u-50488 and spiradoline

The effects of opiates on vasopressin secretion have been controversial for many years. This is probably due to the existence of different types of opioid receptors and to the lack of specificity of the compounds used. Specific kappa agonists, which have been described recently, produce a marked diuretic effect without any associated increase in electrolyte elimination. They seem to exert their effects through an interaction with kappa receptors situated on nerve terminals and/or pituicytes. These receptors could be directly coupled to L-type calcium channels, their activation leading to a decrease in the effectiveness of action potentials to evoke vasopressin secretion from nerve terminals in the neurohypophysis. This mechanism of action may explain the decrease in plasma vasopressin levels induced by kappa agonists.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Benzomorphans; Diuretics; Paraventricular Hypothalamic Nucleus; Pyrrolidines; Rats; Receptors, Opioid; Receptors, Opioid, kappa; Supraoptic Nucleus; Vasopressins

Our previous work indicated that pretreatment with the selective kappa-opioid receptor (KOPr) agonist, U69593, attenuated the ability of priming injections of cocaine to reinstate extinguished cocaine-seeking behavior. The present study expanded these initial tests to include other traditional KOPr agonists, U50488H, spiradoline (SPR), and salvinorin A (Sal A), an active constituent of the plant Salvia divinorum. Following acquisition and stabilization of cocaine self-administration, cocaine-produced drug-seeking was measured. This test was conducted in a single day and comprised an initial phase of self-administration, followed by a phase of extinguished responding. The final phase examined reinstatement of extinguished cocaine self-administration followed by a priming injection of cocaine (20.0mg/kg, intraperitoneal (I.P.)) in combination with the various KOPr agonists. Cocaine-induced drug-seeking was attenuated by pretreatment with U69593 (0.3mg/kg, subcutaneous (S.C.)), U50488H (30.0mg/kg, I.P.), SPR (1.0, 3.0mg/kg, I.P.) and Sal A (0.3, 1.0mg/kg, I.P.). Sal A (0.3, 1.0mg/kg, I.P.) had no effect on operant responding to obtain sucrose reinforcement or on cocaine-induced hyperactivity. These findings show that Sal A, like other traditional KOPr agonists attenuates cocaine-induced drug-seeking behavior.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Behavior, Addictive; Benzeneacetamides; Cocaine; Diterpenes, Clerodane; Male; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Self Administration

Although studies suggest that 2-(3,4-dichlorophenyl-N-methyl-N-[(1S)-1-(3-isothiocyanatophenyl)-2-(1-pyrrolidinyl) ethyl] acetamide (DIPPA) has transient kappa-opioid-mediated agonist effects followed by long-lasting kappa-antagonist effects, its behavioral and pharmacological actions have not been systematically examined and there is evidence suggesting that some of its effects are species dependent. The purpose of this investigation was to examine the actions of DIPPA in different behavioral procedures and in three species. In a pigeon drug discrimination procedure, DIPPA and the kappa-opioids U50,488 and ICI-199441 substituted fully for the stimulus effects produced by spiradoline. For DIPPA, this effect was observed between 0.25 and 4 h after administration. In a warm water tail-withdrawal procedure, DIPPA failed to produce antinociception in rats or mice even when relatively high doses were tested using pretreatment intervals ranging from 0.25 to 24 h. In this procedure, DIPPA antagonized the effects of spiradoline and U50,488 in mice. In rats, DIPPA antagonized the effects of U50,488 but not those of spiradoline. Taken together, these results suggest that DIPPA may function as a low-efficacy kappa-opioid and have a long duration of action, and there may be some species differences in its behavioral profile. This profile of action, however, differs from other low-efficacy kappa-opioids.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Acetamides; Analgesics; Analgesics, Non-Narcotic; Animals; Columbidae; Conditioning, Operant; Dextroamphetamine; Discrimination Learning; Discrimination, Psychological; Dopamine Uptake Inhibitors; Isothiocyanates; Mice; Narcotics; Pain Measurement; Pyrrolidines; Rats; Rats, Long-Evans; Reaction Time; Receptors, Opioid, kappa

The purpose of the present study was to examine sensitivity to the antinociceptive effects of kappa opioids during chronic treatment with the nonselective opioid antagonist naltrexone. In a warm-water tail-withdrawal procedure, rats were restrained and the latencies to remove their tails from water maintained at 50 and 55 degrees C were recorded. Prior to chronic treatment, spiradoline, U50,488 and (-)-pentazocine produced dose-dependent increases in tail-withdrawal latencies at both 50 and 55 degrees C. Chronic treatment with 3.0 mg/kg naltrexone twice daily (b.i.d.) failed to alter sensitivity to the antinociceptive effects of spiradoline when tested 24 h following naltrexone administration. When the maintenance dose of naltrexone was increased to 30 mg/kg b.i.d., sensitivity to the effects of spiradoline was reduced when tested 24 h after naltrexone administration, but enhanced when tested 48 h after naltrexone administration. Enhanced sensitivity was also observed to the antinociceptive effects of U50,488 and (-)-pentazocine when tested 48 h after chronic treatment with 30 mg/kg naltrexone. After termination of chronic treatment, sensitivity to the antinociceptive effects of spiradoline, U50,488 and (-)-pentazocine returned to that originally observed prior to naltrexone treatment. These data indicate that chronic naltrexone treatment enhances sensitivity to the antinociceptive effects of kappa opioids, and that this effect is both dose and time dependent.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Analgesics, Non-Narcotic; Animals; Dose-Response Relationship, Drug; Drug Administration Schedule; Male; Naltrexone; Narcotic Antagonists; Pain; Pain Measurement; Pentazocine; Pyrrolidines; Rats; Rats, Long-Evans; Receptors, Opioid, kappa

Significant differences in the potency and effectiveness of opioid analgesics have been reported in subject populations differing in age. Although the relationship between aging and sensitivity to the antinociceptive effects of mu opioids has been examined extensively, relatively few studies have examined this relationship in kappa opioids.. The purpose of the present investigation was to examine the antinociceptive effects of selected kappa and mixed-action opioids in young (3 months) and aged (21 months) male rats.. In a warm-water, tail-withdrawal procedure, rats were restrained and the latencies to remove their tails from 50 degrees C (low temperature) and 55 degrees C (high temperature) water were measured. Selected kappa (U69,593, U50,488) and mixed-action (butorphanol, nalbuphine) opioids were tested alone, and in combination with the high-efficacy, kappa-opioid spiradoline.. All test drugs were more effective (i.e., produced a greater maximal effect) in aged rats than in young rats at both water temperatures. In drug combination tests, U69,593 and U50,488 enhanced the effects of spiradoline under conditions in which they failed to produce high levels of antinociception when administered alone. In contrast, butorphanol and nalbuphine antagonized the effects of spiradoline under conditions in which they failed to produce high levels of antinociception when administered alone.. These data may be taken as evidence that: (1) aged male rats are more sensitive than young male rats to the antinociceptive effects of kappa opioids, (2) U69,593 and U50,488 display agonist activity in the warm-water, tail-withdrawal procedure under some conditions in which they fail to produce antinociceptive effects, and (3) butorphanol and nalbuphine possess only limited agonist activity at the kappa receptor.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Age Factors; Analgesics; Analgesics, Non-Narcotic; Analgesics, Opioid; Analysis of Variance; Animals; Benzeneacetamides; Butorphanol; Cold Temperature; Dose-Response Relationship, Drug; Drug Synergism; Male; Nalbuphine; Pain; Pain Measurement; Pyrrolidines; Rats; Rats, Inbred F344; Reaction Time; Receptors, Opioid, kappa

Recent studies indicate that sex and rodent strain are determinants of sensitivity to opioid-induced antinociception.. The present study examined the influence of sex and rat strain on kappa opioid-induced antinociception using a series of kappa opioids that vary in their relative effectiveness.. In a warm-water (50, 52 and 55C) tail-withdrawal procedure, the antinociceptive effects of kappa opioids were determined in male and female rats of the F344, Lewis and Sprague-Dawley (SD) strains.. In both males and females of each strain, spiradoline produced high levels of antinociception across all nociceptive stimulus intensities, whereas U50,488 produced high levels only at the low and moderate nociceptive stimulus intensities. Sex differences in the potency and effectiveness of these kappa opioids were relatively small and not consistently obtained. Enadoline, bremazocine and nalorphine were less effective than spiradoline in producing antinociception, and at low and moderate nociceptive stimulus intensities these opioids were both more potent and effective in F344 and SD males than their female counterparts. In contrast, in Lewis rats, only bremazocine was more potent and effective in males. In combination tests, bremazocine shifted the spiradoline dose-effect curve leftward and/or upward in males and rightward in females (i.e., antagonized spiradoline). In contrast, in both males and females enadoline shifted the spiradoline dose-effect curve leftward and/or upward.. These data indicate that kappa opioids were generally more potent and effective as antinociceptive agents in males than females. Similar to data obtained with micro opioids, the magnitude of these sex differences was generally larger with the less effective kappa opioids and determined, in part, by rat strain and nociceptive stimulus intensity.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Benzofurans; Benzomorphans; Female; Male; Nalorphine; Narcotics; Pyrrolidines; Rats; Rats, Inbred F344; Rats, Inbred Lew; Rats, Inbred Strains; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Sex Characteristics

Eight kappa-opioid receptor agonists were examined for their effects in squirrel monkeys responding under a fixed interval 3-min schedule of stimulus termination. Six of these kappa-opioid receptor agonists decreased dose-dependently the total number of responses and with an order of potency consistent with kappa-opioid receptor interaction. Three of these kappa-opioid receptor agonists, bremazocine, U69,593 [[(5a,7a,8b)-(+)-N-[7-(1-pyrrolidinyl)-1-oxaspiro(4,5)dec-8-yl)] benzeneacetamide] and enadoline, were evaluated following pretreatment with 1.0 mg/kg of naltrexone or 3.0 mg/kg of norbinaltorphimine. The effects of the three agonists were antagonized significantly by naltrexone, but only those of bremazocine and U69,593 were antagonized significantly by norbinaltorphimine. Statistical analysis of the data averaged over six monkeys revealed that naltrexone was significantly more potent than norbinaltorphimine at antagonizing enadoline and U69,593, but naltrexone and norbinaltorphimine were equipotent at antagonizing bremazocine. Moreover, naltrexone was 8-fold more potent at antagonizing U69,593 and enadoline than at antagonizing bremazocine. These results suggest that under these conditions the effects of U69,593 and enadoline may be mediated, in part, by a different receptor population, perhaps a subtype of kappa-opioid receptors, from the one that mediates the effects of bremazocine.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Behavior, Animal; Benzeneacetamides; Benzofurans; Benzomorphans; Conditioning, Operant; Dose-Response Relationship, Drug; Ethylketocyclazocine; Nalorphine; Naltrexone; Narcotic Antagonists; Pyrroles; Pyrrolidines; Receptors, Opioid, kappa; Reinforcement Schedule; Saimiri; Thiophenes

1. The kappa 1 and kappa 2 opioid receptor agonists U-62066 (8 mg/kg, i.p.) and (-)-bremazocine (0.7 mg/kg, i.v.), respectively, both exhibit anti-arrhythmic properties against adrenaline-induced dysrhythmias in rats. 2. In contrast, (+)-bremazocine has no effect on adrenaline-induced dysrhythmias. 3. The kappa 1 opioid receptor agonists U-50488 (110 nmol) and [D-Ala2]-dynorphin A (20 nmol) and the kappa 2 opioid receptor agonist (-)-bremazocine (30 nmol) exhibit pro-arrhythmic properties following intracerebroventricular administration. 4. Prior administration of the kappa opioid receptor antagonist nor-binaltorphimine doses i.c.v. (14 nmol), i.p. (10 mg/kg), completely abolishes the pro-arrhythmic (BNI, i.c.v., 14 nmol) as well as anti-arrhythmic (BNI, 10 mg/kg, i.p.) effects of the kappa opioid receptor agonists. 5. Neither hexamethonium (10 mg/kg, i.v.) nor atropine (1 mg/kg, i.v.) have any effect on the anti-arrhythmic actions of the kappa 1 opioid receptor agonist U-62066 following systemic administration. 6. It is suggested that the anti-arrhythmic effects of U-62066 and (-)-bremazocine are associated with the activation of peripheral kappa opioid receptors and do not depend on the activation of kappa opioid receptors in the autonomic nervous system.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Anti-Arrhythmia Agents; Antihypertensive Agents; Arrhythmias, Cardiac; Benzomorphans; Dynorphins; Male; Pyrrolidines; Rats; Rats, Wistar; Receptors, Opioid, kappa

Comparative centrally mediated hypotensive effects of three nonpeptide kappa opioid agonist drugs (bremazocine, spiradoline, and U-50,488H) were evaluated in chloralose-anesthetized male spontaneously hypertensive rats (SHRs) and in normotensive Wistar-Kyoto (WKY) and Sprague-Dawley (SD) rats. The drugs were administered unilaterally into previously established active hypotensive sites in the dorsal hippocampus at doses of 12, 24, and 48 nmol. Each drug produced dose-related decreases in mean arterial pressure, ranging from -5 to -40% of predrug control values, with bremazocine being somewhat more effective than spiradoline, which was in turn slightly more active than U-50,488H. The effects were only marginally greater in SHRs than in normotensive controls. Each drug caused a modest decrease in heart rate, but except for the highest dose of bremazocine, the effects were not statistically significant. The onset of hypotension after intrahippocampal injection of each agent was approximately 2 min and lasted approximately 30 min with U-50,488H and spiradoline and >60 min with bremazocine. The responses to all three drugs were completely blocked by prior injection of the active hippocampal sites with nor-binaltorphimine (nor-BNI), a selective kappa-receptor antagonist. Because bremazocine is more selective for kappa-2 opioid receptors, whereas U-50,488H and spiradoline favor the kappa-1 subtype, the results suggest that drugs active on each of these subtypes should be investigated as potential antihypertensives.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Antihypertensive Agents; Benzomorphans; Dose-Response Relationship, Drug; Hippocampus; Male; Naltrexone; Narcotic Antagonists; Pyrrolidines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Opioid, kappa

The blockade of veratrine-stimulated phosphoinositide breakdown in rat cerebral cortical miniprisms has been used as a model of drug action on voltage-dependent sodium channels. The kappa-opioid agonists bremazocine, (+/-)- and (+)-trans-U-50488, U-62066 (spiradoline) and U-69593 inhibited the response to veratrine with IC50 values of 35, 13, 15, 9, and > 100 microM, respectively. Bremazocine, at concentrations inhibiting the response to veratrine, did not inhibit the phosphoinositide breakdown response to the sodium ionophore monensin, indicating the specificity of the assay for sodium channels. The inhibitory actions of bremazocine upon veratrine-stimulated phosphoinositide breakdown were not antagonised by naloxone. This study thus confirms previous data suggesting that the kappa-opioid receptor agonists can affect Na(+)-channel function in a manner unrelated to their actions at kappa-opioid receptors. However, for the compounds tested, such effects are only found at rather high concentrations of the compounds.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Benzeneacetamides; Benzomorphans; Brain; Disease Models, Animal; Inositol Phosphates; Naloxone; Pyrrolidines; Rats; Receptors, Opioid, kappa; Sodium Channels

This study describes the coupling of the recombinant rat kappa-opioid receptor expressed in Chinese hamster ovary (CHO) cells to adenylyl cyclase and the effects of receptor density. The binding of [3H]diprenorphine ([3H]DPN) was dose dependent and saturable in membranes prepared from cells of early (p4-7) and late (p14-17) passage after transfection. As passage increased the receptor numbers (Bmax) declined from 231 +/- 24 (early) to 31 +/- 2 fmol/mg protein (late) but the equilibrium dissociation constant (Kd) did not change. Spiradoline dose dependently displaced [3H]DPN from membranes prepared from early and late cells revealing both high (Ki[H]) and low (Ki[L]) affinity binding sites. There were no significant differences in the proportion of these sites (approximately 50% Ki(L):50% Ki[H]), and whilst spiradoline was generally less potent in late cells the differences were small and failed to reach statistical significance. In contrast, spiradoline produced a dose dependent inhibition of forskolin stimulated cAMP formation in whole cells with pIC50 of 8.62 and 8.00 in early compared with late cells. In addition, the maximum inhibition was dramatically reduced from 47 to 22%. Etorphine, (+/-)bremazocine, ICI-204,448 and (+/-)trans-U-50488 methanesulfonate (1 microM), compounds with activity at kappa-receptors, produced a greater inhibition of cAMP formation in early (42.2, 45.8, 50.2 and 50.5%, respectively) than late (12.9, 11.8, 13.5 and 7.8%, respectively) cells, indicating that expression dependent inhibition of cAMP formation was not kappa-agonist specific. Collectively, these data suggest that in CHO cells, kappa-opioid receptor coupling to adenylyl cyclase is dependent on receptor expression levels.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Adenylyl Cyclases; Analgesics; Animals; Benzomorphans; CHO Cells; Colforsin; Cricetinae; Cyclic AMP; Diprenorphine; Dose-Response Relationship, Drug; Etorphine; Gene Expression; Narcotic Antagonists; Phosphodiesterase Inhibitors; Pyrrolidines; Rats; Receptors, Opioid, kappa; Transfection

Striatal dynorphin-containing neurons receive dopaminergic inputs from the substantia nigra pars compacta and project primarily to the substantia nigra pars reticulata and entopeduncular nucleus. These neurons mainly express dopamine (DA) D1 receptors and thus dynorphin system stimulation might be expected largely to influence D1 receptor agonist or antagonist effects on motor function. It is well known the interaction existing between DA D1 and D2 drugs in the induction of behavioral effects. However, the effects of dynorphin on selective D1 and D2 DA agonist and antagonist-induced behaviors have not yet been investigated. Administration of the kappa agonists spiradoline (0.5, 1 and 5 mg/kg) or U50,488H (1, 10 and 25 mg/kg) decreased non-stereotyped grooming induced by the selective D1 agonist SKF38393. This effect was inhibited by the non-selective opioid receptor antagonist naloxone (20 mg/kg) and by the selective kappa antagonist nor-binaltorphimine (nor-BNI, 20 mg/kg). Stereotypies induced by the selective D2 agonist quinpirole were decreased by spiradoline (1 and 5 mg/kg) and by U50,488H (1, 10 and 25 mg/kg), while jerking movements of a type associated with increased D2 receptor and decreased D1 receptor stimulation emerged. Kappa agonist effects were inhibited by the prior administration of SKF38393 (10 mg/kg); these inhibitory effects were blocked by prior administration of the D1 antagonist SCH23390 (5 mg/kg). Naloxone reversed the effects of both kappa agonists on quinpirole-induced stereotypies. Kappa agonists increased D1 antagonist-induced catalepsy, but had no effect on D2 antagonist-induced catalepsy. Naloxone and nor-BNI inhibited this effect. These results suggest that the motoric effects of D1 receptor antagonists in part reflect stimulation of striatal dynorphin containing efferents.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Behavior, Animal; Catalepsy; Dopamine Agonists; Dopamine Antagonists; Dose-Response Relationship, Drug; Male; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa

The present study examined whether the kappa-opioid agonists U50,488H (trans-(+/-)-3,4-dichloro-N-methyl-N[-2-(1-pyrrolidinyl)- cyclohexyl]-benzeacetamide methane sulphonate), bremazocine, spiradoline and ICI 197067 bind to sigma sites in guinea-pig tissues using in vitro, semi-quantitative receptor autoradiography and receptor binding, and compared the binding profile so obtained with those for several selective sigma ligands. Guinea-pigs were killed and their brians, livers and spleens were removed, tissue sections cut and processed for sigma binding site autoradiography using (+)-[3H]-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ((+)-[3H]-3-PPP), or tissue was wiped and determined by liquid scintillation. Serial slide-mounted sections were incubated with 9-10 concentrations (1 nM-10 microM) of kappa opioids and their potency to inhibit (+)-[3H]-3-PPP binding compared with that of the sigma ligands haloperidol, DTG (1,3 di(o)-tolylguanidine), (+)-3-PPP, (+) and (-)pentazocine, SR 31742A and rimcazole (n = 3, duplicate determinations). Binding of (+)-[3H]-3-PPP to untreated, matched serial tissue sections was used as control. Kd values were estimated in brain, liver and spleen using quantitative, saturation binding analysis, IC50 values were determined from the binding data obtained by slide wiping experiments for each drug, and Ki values were calculated using the Cheng-Prussoff equation. All four kappa opioids inhibited (+)-[3H]-3-PPP binding to sigma 1-receptors with order of potency: brain: U50,488H = spiradoline > bremazocine > ICI 197067; liver: spiradoline > U50,488H > ICI 197067 > bremazocine; spleen: U50,488H > spiradoline > ICI 197067 > bremazocine. By comparison, the sigma ligands inhibited (+)-[3H]-3-PPP binding to matched, serial slide-mounted brain tissue sections (similar results in liver and spleen) with order of potency: SR 31742A > haloperidol > (+)pentazocine > (+)-3-PPP > DTG > (-)pentazocine > rimcazole. (+)-[3H]-3-PPP autoradiography confirmed these binding data. It is concluded that the kappa opioids tested moderately inhibit (+)-[3H]-3-PPP binding to sigma 1-receptors in guinea-pig brain, liver and spleen tissue with Ki values comparable to some selective sigma ligands and therefore are not opioid selective.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Autoradiography; Benzomorphans; Binding Sites; Brain; Guinea Pigs; Liver; Piperidines; Pyrrolidines; Receptors, Opioid, kappa; Receptors, sigma; Spinal Cord; Spleen

The selective kappa agonists U50488 (10 mg/kg, i.p.) and spiradoline (1 mg/kg, i.p.) attenuated the locomotor activating effects of a morphine challenge (5 mg/kg, i.p.) administered 19 h later in rats. This antagonism of morphine by a kappa agonist was reversed by the selective kappa antagonist, norbinaltorphimine (10 mg/kg, s.c.). Furthermore, the kappa opioid antagonism of morphine was enhanced by prior morphine exposure (2 doses of 30 mg/kg, i.p. administered once a day for 2 days). The present data suggest that kappa-micro opioid interactions may occur over time periods that exceed the acute durations of drug actions.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Analgesics, Opioid; Analysis of Variance; Animals; Behavior, Animal; Female; Locomotion; Morphine; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Time Factors

Two kappa agonists, U50,488 and spiradoline, produced dose-related acute decreases in both morphine and cocaine self-administration in rats; higher doses of both agents were required to decrease rates of bar-pressing for water. On the day after kappa agonist administration, both agents produced extinction-like patterns of responding in many rats self-administering morphine or cocaine but not in rats responding for water. Two days after their administration, both U50,488 and spiradoline produced significant decreases in both morphine and cocaine intake; some rats continued to show decreases in drug self-administration for 5-6 days. Although the kappa antagonist nor-binaltorphimine (10 mg/kg s.c.) had no effect itself on either morphine or cocaine self-administration, it fully antagonized the effects of U50,488 (10 m/kg i.p.). The results suggest that although endogenous kappa opioid systems may not tonically modulate mechanisms involved in drug reinforcement, pharmacological activation of kappa pathways may be a novel and effective pharmacological approach to treating both opioid and stimulant addiction.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Cocaine; Dose-Response Relationship, Drug; Extinction, Psychological; Female; Morphine; Naltrexone; Narcotics; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Reinforcement, Psychology; Self Administration

The goal of the present study was to determine whether the serotonin (5-HT) system is involved in the effects of kappa opioids as measured with the squirrel monkey shock titration procedure. With this procedure, electric shock was delivered to the monkey's tail and scheduled to increase once every 15 sec from 0.01 to 2.0 mA in 30 steps. Monkeys responded under a fixed ratio 5 schedule to determine the level at which shock intensity was maintained. The intensity below which monkeys maintained shock 50% of the time, or the median shock level (MSL), and the rate of responding in the presence of shock (RR) were determined after the administration of saline and all drug combinations. The kappa opioids U50,488 and spiradoline increased MSL and decreased RR in a dose-dependent manner. The effects of U50,488 and spiradoline on both RR and MSL were enhanced in all three monkeys by the 5-HT2 antagonists ketanserin and pirenperone and in one monkey by another 5-HT2 antagonist, LY 53857. The effects of U50,488, but not spiradoline, were enhanced to a lesser degree by the 5-HT1A receptor agonist 8-OH-DPAT. The effects of U50,488 but not altered by the receptor agonist DOI, the 5-HT3 receptor antagonist MDL 72222 or the alpha-1 adrenergic receptor antagonist prazosin. These results suggest that the effects of kappa opioids in the shock titration procedure probably involve serotonergic mechanisms that are modulated via 5-HT2 and, perhaps, 5-HT1A receptors. Moreover, these interactions probably reflect nonspecific decreases in RR rather than alterations in the antinociceptive effects of kappa opioids.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; 8-Hydroxy-2-(di-n-propylamino)tetralin; Adrenergic alpha-Antagonists; Analgesics; Animals; Drug Interactions; Electric Stimulation; Male; Prazosin; Pyrrolidines; Receptors, Opioid, kappa; Saimiri; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists

Neurochemical and behavioral investigations were made to assess the role of central dopaminergic systems in mouse locomotor activity and analgesia by spiradoline mesylate. Analgesic activities of the kappa-opioid-receptor agonists spiradoline and U-50488H were not altered by haloperidol or L-dopa, whereas morphine analgesia was enhanced by haloperidol but attenuated by L-dopa. Spiradoline decreased spontaneous locomotor activity in mice and inhibited methamphetamine- or morphine-induced locomotor activity. In contrast, morphine given alone increased locomotor activity and enhanced methamphetamine-induced locomotor activity. In a neurochemical study, spiradoline decreased the amounts of dopamine metabolites in the striatum, but did not alter them in the brainstem and cerebral cortex. Morphine increased the dopamine metabolite contents in all three brain regions tested. These results suggest that inhibition of the dopaminergic pathway in the brain by spiradoline may be involved in its suppression of locomotor activity, but not in its analgesia; whereas, stimulation of the dopaminergic pathway by morphine seems to function in both behaviors: enhancement of locomotor activity and inhibition of analgesia.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Brain; Brain Stem; Cerebral Cortex; Corpus Striatum; Dopamine; Haloperidol; Levodopa; Male; Methamphetamine; Mice; Morphine; Motor Activity; Pyrrolidines

(+-)-(5 beta,7 alpha,8 beta)-3,4-Dichloro-N-methyl-N-[3-methylene-2- oxo-8-(1-pyrrolidinyl)-1-oxaspiro[4,5]dec-7-yl]benzeneacetamide (14) and its (5 alpha,7 alpha,8 beta) diastereomer 15 have been synthesized from 1,4-cyclohexanedione monoethylene ketal (1) in 10 steps. Compound 14, which we have designated SMBU-1, was found to bind with moderate affinity (Ki = 109 nM) and good selectivity (mu/kappa = 29) to the kappa opioid receptor, while 15 was only 1/10 as potent as a kappa ligand. Preincubation of brain membranes with 14 resulted in wash-resistant inhibition of kappa-receptor binding (69 +/- 6% of control at 10(-6) M). The ketone precursor trans-N-methyl-N-[5-oxo-2-(1- pyrrolidinyl)cyclohexyl]benzeneacetamide (12) showed a higher kappa-affinity (Ki = 78 nM) and a much higher kappa-selectivity (mu/kappa = 166) than 14. Compound 10, the ethylene ketal precursor of 12, exhibited a similar receptor binding profile to 14, with increased kappa-selectivity (mu/kappa = 55), while ketal 11, being a regioisomer of 10 and an oxygen isostere of the kappa-selective analgesic spiradoline (U-62,066), demonstrated the highest kappa-affinity (Ki = 1.5 nM) and kappa-selectivity (mu/kappa = 468) observed in this series.

Topics: Benzeneacetamides; Magnetic Resonance Spectroscopy; Molecular Structure; Pyrrolidines; Receptors, Opioid; Receptors, Opioid, kappa; Spiro Compounds; Stereoisomerism; Structure-Activity Relationship

Kappa opioid agonists are known to inhibit dopamine release. We sought to determine the site of this action and the relationship of tolerance to this effect. Microdialysis perfusion of the nucleus accumbens in unanesthetized rats was used to monitor dopamine release, as well as DOPAC, HVA, and 5-HIAA efflux. Administration of the kappa agonist U-50488H (0.5-10 mg/kg, s.c.) resulted in a dose-related inhibition of basal dopamine release and a delayed reduction in HVA efflux. When added directly to the perfusion medium, U-50488H (10 microM) similarly reduced dopamine release and HVA efflux; however, a much higher concentration (1 mM) produced a transient increase in dopamine release. The more potent kappa agonist, spiradoline mesylate (5 mg/kg, s.c.) caused a more profound and long lasting reduction in dopamine release than that observed with U-50488H. Repeated injections of spiradoline (7 injections over 3 days at 5 and 10 mg/kg, s.c.) resulted in a persistent reduction in dopamine release with no further reduction in release being observed following an acute injection of spiradoline (1 mg/kg, s.c.). We conclude that kappa agonists act to inhibit dopamine release from the nucleus accumbens via a direct effect in that region, and that tolerance does not occur to this neurochemical effect. Thus, kappa agonists may prove useful in chronic conditions resulting from excessive dopamine release.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; 3,4-Dihydroxyphenylacetic Acid; Analgesics; Animals; Dopamine; Drug Tolerance; Homovanillic Acid; Hydroxyindoleacetic Acid; Male; Nucleus Accumbens; Perfusion; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa

In guinea pig ileum, spiradoline (2 x 10(-6) M or greater) and U-50488H (3 x 10(-6) M or greater) suppressed contractile responses to acetylcholine (ACh), histamine, and BaCl2. Inhibition by spiradoline (2 x 10(-5) M) of ACh-induced contractions was not antagonized by pretreatment with naloxone (3 x 10(-4) M). Spiradoline (2 x 10(-8) M or greater) and U-50488H (3 x 10(-8) M or greater) caused dose-dependent inhibition of the contractile response of guinea pig ileum to transmural electric stimulation. The inhibitory effect of spiradoline or of U-50488H at low concentrations was reduced by a high concentration of naloxone (3 x 10(-4) M). Spiradoline at low concentrations ranging from 2 x 10(-9) to 2 x 10(-7) M reduced spontaneous contractions in rabbit ileum. Naloxone (3 x 10(-4) g/ml) antagonized the spiradoline-induced inhibition, but marked inhibition by spiradoline at 10(-4) g/ml was not restored by naloxone. These results suggest that both kappa agonists exert presynaptic inhibitory action on cholinergic nerve endings in the myenteric plexus at a low concentration range of 10(-9) to 10(-7) M and directly inhibit the smooth-muscle motility of the gut at greater concentrations.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Gastrointestinal Motility; Guinea Pigs; Ileum; Male; Morphine; Myenteric Plexus; Naloxone; Pyrrolidines; Rabbits; Receptors, Neurotransmitter; Receptors, Opioid; Receptors, Opioid, kappa

When co-administered intracisternally, the selective delta-opioid agonist [D-Pen2,5]enkephalin (DPDPE), which had no significant effect on the cough reflex, consistently and significantly decreased the antitussive potencies of kappa-receptor agonists, U-50,488H and U-62,066E. The decrease in the antitussive effects of these kappa-receptor agonists caused by DPDPE were prevented by selective delta receptor antagonist, naltrindole. These results suggest that delta receptors may play an inhibitory role in antitussive processes that are mediated by the kappa-receptors.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Antitussive Agents; Cough; Enkephalin, D-Penicillamine (2,5)-; Enkephalins; Indoles; Male; Morphinans; Naltrexone; Narcotic Antagonists; Pyrrolidines; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, kappa; Reflex

This study represents the initial step in assessing the discriminative effects of spiradoline (U62,066), a potent congener of the selective kappa-opioid agonist, U50,488. Separate groups of rats were trained to discriminate between SC injections of saline and either 3.0 mg/kg spiradoline or 3.0 mg/kg morphine in a discrete-trial shock-avoidance/escape procedure. Spiradoline-trained rats generalized completely to U50,488 (ED50S for spiradoline and U50,488 were 0.66 and 8.71 mg/kg, respectively), but selected the choice lever appropriate for saline in generalization tests with graded doses of morphine, phencyclidine, and agonist-antagonist opioids with varying degrees of kappa activity, ethylketocyclazocine, nalorphine, and butorphanol. Morphine-trained rats did not generalize to spiradoline. Naltrexone (0.01 or 0.1 mg/kg) blocked surmountably the discriminative effects of both spiradoline and morphine, but was approximately 10-fold less potent against spiradoline. These results indicate that the discriminative effects of spiradoline are mediated by kappa-opioid receptors; meaningful mu-opioid and PCP/sigma components of action were not in evidence. The potency and apparent pharmacological selectivity of spiradoline suggest the potential value of this drug for studying kappa-opioid-mediated stimulus control of behavior.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Butorphanol; Discrimination, Psychological; Ethylketocyclazocine; Generalization, Stimulus; Male; Morphine; Nalorphine; Phencyclidine; Pyrrolidines; Rats; Rats, Inbred Strains; Reaction Time; Receptors, Opioid; Receptors, Opioid, kappa; Receptors, Opioid, mu

We examined whether the chronic administration of selective kappa-opioid agonists could produce antitussive tolerance, in a comparison with the mu-opioid morphine. A certain degree of tolerance to the antitussive effects of morphine appeared in rats treated chronically with this drug. However, chronic administration of U-50,488H and U-62,066E, highly selective agonists for the kappa-opioid receptor, does not result in the development of tolerance to their respective antitussive effects. These results suggest that the ability of kappa-opioid agonists to cause tolerance to their respective antitussive effects was lower than that of a mu-opioid agonist.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Antitussive Agents; Binding Sites; Brain Stem; Drug Tolerance; Male; Morphine; Pyrrolidines; Rats; Rats, Inbred Strains; Receptors, Serotonin; Serotonin

The effects of highly selective agonists of kappa-opioid receptors, namely U-50,488H and U-62,066E, on the capsaicin-induced cough reflex in rats were studied. Intracisternal (i.cist.) injection of U-50,488H and of U-62,066E significantly decreased the number of coughs in a dose-dependent manner. The antitussive potency of i.cist. injection of these two kappa-opioid agonists was similar to that of morphine. Intraperitoneal (i.p.) injection of U-50,488H and of U-62,066E also decreased the number of coughs, again in a dose-dependent manner. The antitussive effects of U-50,488H and U-62,066E were blocked by norbinaltorphimine, an antagonist of kappa-opioid receptors. Methysergide, administered i.cist. (3 nmol), antagonized the antitussive effects of U-50,488H and U-62,066E. However, ketanserin had no effect on the antitussive effects of these kappa-opioid agonists. These data suggest that U-50,488H and U-62,066E exert their antitussive effect on rats through stimulation of kappa-opioid receptors. Furthermore, with respect to the antitussive effects of kappa-opioid agonists, the system that involves 5-HT1 receptors may be more important than the system that involves 5-HT2 receptors.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Antitussive Agents; Cisterna Magna; Cough; Injections; Ketanserin; Male; Methysergide; Morphine; Naloxone; Naltrexone; Pyrrolidines; Rats; Rats, Inbred Strains; Reflex

Administered i.p. to mice, the selective kappa receptor agonists U-50488H and spiradoline (U-62066) were more potent on the tail-flick than on the hot-plate analgesic assay. Both were more potent after i.s. rather than i.c. administration, a result consistent with earlier demonstrations that tail-flick analgesia is generally dependent upon spinal mechanisms. Intraspinal U-50488H was not effective in elevating rat tail-flick latencies. Both drugs increased the thresholds for cat spinal cord nociceptive neurons to respond to a noxious heat stimulus. However, maximal responses of spinal cord neurons to nociceptive stimuli were not altered. It is concluded that although spinal cord sites may be critical to kappa receptor analgesic mechanisms, the effects are quite distinct from spinal cord effects observed previously with classical narcotic analgesics.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Male; Mice; Pyrrolidines; Rats; Receptors, Opioid; Receptors, Opioid, kappa; Spinal Cord

Spiradoline (a congener of the kappa opioid agonist, U-50488H) was evaluated for analgesic and related activities in rodents. In nine antinociceptive assays utilizing various thermal, pressure and chemical and physical irritants, the potency of spiradoline ranges from 4.7 to 23 (mean = 13) times that of U-50488H. Naloxone blocks the analgesic effect of spiradoline. The in vivo naloxone pA2 for this antagonism is much lower than that for the antagonism of morphine and approximates that of U-50488H. The analgesic potency of spiradoline is greatly reduced in mice made tolerant to U-50488H but not in those made tolerant to morphine. Repeated treatment with spiradoline does not induce physical dependence as evidenced by a lack of naloxone-precipitated jumping and withdrawal-induced hyperalgesia. In sum, these observations suggest that spiradoline is a potent kappa agonist analgesic. However, further evaluation of spiradoline revealed differences between this compound and U-50488H. We have previously shown that the analgesic effect of the latter compound, but not that of morphine, is profoundly antagonized by reserpine or p-chlorophenylalanine. In contrast, spiradoline is only marginally antagonized by these serotonin-depleting treatments. Evaluation of the enantiomers of spiradoline revealed that the (-)-enantiomer is more than 30 times as potent as the (+)-enantiomer in analgesic tests. The (-)-enantiomer is similar to U-50488H with regard to antagonism by p-chlorophenylalanine, lack of physical dependence-inducing properties and cross-tolerance. In contrast the (+)-enantiomer induces physical dependence and displays marked cross-tolerance in morphine-tolerant mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Drug Tolerance; Female; Fenclonine; Male; Mice; Morphine; Naloxone; Pyrrolidines; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, kappa

The ability of the kappa-opioid receptor agonists U50488H and U62066E (spiradoline mesylate) compared with the non-kappa close structural analogue U54494A to affect postischemic necrosis of the selectively vulnerable hippocampal CA1 neurons was examined in male Mongolian gerbils. The gerbils were treated with either saline vehicle or 10 mg/kg i.p. of one of the test drugs 30 minutes before and again 2 hours after a 10-minute period of bilateral carotid artery occlusion or sham occlusion under light methoxyflurane anesthesia. Seven days after ischemia and reperfusion the brains were perfusion-fixed, and hippocampal CA1 cells were counted in a blind fashion. In ischemic gerbils that received only vehicle, there was a 78.9% loss of CA1 neurons compared with sham-occluded gerbils. In contrast, in U50488H-treated gerbils, mean cell loss was reduced to 33.9% (p less than 0.01 vs. vehicle-treated group). U62066E was even more effective in reducing postischemic CA1 degeneration to only 20.7% (p less than 0.0001 vs. vehicle-treated group). However, treatment with the non-kappa analogue U54494A did not cause any apparent protection; the gerbils in this group showed an 80.7% loss of CA1 neurons. Our results are consistent with the hypothesis that kappa-receptor stimulation is associated with improved postischemic neuronal preservation.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Brain Ischemia; Gerbillinae; Hippocampus; Male; Necrosis; Neurons; Pyrrolidines; Receptors, Opioid; Receptors, Opioid, kappa

The cardiovascular effects of the selective kappa opioid receptor agonists U50488H and spiradoline mesylate were examined in pentobarbital-anesthetized mongrel dogs and chloralose-anesthetized cats. In the dog studies, U50488H (0.01-3.0 mg/kg, i.v.) produced a dose-related depression in mean arterial pressure (MAP), left ventricular systolic pressure (LVSP), left ventricular dp/dt, and heart rate. These effects were completely reversed by a 1 mg/kg i.v. dose of the opioid receptor antagonist naloxone. A second kappa agonist, spiradoline mesylate, also produced a naloxone-reversible cardiovascular depression. Furthermore, the compound did not interfere with the positive inotropic or hypertensive effects of norepinephrine (1 microgram/kg, i.v.), showing that the cardiovascular depressant effects of the kappa agonist are unrelated to interference with alpha- or beta-adrenergic receptor mechanisms. In normal cats anesthetized with chloralose, which produces less depression of sympathetic tone than does pentobarbital, spiradoline mesylate did not decrease the MAP in i.v. doses up to 1.0 mg/kg. However, a dose-related increase in sympathetic nerve discharge (SND) was observed (+290% at 1.0 mg/kg). In contrast, in baroreceptor-denervated cats, spiradoline mesylate caused a dose-related hypotensive effect with no change in SND. These results show that the cardiovascular effects of the kappa agonists are peripherally mediated and that reflex sympathetic activity, if uncompromised, can produce a full compensation.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Anesthesia; Animals; Blood Pressure; Cardiovascular Physiological Phenomena; Cardiovascular System; Cats; Chloralose; Depression, Chemical; Dogs; Female; Heart Rate; Male; Myocardial Contraction; Naloxone; Norepinephrine; Pentobarbital; Pyrrolidines; Receptors, Opioid; Receptors, Opioid, kappa; Sympathetic Nervous System