benzofurans and spiradoline

Kappa agonists can attenuate reinstatement of cocaine-seeking behavior induced by cocaine priming. The mechanisms underlying this effect have not been characterized fully but may have a serotonergic component as kappa agonists also increase the release of serotonin (5-hydroxytryptamine, 5-HT).. This study investigated the role of kappa opioid receptor and 5-HT mechanisms in kappa agonist-induced attenuation of cocaine priming in monkeys.. Squirrel monkeys were trained to self-administer cocaine (0.18-0.3 mg/kg/injection) under a second-order schedule in which drug seeking was maintained jointly by cocaine injections and a cocaine-paired visual stimulus. In extinction sessions, saline was substituted for cocaine, and the cocaine-paired stimulus was omitted. During test sessions, only saline was available for self-administration, and response-contingent presentations of the cocaine-paired stimulus were restored.. Priming injections of cocaine (0.1-1.0 mg/kg) induced reinstatement of drug seeking. Maximal levels of responding were similar to those maintained by active cocaine self-administration. Pretreatment with the kappa agonists enadoline (0.01 mg/kg) and spiradoline (0.3 mg/kg) or the 5-HT transport inhibitors fluoxetine (5.6 mg/kg) and citalopram (10.0 mg/kg) attenuated the priming effects of cocaine, shifting the cocaine dose-response function rightward and downward. Inhibition of cocaine-induced reinstatement of drug seeking by spiradoline and fluoxetine was reversed by R(+)8-hydroxy-2-(di-n-propylamino)tetralin (0.03 mg/kg), a 5HT(1A) agonist that inhibits 5-HT release. The effects of spiradoline also were reversed by the kappa antagonist nor-binaltorphimine (10.0 mg/kg).. Results suggest that the capacity of kappa opioid agonists to increase extracellular 5-HT levels may at least partially underlie kappa agonist-induced modulation of cocaine seeking.

Topics: Animals; Benzofurans; Citalopram; Cocaine-Related Disorders; Dose-Response Relationship, Drug; Fluoxetine; Ligands; Naltrexone; Pyrrolidines; Receptors, Opioid, kappa; Saimiri; Selective Serotonin Reuptake Inhibitors; Self Administration; Serotonin; Serotonin 5-HT1 Receptor Agonists

Kappa opioid agonists were at one time proposed as candidate pharmacotherapies for cocaine addiction, mainly because of their ability to decrease dopamine neurotransmission and attenuate the behavioral effects of cocaine in laboratory animals. Recent studies, however, suggest that kappa agonists also may mimic and/or enhance some of the effects of cocaine through mechanisms related to stress. The current study used a reinstatement procedure to examine the ability of the kappa agonists spiradoline and enadoline to reinstate extinguished cocaine seeking in squirrel monkeys previously trained to self-administer cocaine under a second-order schedule of i.v. drug injection. Opioid- and stress-related mechanisms were evaluated in antagonism studies with the opioid antagonists naltrexone and nor-binaltorphimine (nor-BNI), the corticotropin-releasing factor receptor antagonist butyl-ethyl-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo [2,3-d]pyrimidin-4-yl]amine (CP 154,526), and the alpha(2)-adrenoceptor agonist clonidine combined with either spiradoline or enadoline. When tested alone, priming with spiradoline and enadoline induced significant reinstatement of cocaine-seeking behavior to approximately 45% of the maximum reinstatement induced by cocaine. Reinstatement of cocaine seeking induced by intermediate doses of spiradoline was greater in the presence than in the absence of response-contingent presentations of a cocaine-paired stimulus. Spiradoline- and enadoline-induced reinstatement of drug seeking was attenuated by naltrexone but not by nor-BNI. Spiradoline-induced reinstatement of cocaine seeking was also antagonized by CP 154,526 and clonidine. The results point to interactions between a subpopulation of kappa opioid receptors and central corticotropin-releasing factor and noradrenergic stress systems in the reinstatement of cocaine seeking induced by kappa agonists.

Topics: Animals; Behavior, Addictive; Benzofurans; Clonidine; Cocaine-Related Disorders; Corticotropin-Releasing Hormone; Male; Naltrexone; Norepinephrine; Pyrrolidines; Receptors, Opioid; Receptors, Opioid, kappa; Saimiri; Self Administration; Stress, Psychological

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

Microdialysis was utilized to evaluate the effects of selective kappa-opioid receptor agonists on dopamine levels in the dorsal caudate of conscious rats. Subcutaneous administration of equivalent antinociceptive doses of spiradoline--(+/-)-(5 alpha, 7 alpha, 8 beta)-3, 4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4,5]dec-8-yl] benzeneacetamide--(U62066; 12 mg/kg), BRL 52656--(2S)-1-[(4- trifluoromethylphenyl)acetyl]-2-[(1-pyrrolidinyl)methyl]piperidine--(2 mg/kg) and enadoline--(-)-(5 beta, 7 beta, 8 alpha)-N-methyl-N-[7-(1- pyrrolidinyl)-1-oxaspiro[4,5]dec-8-yl]benzo[b]furan-4-acetamide-- (CI-977; 0.1 mg/kg) produced similar, statistically significant decreases in dorsal caudate dopamine levels; BRL 53001--(2S)-2- (dimethylaminomethyl)-1-[(5,6,7,8-tetrahydro-5-oxo-2-naphthyl)ace tyl] piperidine--(12 mg/kg) was, however, without effect. At a higher dose (36 mg/kgP, BRL 53001 also caused a significant reduction in dopamine levels. BRL 52974--4-(1-pyrrolidinylmethyl) 5-[(3,4-dichlorophenyl)acetyl]-4,5,6,7-tetrahydroimidazo[4,5-c] pyridine, a selective kappa-opioid receptor agonist with limited ability to cross the blood brain barrier or produce antinociceptive effects, had no effect on dopamine levels at 10 mg/kg s.c. Overall, these findings suggest that selective kappa-opioid receptor agonists decrease dopamine levels in the dorsal caudate of rats via a central locus of action. Furthermore, compared to other kappa-opioid receptor agonists, BRL 53001 appears to have a reduced propensity to decrease dopamine levels at equianalgesic doses.

Topics: Analgesics; Animals; Anti-Arrhythmia Agents; Benzofurans; Caudate Nucleus; Chromatography, High Pressure Liquid; Diuretics; Dopamine; Injections, Subcutaneous; Male; Microdialysis; Pyridines; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Structure-Activity Relationship

Effects of the kappa opioid agonists, spiradoline (U62,066), enadoline (CI-977) and U69,593, were examined alone and in combination with the opioid antagonists quadazocine and beta-funaltrexamine in squirrel monkeys that responded under a schedule of shock titration. When given alone, each of these agonists increased the intensity at which the monkeys maintained shock 50% of the time (median shock level, MSL). Lower doses of spiradoline, enadoline and U69,593 increased response rates in some monkeys and higher doses decreased response rates in all monkeys. When given in combination with the opioid antagonist quadazocine, the dose-effect curves of each agonist, both for MSL and response rates, were shifted to the right in a dose-related and parallel manner. The slopes for the regression lines of the Schild plots for each agonist-quadazocine interaction approximated unity and apparent pA2 values for quadazocine in combination with these agonists ranged between 6.68 and 6.81 for MSL and between 6.63 and 6.87 for response rate. The effects of these agonists were not changed by an 8.0 mg/kg dose of beta-funaltrexamine that markedly antagonized the effects of morphine. These results parallel those previously obtained with other kappa agonists, such as bremazocine and U50,488 and suggest that the antinociceptive effects of spiradoline, enadoline and U69,593 in the shock-titration procedure in squirrel monkeys relate to activity at non-mu, probably kappa, opioid receptors.

Topics: Analgesics; Animals; Azocines; Benzeneacetamides; Benzofurans; Dose-Response Relationship, Drug; Male; Morphine; Naltrexone; Narcotic Antagonists; Pyrrolidines; Receptors, Opioid, kappa; Saimiri