piperidines and bremazocine

Although participation of opioids in antinociception induced by cannabinoids has been documented, there is little information regarding the participation of cannabinoids in the antinociceptive mechanisms of opioids. The aim of the present study was to determine whether endocannabinoids could be involved in peripheral antinociception induced by activation of mu-, delta- and kappa-opioid receptors.. Nociceptive thresholds to mechanical stimulation of rat paws treated with intraplantar prostaglandin E2 (PGE2, 2 microg) to induce hyperalgesia were measured 3 h after injection using an algesimetric apparatus. Opioid agonists morphine (200 microg), (+)-4-[(alphaR)-alpha-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC80) (80 microg), bremazocine (50 microg); cannabinoid receptor antagonists N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251) (20-80 microg), 6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl(4-methoxyphenyl) methanone (AM630) (12.5-100 microg); and an inhibitor of methyl arachidonyl fluorophosphonate (MAFP) (1-4 microg) were also injected in the paw.. The CB1-selective cannabinoid receptor antagonist AM251 completely reversed the peripheral antinociception induced by morphine in a dose-dependent manner. In contrast, the CB2-selective cannabinoid receptor antagonist AM630 elicited partial antagonism of this effect. In addition, the administration of the fatty acid amide hydrolase inhibitor, MAFP, enhanced the antinociception induced by morphine. The cannabinoid receptor antagonists AM251 and AM630 did not modify the antinociceptive effect of SNC80 or bremazocine. The antagonists alone did not cause any hyperalgesic or antinociceptive effect.. Our results provide evidence for the involvement of endocannabinoids, in the peripheral antinociception induced by the mu-opioid receptor agonist morphine. The release of cannabinoids appears not to be involved in the peripheral antinociceptive effect induced by kappa- and delta-opioid receptor agonists.

Topics: Amidohydrolases; Analgesics, Opioid; Animals; Arachidonic Acids; Benzamides; Benzomorphans; Cannabinoid Receptor Modulators; Dinoprostone; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Inhibitors; Hyperalgesia; Indoles; Male; Morphine; Organophosphonates; Pain; Pain Measurement; Piperazines; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu

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

Topics: Animals; Benzomorphans; Binding, Competitive; Brain; Dynorphins; Female; Haloperidol; In Vitro Techniques; Mice; Morphinans; Peptide Fragments; Phencyclidine; Piperidines; Receptors, Opioid

In each of two components of a multiple schedule, patas monkeys were required to respond on a right or left lever depending upon the stimulus combination (a color and a geometric form) presented. Reinforcement of a response in the presence of one stimulus (the form) was conditional upon the other stimulus (the color). The completion of a two-member chain of discriminations produced a food pellet. Errors produced a brief timeout. One component of the multiple schedule was a repeated-acquisition task in which the discriminative stimuli for left- and right-lever responses changed each session (learning). In the other component, the discriminative stimuli were the same each session (performance). Dose-effect curves were determined for the kappa agonists bremazocine, tifluadom, ethylketocyclazocine and U50488H. Each drug produced dose-related decreases in overall response rate but had little or no effect on accuracy in either learning or performance. The rate-decreasing effects of ethylketocyclazocine and tifluadom were due to a dose-related pause at the start of the session, whereas those of bremazocine and U50488 were due largely to sporadic pausing throughout the session. Naltrexone blocked the effects of each drug whereas quaternary naltrexone had no effect. In contrast to the kappa agonists, dexoxadrol produced a dose-related disruption in accuracy of responding in learning. Dexoxadrol also decreased response rate in both acquisition and performance in a dose-related manner. Naltrexone attenuated the effects of low doses of dexoxadrol on accuracy, but failed to block the disruptive effects of higher doses.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Analgesics; Animals; Benzomorphans; Conditioning, Psychological; Cyclazocine; Dioxolanes; Dioxoles; Discrimination Learning; Dose-Response Relationship, Drug; Erythrocebus patas; Ethylketocyclazocine; Female; Macaca fascicularis; Male; Naltrexone; Piperidines; Receptors, Opioid; Receptors, Opioid, kappa

The effects of various opioid agonists and antagonists on urination were studied in the normally hydrated rat. Two kappa agonists, U-50,488H and proxorphan, markedly increased urination. The increased urination produced by U-50,488H was antagonized by opioid antagonists in a potency order which indicated that the effects were due to an action at kappa opioid receptors. Mu agonists decreased urination and were blocked by low doses (0.01 and 0.1 mg/kg) of naloxone, whereas kappa agonists increased urination and were only blocked by a high dose (10 mg/kg) of naloxone. The diuretic effects of U-50,488H and ketazocine, but not proxorphan and bremazocine, were reduced by morphine, consistent with the idea that proxorphan and bremazocine have morphine antagonist activity. Water deprivation produced a shift to the right for the dose-effect curve for bremazocine-induced diuresis. Kappa agonists were ineffective in increasing urination in Brattleboro rats that were homozygous for diabetes insipidus, whereas mu agonists were still effective in decreasing urination. The data are consistent with the hypothesis that kappa agonists inhibit release of vasopressin from the neurohypophysis and this decrease in vasopressin release leads to increased urination. The effects of opioids on urination in the normally hydrated rat can be extremely useful in classifying the activities of opioid on mu and kappa receptors in vivo.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Benzomorphans; Cyclazocine; Diuresis; Ethylketocyclazocine; Male; Morphinans; Naloxone; Narcotic Antagonists; Narcotics; Piperidines; Pyrrolidines; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, kappa; Receptors, Opioid, mu; Urination