Activation of peripheral kappa opioid receptors inhibits capsaicin-induced thermal nociception in rhesus monkeys. (1/143)

8-Methyl-N-vanillyl-6-nonenamide (capsaicin) was locally applied in the tail of rhesus monkeys to evoke a nociceptive response, thermal allodynia, which was manifested as reduced tail-withdrawal latencies in normally innocuous 46 degrees C water. Coadministration of three kappa opioid ligands, U50,488 (3.2-100 microgram), bremazocine (0.1-3.2 microgram), and dynorphin A(1-13) (3.2-100 microgram), with capsaicin in the tail dose-dependently inhibited capsaicin-induced allodynia. This local antinociception was antagonized by a small dose of an opioid antagonist, quadazocine; (0.32 mg), applied in the tail; however, this dose of quadazocine injected s.c. in the back did not antagonize local U50,488. Comparing the relative potency of either agonist or antagonist after local and systemic administration confirmed that the site of action of locally applied kappa opioid agonists is in the tail. In addition, local nor-binaltorphimine (0.32 mg) and oxilorphan (0.1-10 microgram) antagonist studies raised the possibility of kappa opioid receptor subtypes in the periphery, which indicated that U50,488 produced local antinociception by acting on kappa1 receptors, but bremazocine acted probably on non-kappa1 receptors. These results provide functional evidence that activation of peripheral kappa opioid receptors can diminish capsaicin-induced allodynia in primates. This experimental pain model is a useful tool for evaluating peripherally antinociceptive actions of kappa agonists without central side effects and suggests new approaches for opioid pain management.  (+info)

Effects of nicotinic receptor agonists on beta-amyloid beta-sheet formation. (2/143)

Previously we demonstrated that nicotinic acetylcholine receptor stimulation protects neurons against beta-amyloid (Abeta)-induced cytotoxicity. In the present study, the effects of nicotinic receptor agonists on the beta-sheet formation were investigated using a thioflavin T (ThT)-based fluorescence assay. Nicotine, cytisine (an alpha4beta2 agonist), and 3-(2,4)-dimethoxybenzylidene anabaseine (DMXB, an alpha7 agonist) did not reduce fluorescence intensity when these agents were added to the beta-sheet-formed Abeta. Simultaneous incubation of Abeta with nicotinic agonists also did not cause a reduction in fluorescence intensity. This data suggests that nicotinic receptor agonists do not influence the formation of the beta-sheet structure.  (+info)

Increased nicotinic receptors in brains from smokers: membrane binding and autoradiography studies. (3/143)

Chronic administration of nicotine increases the density of neuronal cholinergic nicotinic receptors in cells and in rodent brain, and similar increases have been reported in brains from human smokers. To further examine this phenomenon, we measured nicotinic receptor binding sites in brain regions from matched populations of smokers and nonsmokers. We first measured binding of [3H](+/-)epibatidine ([3H]EB) and [3H]cytisine in homogenate preparations from samples of prefrontal and temporal cerebral cortex. Binding of each radioligand was significantly higher (250-300%) in both cortical regions from brains of smokers. Frozen sections from each of the cerebral cortical regions and the hippocampus were used for autoradiographic analysis of [3H]EB binding. In cerebral cortex, binding was most dense in layer VI in the prefrontal cortex and layers IV and VI in the temporal cortex. Densitometric analysis of [3H]EB binding sites revealed marked increases of 300 to 400% of control in all cortical regions examined from smokers' brains. Binding in the hippocampal formation was heterogeneously distributed, with dense areas of binding sites seen in the parasubiculum, subiculum, and molecular layer of the dentate gyrus, and the lacunosum-moleculare layer of the CA1/2. Binding of [3H]EB was significantly higher in all six regions of the hippocampus examined from brains of smokers compared with nonsmokers. These increases ranged from 160% of control in parasubiculum to 290% in the molecular layer of the dentate gyrus. The increase in nicotinic receptors in the cerebral cortex and hippocampus of smokers may modify the central nervous system effects of nicotine and contribute to an altered response of smokers to nicotine.  (+info)

kappa-Opioid receptor effects of butorphanol in rhesus monkeys. (4/143)

Butorphanol and nalbuphine have substantial affinity for mu and kappa-opioid receptor sites, yet their behavioral effects in monkeys are largely consistent with a mu receptor mechanism of action. Using ethylketocyclazocine (EKC) discrimination and diuresis assays in rhesus monkeys (Macaca mulatta), the purpose of the current investigation was to characterize the in vivo kappa-opioid activity of these compounds through the use of an insurmountable mu-opioid receptor antagonist, clocinnamox. Alone, butorphanol (0.001-0.032 mg/kg i.m.) failed to generalize to EKC, and pretreatment with the competitive opioid receptor antagonist quadazocine (0.1 or 0.32 mg/kg i.m.) did not alter this generalization. At 24 h after clocinnamox (0.1 mg/kg i.m.) administration, butorphanol fully generalized to EKC, and this generalization was maintained in two of three monkeys at 72 h. Parallel results were observed in diuresis: butorphanol alone and in the presence of quadazocine (1 mg/kg i.m.) did not alter urine output, and a marked diuretic effect was demonstrated 24 h to 2 weeks after clocinnamox administration. Clocinnamox did not alter the discriminative stimulus or diuretic effects of nalbuphine or of the kappa-opioid receptor agonists EKC or U69593. These results are consistent with an in vivo agonist activity of butorphanol at kappa-opioid receptors that can only be demonstrated when an insurmountable antagonist has substantially eliminated the dominant receptor population through which it exerts its action.  (+info)

Effects of systemically administered dynorphin A(1-17) in rhesus monkeys. (5/143)

The effects of i.v. dynorphin A(1-17) and its main nonopioid biotransformation fragment, dynorphin A(2-17), were compared in rhesus monkeys with those of the selective kappa-opioid agonist, U69, 593, in assays of operant behavior, thermal antinociception, and neuroendocrine function (prolactin release). Dynorphin A(1-17) (0. 1-3.2 mg/kg i.v.) and U69,593 (0.001-0.032 mg/kg s.c.) decreased rates of schedule-controlled (fixed ratio 20) food-reinforced responding, whereas dynorphin A(2-17) (1-3.2 mg/kg i.v.) was ineffective. Pretreatment studies with the opioid antagonist quadazocine (0.32 mg/kg s.c.) revealed that the operant effects of dynorphin A(1-17) were not mediated by kappa- or micro-opioid receptors. A different profile was observed in the warm water tail withdrawal assay of thermal antinociception, where both dynorphin A(1-17) and A(2-17) (0.032-3.2 mg/kg i.v., n = 4) were modestly effective in 50 degrees C water, and both were ineffective in 55 degrees C water. By comparison, U69,593 (0.032-0.18 mg/kg s.c.) was maximally effective in 50 degrees C water and partially effective in 55 degrees C. kappa-opioid agonists increase serum levels of prolactin in animals and humans. Dynorphin A(1-17) (ED(50) = 0.0011 mg/kg i.v.), similar to U69,593 (ED(50) = 0.0030 mg/kg i.v.), was very potent in increasing serum prolactin levels in follicular phase female rhesus monkeys, whereas dynorphin A(2-17) (0.32 mg/kg i.v.) was ineffective. The effects of dynorphin A(1-17) and U69,593 on serum prolactin were both antagonized by quadazocine (0.32 mg/kg s.c.) in a surmountable manner, consistent with opioid receptor mediation. The present studies show that serum prolactin levels are a sensitive quantitative endpoint to study the systemic effects of the endogenous opioid peptide, dynorphin A(1-17), in primates.  (+info)

Discriminative stimulus effects of the nonpeptidic delta-opioid agonist SNC80 in rhesus monkeys. (6/143)

Five rhesus monkeys were trained to discriminate the nonpeptidic, delta-opioid agonist SNC80 (0.32 mg/kg i.m.) from saline by using a food-reinforced drug-discrimination procedure. Cumulative doses of SNC80 produced a dose-dependent increase in SNC80-appropriate responding and a dose-dependent decrease in response rate. In time-course studies, peak effects of the training dose of SNC80 were observed after 15 min, and these effects diminished over 240 min. In substitution studies, other piperazinyl benzamide delta agonists (SNC86, SNC162, and SNC243A) substituted for SNC80 with relative potencies similar those of SNC80. However, SNC67, the (-)-enantiomer of SNC80, did not occasion SNC80-appropriate responding up to a dose (32.0 mg/kg) that produced convulsions in one monkey. The mu agonists morphine and fentanyl and the kappa agonists U-50,488 and enadoline failed to substitute for SNC80 up to doses that eliminated responding. Two nonopioids (the N-methyl-D-aspartate antagonist ketamine and the monoamine reuptake inhibitor cocaine) also produced primarily saline-appropriate responding. Both the discriminative stimulus and rate-decreasing effects of SNC80 were antagonized by the delta-selective antagonist naltrindole (0.01-1.0 mg/kg) but not by doses of the opioid antagonist quadazocine (0.1-1.0 mg/kg) that block the effects of mu and kappa agonists. These data suggest that the discriminative stimulus effects of SNC80 are mediated by delta-opioid receptors and that the discriminative stimulus effects of delta opioids in primates can be differentiated from the effects of other opioid and nonopioid compounds.  (+info)

Effects of flupenthixol and quadazocine on self-administration of speedball combinations of cocaine and heroin by rhesus monkeys. (7/143)

The simultaneous i.v. administration of heroin and cocaine, called "speedball," is often reported clinically, and identification of effective pharmacotherapies for polydrug abuse is a continuing challenge. This study compared the effects of treatment using combinations of dopamine and opioid antagonists with each antagonist alone on speedball self-administration by rhesus monkeys. Speedballs (0.01 mg/kg/inj cocaine and 0.0032 mg/kg/inj heroin) and food (1 g banana pellets) were available in four daily sessions on a second-order schedule of reinforcement [FR4 (VR16:S)]. Monkeys were treated for 10 days with saline or ascending 1:10 dose combinations of the dopamine antagonist flupenthixol and the opioid antagonist quadazocine. The combination of flupenthixol (0.018 mg/kg/day) + quadazocine (0.18 mg/kg/day) significantly reduced speedball self-administration in comparison to the saline treatment baseline (p < .05), whereas, the same doses of each antagonist alone had no significant effect on speedball-maintained responding. Treatment with 0.018 mg/kg/day flupenthixol + 0.18 mg/kg/day quadazocine produced a 3-fold rightward shift in the speedball (3:1 cocaine-heroin combination) dose-effect curve. Food-maintained responding was similar during treatment with saline and with flupenthixol + quadazocine combinations. These findings suggest that medication mixtures designed to target both the stimulant and opioid component of the speedball combination, may be an effective approach to polydrug abuse treatment.  (+info)

Diversity and distribution of nicotinic acetylcholine receptors in the locus ceruleus neurons. (8/143)

The neurons of the locus ceruleus are responsible for most of the noradrenergic innervation in the brain and nicotine potentiates noradrenaline release from their terminals. Here we investigated the diversity and subcellular distribution of nicotinic acetylcholine receptors (nAChRs) in the locus ceruleus both somatically, by combining single-cell reverse transcription-PCR with electrophysiological characterization, and at the level of nerve terminals, by conducting noradrenaline efflux experiments. The proportion of neurons in the locus ceruleus expressing the nicotinic subunit mRNAs varied from 100% (beta2) to 3% (alpha2). Yet, two populations of neurons could be distinguished on the basis of the pattern of expression of nAChR mRNAs and electrophysiological properties. One population (type A) of small cells systematically expressed alpha3 and beta4 mRNAs (and often alpha6, beta3, alpha5, alpha4), and nicotinic agonists elicited large currents with a potency order of cytisine > nicotine. Another population (type B) of cells with large soma did not contain alpha3 and beta4 mRNAs but, systematically, alpha6 and beta3 (and often alpha4) and responded to nicotinic agonists in the order of nicotine > cytisine. The nicotinic modulation of noradrenaline release in the hippocampus displayed an order of potency nicotine > cytisine, suggesting that noradrenergic terminals in the hippocampus originate largely from type B cells of the locus ceruleus. Accordingly, immunocytochemical labeling showed that beta3 is present in hippocampal terminals. The alpha6beta3beta2(alpha4) heterooligomer thus behaves as the main nicotinic regulator of the ceruleo-hippocampal pathway.  (+info)

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