performed univariate and multivariate analyses for comparison between the two groups. We also evaluated the efficacy of Pethilorfan retrospectively. RESULTS: The Pethilorfan group included more women with prolonged and/or operative deliveries than the control group. Nevertheless, no significant differences were seen between the two groups in the rates of Apgar scores less than 7 at 1 or 5 min, composite neonatal morbidities, hyperbilirubinemia or respiratory disturbances. The incidence of suckling difficulties lasting over 24 h and the breastfeeding rates at discharge or after 1 month were also similar. Maternal adverse effects of Pethilorfan were generally mild and transient. The efficacy ratio of Pethilorfan was 83.6%, although its analgesic effect was usually incomplete. CONCLUSION: Pethilorfan can be used safely for labor pain relief without increasing maternal or neonatal morbidities, or impeding breastfeeding, if it is administered at a prudent dosage. Parenteral opioids including Pethilorfan should remain as an option for treating women in labor pain, particularly when epidural analgesia is not readily available or contraindicated.

Sigma-2 receptors are specifically localized to lipid rafts in rat liver membranes.

We have previously shown that sigma-2 receptors are relatively difficult to solubilize (Eur. J. Pharmacol. 304 (1996) 201), suggesting possible localization in detergent-resistant lipid raft domains. Rat liver membranes were treated on ice with 1% Triton X-100 or 20 mM 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS), and the extract subjected to centrifugation on a discontinuous gradient of 5%, 38%, and 40% sucrose. Gradient fractions were analyzed for sigma-1 receptors using [3H]+-pentazocine and for sigma-2 receptors using [3H]1,3-di-o-tolylguanidine ([3H]DTG), in the presence of dextrallorphan. Flotillin-2 was assessed by immunoblotting as a marker for lipid rafts. Sigma-2 receptors were found to discretely co-localize with flotillin-2 in lipid raft fractions. However, sigma-1 receptors were found throughout the gradient. Rafts prepared in CHAPS had sigma-2 receptors with normal pharmacological characteristics, whereas those in Triton X-100-prepared rafts had about seven-fold lower affinity for [3H]DTG and other ligands. Thus, sigma-2 receptors are resident in membrane lipid rafts, whereas sigma-1 receptors appear in both raft and non-raft membrane domains. Lipid rafts may play an important role in the mechanism of sigma-2 receptor-induced apoptosis.

Expression of opioid receptors in osteoblast-like MG-63 cells, and effects of different opioid agonists on alkaline phosphatase and osteocalcin secretion by these cells.

We have previously shown that several stressful situations associated with tissue injury determine a decrease in serum osteocalcin concentration. Since reduced osteocalcin production is a marker of decreased osteoblastic activity, this finding could be related to the pathogenesis of osteoporosis secondary to some diseases. Endogenous opioids are involved in stress response. Proenkephalin-derived peptides have been shown to inhibit alkaline phosphatase activity, another marker of bone formation, in the murine cell line ROS-17/2.8. On the other hand, serum osteocalcin has been reported as being low in heroin abusers. We have therefore thought it of interest to study the presence of opioid receptors in the human osteoblast-like cell line MG-63, and to evaluate the effects of different opioid agonists on the secretion of alkaline phosphatase and osteocalcin by these cells. The presence of opioid receptors was studied by means of RT-PCR and immunohistochemistry. RT-PCR studies suggested the presence of specific mRNA for the three types of receptors, and immunohistochemistry clearly showed their occurrence. Osteocalcin synthesis was significantly inhibited by high concentrations of the mu agonists morphine and (D-Ala(2), N-MePhe(4),Gly(5)-ol)-enkephalin although no changes were seen with the delta agonist (D-Ala(2),D-leu(5))-enkephalin. Morphine-induced osteocalcin inhibition was abolished when osteoblastic cells were incubated simultaneously with naloxone, whereas it was potentiated when cells were preincubated with naloxone. None of the opioid agonists modified the secretion of alkaline phosphatase. In conclusion, human osteoblast-like cells MG-63 express the three types of opioid receptors. Endogenous opioids may be involved in the reduction of osteocalcin observed in stressful situations associated with tissue injury.

A sigma-1 receptor selective analogue of BD1008. A potential substitute for (+)-opioids in sigma receptor binding assays.

A simple, achiral monoamine sigma-1 (sigma1) receptor selective ligand (sigma2Ki/sigma1Ki>2000) is described, which could replace the chiral (+)-pentazocine or dextrallorphan as a sigma1 masking agent in sigma2 binding assays.

Targeting sigma receptor-binding benzamides as in vivo diagnostic and therapeutic agents for human prostate tumors.

Sigma receptors are known to be expressed in a variety of human tumor cells, including breast, neural, and melanoma tumors. A very high density (1.0-1.5 million receptors/cell) of sigma receptors was also reported in a human androgen-dependent prostate tumor cell line (LNCaP). In this study, we show that a very high density of sigma receptors is also expressed in an androgen-independent human prostate tumor cell line (DU-145). Pharmacological binding studies using the sigma-1-selective ligand [3H](+)-pentazocine showed a high-affinity binding (Kd = 5.80 nM, Bmax = 1800 fmol/mg protein). Similarly, binding studies with [3H]1,3-di-o-tolylguanidine in the presence of dextrallorphan also showed a high-affinity binding (Kd = 15.71 nM, Bmax = 1930 fmol/mg protein). Radioiodinated benzamide N-[2-(1'-piperidinyl)ethyl]-3-[125I]iodo-4-methoxybenzamide ([125I]PIMBA) was also shown to bind DU-145 cells in a dose-dependent manner. Three different radioiodinated benzamides, [125I]PIMBA, 4-[125I]iodo-N-[2-(1'-piperidinyl)ethyl]benzamide, and 2-[125I]-N-(N-benzylpiperidin-4-yl)-2-iodobenzamide, were screened for their potential to image human prostate tumors in nude mice bearing human prostate cells (DU-145) xenografts. All three compounds showed a fast clearance from the blood pool and a high uptake and retention in the tumor. Therapeutic potential of nonradioactive PIMBA was studied using in vitro colonogenic assays. A dose-dependent inhibition of cell colony formation was found in two different human prostate cells. These results demonstrate the potential use of sigma receptor binding ligands in non-invasive diagnostic imaging of prostate cancer and its treatment.

The mu opioid irreversible antagonist beta-funaltrexamine differentiates the discriminative stimulus effects of opioids with high and low efficacy at the mu opioid receptor.

The purpose of the present study was to determine the relative intrinsic efficacy of various opioids using the irreversible mu opioid antagonist beta-funaltrexamine (betaFNA). To this end, pigeons were trained to discriminate 3.0 (n=6) or 1.8 (n=1) mg/kg morphine from distilled water in a two-key, food-reinforced, drug discrimination procedure. The mu opioids fentanyl, l-methadone, buprenorphine, butorphanol, nalorphine, nalbuphine and levallorphan, as well as the delta opioid BW373U86, substituted completely for the morphine stimulus. The stimulus effects of morphine were antagonized (i.e., produced a significant increase in the ED50 value) by a 10 mg/kg but not a 5 mg/kg dose of betaFNA. Antagonist effects of betaFNA were observed following a 2-h pretreatment, but not following 26-, 50-, 74-, 98- or 146-h pretreatments. The stimulus effects produced by fentanyl, l-methadone and buprenorphine were not antagonized by doses of betaFNA as high as 20, 10 and 10 mg/kg, respectively. The lowest dose of betaFNA required to antagonize the stimulus effects of butorphanol was 10 mg/kg, whereas the effects of nalorphine, nalbuphine and levallorphan were antagonized by a dose of betaFNA as low as 5 mg/kg. The delta BW373U86 substituted for the morphine stimulus, and this effect was not antagonized by 10 mg/kg betaFNA. The pkB values for naloxone (1.0 mg/kg) against the stimulus effects of fentanyl (6.70) and morphine (6.52) were considerably higher than that for BW373U86 (4.60), indicating further that the morphine-like stimulus effects produced by BW373U86 were not mediated by activity at the mu opioid receptor. These findings indicate that the strategy of irreversible antagonism can be used effectively to differentiate opioids with varying degrees of intrinsic efficacy at the mu opioid receptor in a pigeon drug discrimination procedure. In particular, the ranking of these drugs by relative intrinsic efficacy at the mu opioid receptor is: l-methadone=fentanyl> or =buprenorphine> or =morphine> or =butorphanol>nalorphine=nalbuphine=levallorphan. Additionally, the short-acting effect of betaFNA in the pigeon suggests that the recovery of mu opioid receptor function varies across species.

Analysis of 16,16-dimethylprostaglandin E2-induced diarrhea in cecectomized rats.

The 16,16-dimethylprostaglandin E2 (dmPGE2)-induced diarrhea was analyzed in cecectomized rats prepared by resecting the cecum and its vasculature without disturbing the ileocecal junction. dmPGE2 (0.1-1.0 mg/kg, p.o.) dose-dependently increased the number of defecation episodes and induced a soft and watery stool in cecectomized rats. At 0.3 mg/kg, the diarrhea-inducing effects of dmPGE2 were more pronounced in cecectomized than in control rats. When given i.p., dmPGE2 (0.3 mg/kg) induced a watery stool in cecectomized and control rats with the same efficacy, although these effects were short-lasting as compared to oral administration. Castor oil (4 ml/kg, p.o.) also induced diarrhea, but did not produce a watery stool in cecectomized rats. There were no differences between cecectomized and control rats in basal small intestinal transits or in dmPGE2 (0.3 mg/kg, p.o.)-induced enhancements. Moreover, the basal and dmPGE2-induced jejunal net fluid transfers were the same in cecectomized and in control rats. On the other hand, the enhanced secretion of colonic fluid by dmPGE2, given intraluminally, was only half of that in control rats, whereas the colonic transit-enhancing effect of dmPGE2 in cecectomized rats was more pronounced than in control rats at 15 but not at 30 min after its administration. The basal colonic fluid contents and transits were the same in cecectomized and in control rats. Loperamide and morphine (0.1 and 1.0 mg/kg, s.c.) inhibited the dmPGE2 (0.3 mg/kg, p.o.)-induced diarrhea in cecectomized rats. N-methyllevallorphan (5 mg/kg, s.c.) completely antagonized the inhibitory effect of loperamide and partly antagonized the effect of morphine. These results suggest that oral administration of dmPGE2 induces a more pronounced secretory diarrhea in cecectomized than in control rats, probably due to the lack of the reservoir function of the cecum in the operated animals. This secretory diarrhea model is suitable for evaluating the antidiarrheal activity of drugs.

Changes in self-stimulation response during chronic morphine treatment and after withdrawal of morphine in rats.

Morphine (5-20 mg/kg, s.c.) dose-dependently inhibited the hypothalamic self-stimulation response 1-2 hr after administration of the drug. Thereafter, slight increase in the self-stimulation response was seen 4-8 hr after drug administration. The depressant effect induced by 10 mg/kg, s.c. of morphine on the self-stimulation response was antagonized by 1 mg/kg, s.c. of levallorphan. Repeated administration of morphine (10 mg/kg, s.c.) resulted in an increase of the self-stimulation response. The self-stimulation response rate was increased significantly 24 and 48 hr after withdrawal of morphine in chronic-morphine-treated rats; In these rats, the initial dose of morphine (10 mg/kg, injected s.c. twice daily 7 days a week) was increased gradually until at the end of 5 weeks, each dose was 50 mg/kg, s.c.

Rat liver and kidney contain high densities of sigma 1 and sigma 2 receptors: characterization by ligand binding and photoaffinity labeling.

Rat liver and kidney were investigated for the presence of sigma (sigma) receptor subtypes by radioligand binding with three highly selective sigma probes and by photoaffinity labeling using [3H]azido-di-o-tolylguanidine ([3H]azido-DTG). [3H](+)-Pentazocine, a highly selective sigma 1 probe, bound to sites in liver membranes with Kd = 7.5 nM and Bmax3 = 2929 fmol/mg protein. [3H](+)-Pentazocine binding sites in kidney had Kd = 23.3 nM and Bmax = 229 fmol/mg protein. [3H]1,3-Di-o-tolylguanidine ([3H]DTG) and [3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ([3H](+)-3-PPP) label both sigma 1 and sigma 2 receptors. Parameters for [3H]DTG in the liver were Kd = 17.9 nM and Bmax = 11,895 fmol/mg protein. Similar parameters were observed for [3H](+)-3-PPP, Kd = 51.9 nM and Bmax = 11,070 fmol/mg protein. [3H]DTG bound to rat kidney with Kd = 45.8 nM and Bmax = 1190 fmol/mg protein. The observation that either [3H]DTG or [3H](+)-3-PPP and [3H](+)-3-PPP labeled a higher number of sites relative to [3H](+)-pentazocine suggested that liver and kidney contain both subtypes of sigma receptor. This was confirmed by competition studies vs. [3H](+)-pentazocine and [3H]DTG (in the presence of dextrallorphan to mask sigma 1 sites). In both tissues, [3H](+)-pentazocine labeled sites with high affinity for haloperidol and enantioselectivity for (+)-benzomorphans over (-)-benzomorphans. [3H]DTG + dextrallorphan labeled sites in both tissues which also had high affinity for haloperidol, but which had the characteristic sigma 2 property of low affinity for (+)-benzomorphans and enantioselectivity for (-)-benzomorphans over the corresponding (+)-isomer. Similar results were obtained with [3H](+)-3-PPP + dextrallorphan. Several novel aryl diamines, such as 1S,2R-cis-N-[2-(3,4-dichlorophenylethyl]-N-methyl-2- (1-pyrrolidinyl)cyclohexylamine (BD737) and N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine (BD1008), bound to both sites with high affinity. Photoaffinity labeling with 10 nM [3H]azido-DTG resulted in specific labeling of polypeptides of 25 kDa and 21.5 kDa. Dextrallorphan (100 nM or 500 nM) completely blocked labeling of the 25 kDa polypeptide, but had no effect on labeling of the lower molecular weight protein. (+)-10,11-Dihydro-5-methyl-5H-dibenzo[a,d]cyclohepten-5,10- imine((+)-MK-801) had no effect on labeling of either polypeptide. These data are consistent with the notion that the 25 kDa and 21.5 kDa proteins represent sigma 1 and sigma 2 receptors, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)

Multiple [3H]DTG binding sites in guinea pig cerebellum: evidence for the presence of non-specific binding.

The characteristics of the low affinity component of 1,3-di(2-[5-3H]tolyl)guanidine binding to the guinea pig cerebellum were investigated. Saturation binding assays where sigma 1 receptors were masked with dextrallorphan indicated that 1,3-di(2-[5-3H]tolyl)guanidine bound to cerebellar membranes in a fashion best described by a 1 site+non-specific binding model with a low density of specific binding sites (Bmax approximately 200 fmol/mg protein). Boiling the cerebellar membranes before addition to the saturation assay had no effect on the density of 1,3-di(2-[5-3H]tolyl)guanidine binding. In contrast, both the Kd and Bmax for 1,3-di(2-[5-3H]tolyl)guanidine binding to liver membranes was significantly reduced by boiling, as was the density of [3H](+)-pentazocine binding to cerebellum and liver. Thus, a substantial component of 1,3-di(2-[5-3H]tolyl)guanidine binding in the guinea pig cerebellum is to non-specific, proteinaceous binding sites with some of the pharmacological characteristics of the sigma 2 binding site.

Effects of sigma ligands on rat cerebellar Purkinje neuron firing: an iontophoretic study.

The electrophysiological responses of rat cerebellar Purkinje neurons to selective sigma ligands applied iontophoretically was examined in urethane anesthetized male Sprague-Dawley rats. 1,3-Di-o-tolylguanidine (DTG), dextrallorphan (DEX), (+)-pentazocine((+)-PENT), (+)-3-(3-Hydroxyphenyl)-N-propylpiperidine ((+)-3-PPP), and the novel diamine BD1008, were ejected from multibarrel pipettes onto individual Purkinje cells. In some neurons, cell firing was inhibited following ejections of all compounds. These inhibitory effects were dose dependent and occurred without changes in spike amplitude or duration, thus ruling out local anesthetic effects as a mechanism. (+)-3-PPP and DEX increased firing rate in 27% and 14% (n = 15, n = 14, respectively) of cells studied. The results of this study indicate that sigma ligands significantly alter the spontaneous firing of Purkinje neurons, consistent with previous work suggesting motor effects of sigma ligands via the rubro-cerebellar circuitry.

A synthetic opioid peptide increases plasma growth hormone and prolactin in Holstein calves.

The effect of the synthetic opioid agonist D-Ala2,N-Me-Phe4,Met(O)5-ol enkephalin (DAMME) on plasma growth hormone (GH) and prolactin (PRL) concentrations in Holstein heifer calves was investigated in this study. The possible site of action of DAMME was determined by pretreating calves with an opioid antagonist that crosses the blood-brain barrier poorly if at all (N-methyl levallorphan-methane sulphonate [MLM]) or one that crosses readily (naloxone [NAL]). All calves were assigned to one of three treatment groups: 1) pretreatment with saline, 2) pretreatment with NAL, or 3) pretreatment with MLM. All groups were injected with DAMME 30 min after pretreatments. Plasma PRL increased after injection of DAMME in calves pretreated with saline. Prolactin concentrations were not different before and after injection of DAMME in calves pretreated with either NAL or MLM. Plasma GH increased after injection of DAMME in saline- and MLM-pretreated calves but was unchanged in NAL-pretreated calves. These data show that peripherally administered DAMME increases plasma GH and PRL in Holstein heifer calves and suggest that DAMME mediates GH release through receptors located somewhere inside the blood-brain barrier, but it can induce PRL secretion at a site located outside the barrier.

Iontophoretic effects of sigma ligands on rubral neurons in the rat.

Iontophoretic application of the sigma ligands, 1,3-di-o-tolylguanidine (DTG), dextrallorphan, and (+)-pentazocine reliably inhibited the firing rate of rubral neurons. Dextrallorphan inhibited 87% of the neurons tested, DTG inhibited 76%, and (+)-pentazocine inhibited 50%. These inhibitions were current dependent and occurred without significant changes in spike amplitude or duration, suggesting that local anesthetic effects were not involved. In contrast to the other sigma ligands, iontophoretic application of (+)-3-PPP in the rat red nucleus resulted in very few inhibitions and tended to elicit weak excitations instead. Only 14% of rubral neurons were inhibited by (+)-3PPP, while 36% were excited. Although unusual, (+)-3-PPP has atypical effects when compared to other sigma ligands in numerous functional assays for sigma receptor activity. (+)-3-PPP, therefore, appears to have complex effects and may act through nonsigma mechanisms or through a different type of sigma binding site than the other compounds. The inhibition of firing rate produced by the more typical sigma ligands may contribute to the postural changes produced by microinjection of sigma ligands into the rat red nucleus.

Effects of naloxone and levallorphan on the spinal cord reflex potentials under the spinal ischemic condition in cats.

The spinal reflex potentials elicited by electrical stimulation of the tibial nerve were recorded from the lumbo-sacral ventral root in spinal cats. When the thoracic aorta and the bilateral internal mammary arteries were occluded for 10 min, the potentials were completely depressed. Reappearance of these potentials could be observed at about 10 min after removal of the occlusion and they gradually recovered. Intravenous injection of naloxone (1 or 10 mg/kg) or levallorphan (0.1 mg/kg) together with removal of occlusion significantly promoted the recovery of the polysynaptic reflex potential. Morphine (5 mg/kg) showed no particular effect on the recovery of potentials. Furthermore, pretreatment with morphine (5 mg/kg) did not influence the effects of these opioid antagonists. These results suggest that naloxone and levallorphan may preserve or potentiate the interneuronal activities of the lumbo-sacral spinal cord under the ischemic condition and that the effects may not be mediated through morphine-like opioid receptors.

Central and peripheral control of postprandial pyloric motility by endogenous opiates and cholecystokinin in dogs.

The role of endogenous opiates and cholecystokinin (CCK) in the control of postprandial pyloric myoelectric activity was investigated in conscious dogs with chronically implanted intraparietal electrodes at the gastroduodenal junction. Meals consisted of either 20 g/kg of canned food (standard meal) or the same food supplemented with 0.5 mL/kg of arachis oil (fat meal). During the 6 hours after standard and fat meals, the number of pyloric spike bursts, 2-4 seconds in duration, was 61.8 +/- 15.8 and 49.9 +/- 12.7/15 minutes, respectively. Administered 15 minutes before a fat meal, naloxone (50 micrograms/kg IV) decreased the number of spike bursts by 31.4%, whereas methyl-levallorphan, a peripheral opiate antagonist, increased postprandial spike activity by 22.2% when administered IV (0.5 mg/kg) and decreased it when administered intracerobroventricularly at a dose of 10 micrograms/kg. These two antagonists administered in the same conditions before a standard meal had no effect on the postprandial spike activity. A 1-hour infusion of cholecystokinin octapeptide (CCK-8), 500 ng.kg-1.h-1 IV and 50 ng.kg-1.h-1 intracerebroventricularly, performed 1 hour after a standard meal induced a 19.6% and 15.8% decrease in the number of pyloric spike bursts, respectively. Both naloxone IV (50 micrograms/kg) and methyl-levallorphan intracerebroventricularly (10 micrograms/kg) administered before the infusion of CCK-8 reinforced this pyloric inhibition, which was antagonized by methyl-levallorphan IV (0.5 mg/kg). The CCK antagonist asperlicin, 200 micrograms/kg IV and 20 micrograms/kg intracerebroventricularly, administered before a fat meal increased pyloric spike bursts by 22.0% and 31.5%, respectively. These results indicate that after a fat meal, endogenous opiates exert a peripheral inhibitory and central stimulatory control of pyloric motility; they suggest the involvement of both peripheral and central release of CCK.

Cross-tolerance and enhanced sensitivity to the response rate-decreasing effects of opioids with varying degrees of efficacy at the mu receptor.

The purpose of the present experiment was to determine whether the effects of opioids with varying degrees of efficacy at the mu receptor are differentially altered in morphine-tolerant pigeons. To this end, dose-effect curves were determined for high, intermediate, and low efficacy mu agonists in pigeons responding under a schedule of food presentation prior to, during, and after exposure to a regimen of chronic morphine administration. In pigeons treated with 56 mg/kg/daily morphine, the dose-effect curves for the rate-decreasing effects of the high-efficacy mu agonists morphine and fentanyl were shifted to the right of their prechronic positions (i.e., tolerance). A small degree of tolerance was also conferred to the intermediate-efficacy mu agonists (-)-pentazocine and (-)-metazocine, but not to nalbuphine or butorphanol. In contrast to the effects obtained with these mu agonists, the chronic morphine regimen shifted the dose-effects curves of the mu antagonist naloxone and the low-efficacy mu agonists nalorphine and levallorphan to the left of their prechronic positions (i.e., enhanced sensitivity). These findings demonstrate that morphine tolerance confers cross-tolerance to other high efficacy mu agonists, enhanced sensitivity to mu antagonists and low efficacy mu agonists, and little or no cross-tolerance to intermediate efficacy mu agonists. Disadvantages of using schedule-controlled responding to examine the effects of intermediate efficacy mu agonists are discussed.

Butorphanol, levallorphan, nalbuphine and nalorphine as antagonists in the squirrel monkey.

The effects of several mixed-action opioid agonist/antagonists were examined alone and in combination with the mu-opioid agonist l-methadone and the kappa-opioid agonist, trans-3,4-dichloro-N-methyl-N[2-(1-pyrrolidinyl)cyclohexyl]benzeneace tam ide (U50,488). Effects were examined in squirrel monkeys responding under a schedule of shock titration. Under this procedure shock was scheduled to increase once every 15 sec from 0.01 to 3.7 mA in 30 steps. Five responses on a lever during the 15-sec shock period terminated the shock for 15 sec, after which the shock resumed at the next lower intensity. The intensity below which the monkeys maintained the shock 50% of the time (median shock level) was determined. l-Methadone and U50,488 produced dose-dependent increases in median shock level. Nalbuphine, butorphanol and levallorphan also increased median shock level, but these increases were much smaller than those observed with l-methadone or U50,488. Nalorphine and naltrexone did not increase median shock level. Butorphanol, levallorphan, nalbupine, nalorphine and naltrexone all produced parallel, rightward shifts in both the l-methadone and U50,488 dose-effect curves. The apparent pA2 values obtained for naltrexone in combination with l-methadone (7.7) were at least one log unit larger than those obtained for naltrexone in combination with U50,488 (6.5). Similar differences were revealed for nalbuphine in combination with l-methadone (6.1) and U50,488 (5.2) as well as for nalorphine in combination with l-methadone (6.0) and U50,488 (5.5).(ABSTRACT TRUNCATED AT 250 WORDS)

Opioid modulation of basal intestinal fluid transport in the mouse: actions at central, but not intestinal, sites.

Central and peripheral sites of opioid action on net basal fluid transport were studied in loops of jejunum in urethane-anesthetized mice. Intracerebroventricular administration of morphine, [D-Ala2, N-MePhe4, Gly-ol]enkephalin (DAMGO), D-Pen2, D-Pen5] enkephalin (DPDPE) or U50,488H produced dose-related increases in net basal intestinal absorption. Intracerebroventricular DAMGO was approximately 2.6, 1278 and 2674 times more potent than morphine, DPDPE and U50,488H, respectively. The increase in net basal fluid absorption mediated by i.c.v. administration of all these compounds, except DPDPE, was antagonized in a dose-related manner by coadministration of i.c.v. naloxone, an opioid antagonist which did not produce any effects when given alone. Neither the increase in net basal fluid absorption produced by DPDPE nor the fluid transport effects produced by the other agonists tested was antagonized by the delta antagonist, N,N-diallyl-Tyr-alpha-aminoisobutyric acid [( Aib]-Aib-Phe-Leu-OH) and no effects were observed with this delta antagonist alone. Intracerebroventricular administration of beta-funaltrexamine (18.8 nmol, 4 hr before testing) blocked the i.c.v. effects of DAMGO, but not those of U50,488H. In contrast to the effects seen following i.c.v. administration of these agonists, no changes in net basal fluid transport were obtained by the i.p. route for DAMGO, DPDPE, [D-Ala2,D-Leu5]enkephalin, [D-Ala2, Met5]enkephalinamide or U50,488H; of the compounds tested, only morphine produced an increase in net basal fluid absorption after i.p. administration. The effects of i.c.v. or i.p. morphine were blocked by i.c.v. SR 58002C, a quaternary opioid antagonist which had no effects alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Non-opioid effects of N-methyl levallorphan in the anaesthetised rat.

1. The effects of the quaternary opioid antagonist N-methyl levallorphan upon cardiovascular responses to non-opioid agonists has been studied in the urethane-anaesthetised rat. 2. N-methyl levallorphan showed an initial nicotinic agonist effect followed by pronounced ganglion blocking activity after intravenous administration. These effects are observed at doses only 2-fold higher than those required to block cardiovascular responses to [Met] enkephalin. 3. The narrow selectivity of N-methyl levallorphan makes this compound inappropriate for opioid antagonist studies where nicotinic receptors may be involved.

[Role of substance P on neurogenic inflammation in the rat dental pulp and inferior lip].

A physiological role of substance P (SP) in inflammatory reaction was examined in the rat incisor pulp and inferior lip. SP content in pulps and lips significantly increased after antidromic stimulation of the inferior alveolar nerve. Following the same stimulation, vascular permeability also increased significantly in pulps and lips, and this permeability response was significantly inhibited by an SP-antagonist. Morphine reduced the permeability response to antidromic stimulation in pulps but had no effect in lips. N-methyl levallorphan (a peripherally selective narcotic antagonist) prevented the morphine-induced reduction, and was more potent than naloxone. Morphine caused a marked increase of SP content in pulps following antidromic stimulation of the inferior alveolar nerve but failed in lips. These suggest a possibility that a peripheral SP release-suppressive mechanism by opiates may exist in pulps but not in lips. The permeability response to antidromic stimulation was also reduced by aspirin and a bradykinin antagonist in both of the tissues, indicating that prostaglandin and bradykinin may be related to this response. Since mepyramine and methysergide inhibited the permeability response in lips but were inactive in pulps, there is a difference in participation of histamine and serotonin between the two tissues. SP injection into the dental pulp and lip induced dye leakage. This response was inhibited by compound 48/80 pretreatment in lips whereas it was resistant in pulps. Histamine content in lips decreased significantly after antidromic stimulation and compound 48/80 pretreatment, but it was not changed in pulps. The present results suggest that in lips after being released from the peripheral sensory nerve endings SP may act on vascular system through histamine release from mast cells, while in pulps SP may directly cause vascular response because mast cells may be few or not exist.