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At least 685 records · Page 38Linked to original sources
PubMed1995

Effects of morphine and ketorolac on thermal allodynia induced by prostaglandin E2 and bradykinin in rhesus monkeys.

When administered s.c. in the tail, both prostaglandin E2 (PGE2; 1.58-158.0 micrograms) and bradykinin (BK; 0.01-1.0 microgram) produced a dose-dependent allodynia in a warm-water tail-withdrawal assay in rhesus monkeys. PGE2 (A50 = 5.3 +/- 0.15 microgram) was 143-fold less potent than BK (A50 = 0.037 +/- 0.012 microgram) in producing allodynia at 42 degrees C. However, PGE2 (15.8 micrograms) was longer acting than an equieffective dose of BK (0.1 microgram), and the highest dose of PGE2 (158.0 micrograms) was the only treatment to produce allodynia when 38 degrees C water was used as the thermal stimulus, suggesting that PGE2 was a more efficacious allodynic agent than BK. Morphine (0.1-3.2 mg/kg) administered s.c. in the back completely blocked the allodynic effects of both BK (0.1 microgram) and PGE2 (15.8 micrograms), although morphine was more than twice as potent against BK (A50 = 0.26 +/- 0.085 mg/kg) than against PGE2 (A50 = 0.65 +/- 0.14 mg/kg). The effects of morphine were antagonized by the opioid antagonist quadazocine (0.1 mg/kg), indicating that morphine's effects were mediated by opioid receptors. The nonsteroidal anti-inflammatory drug ketorolac (0.32-10.0 mg/kg) administered s.c. in the back completely blocked the allodynic effects of BK (A50 = 0.60 +/- 0.095 mg/kg) but did not alter allodynia induced by PGE2. The antiallodynic effects of ketorolac against BK were not antagonized by quadazocine (1.0 mg/kg), indicating that these effects were not mediated by mu or kappa opioid receptors. Furthermore, relative to morphine, ketorolac displayed a slower onset and a longer duration of action. These findings suggest that the allodynic effects of BK in this procedure were mediated entirely by cyclooxygenase products of arachidonic acid metabolism, such as PGE2.

Analgesics, Non-Narcotic↗
PubMed1995

Morphological changes in human erythrocytes induced in vitro by antiarrhythmic drugs.

Several hypotheses suggest that the molecular mechanism of action of class I antiarrhythmic drugs (AAD) involve non-specific interactions of these compounds with phospholipid bilayers of the myocardial membrane that surround and functionally modulate ion transport by sodium channels. As a result of these interactions the channel function would be altered. To probe the validity of these hypotheses three AAD with different degrees of lipophilicity were made to interact in vitro with human erythrocytes in a wide range of concentrations. The most lipophilic drug was asocainol (ASOC), the least one was procainamide (PROC) while the lipophilicity of the third, quinidine (QUIN), lay somewhere between the other two. The observations made by scanning electron microscopy (SEM) showed that the three AAD produced profound shape alterations to the incubated erythrocytes. However, the type and intensity of these changes were dependent on the drug under study and its concentration.

Anti-Arrhythmia Agents↗
PubMed1995

Characterization of [3H]ABT-418: a novel cholinergic channel ligand.

ABT-418 [(S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole] is a potent and selective agonist at neuronal nicotinic acetylcholine receptors (nAChRs) with cognitive enhancing and anxiolytic activities. [3H]ABT-418 was found to bind with high affinity (KD = 2.85 +/- 0.14 nM) to membranes prepared from rat brain. Binding of [3H]ABT-418 was characterized by rapid association (T1/2 = 1.4 +/- 0.3 min) and dissociation (T1/2 = 2.9 +/- 0.4 min) half-times. The pharmacology of [3H]ABT-418 binding was consistent with an interaction with the putative alpha 4 beta 2 nAChR subtype. The nAChR agonists, (-)-nicotine, (-)-cytisine and (+/-)-epibatidine, displayed a high affinity (Ki = 0.8 +/- 0.1, 0.2 +/- 0.1 and 0.05 +/- 0.01 nM, respectively) for [3H]ABT-418 binding sites, whereas among nAChR antagonists examined, only dihydro-beta-erythroidine competed with high affinity (Ki = 32 +/- 1.5 nM). Although autoradiography studies indicate that the binding distribution of [3H]ABT-418 and (-)-[3H]cytisine are largely identical, there are some brain regions including the striatum, olivary pretectal nucleus and the superior colliculus, in which [3H]ABT-418 demonstrates significantly (P < .05) less binding. The data in the present study demonstrate that [3H]ABT-418 binds with high affinity to a population of binding sites in the rat brain that have the pharmacological characteristics of neuronal nAChRs. [3H]ABT-418 may, therefore, serve as a useful radioligand to further probe the observed differences in pharmacological properties between ABT-418 and other nicotinic agonists in vivo.

Alkaloids↗
PubMed1995

Characterization of a series of anabaseine-derived compounds reveals that the 3-(4)-dimethylaminocinnamylidine derivative is a selective agonist at neuronal nicotinic alpha 7/125I-alpha-bungarotoxin receptor subtypes.

Investigation of the naturally occurring, nicotinic agonist anabaseine and novel derivatives has shown that these compounds have cytoprotective and memory-enhancing effects. The hypothesis that these arise at least in part through actions on brain nicotinic receptors was evaluated by examining the ability of these compounds to displace the binding of nicotinic ligands and to affect the function of the alpha 4 beta 2 and alpha 7 receptor subtypes expressed in Xenopus oocytes. The derivative 3-(4)-dimethylaminocinnamylidine anabaseine (DMAC) was found to be a selective alpha 7 receptor agonist; it was more potent than nicotine, acetylcholine, anabaseine, and other derivatives at activating the alpha 7 receptor subtype, while displaying little agonist activity at alpha 4 beta 2 and other receptor subtypes. Compared with anabaseine and the other derivatives, DMAC was the most potent at displacing 125I-alpha-bungarotoxin binding (putative alpha 7) and the least potent at displacing [3H]cytisine binding (putative alpha 4 beta 2) to brain membranes. Independently of agonist activities, all of the novel compounds displayed secondary inhibitory activity at both receptor subtypes. At the alpha 4 beta 2 receptor subtype, inhibition by the 3-(2,4)-dimethoxybenzylidene derivative was enhanced by coapplication of acetylcholine, suggesting a noncompetitive form of inhibition. Anabaseine and nicotine prolonged the time course of activation of alpha 4 beta 2 receptors, compared with acetylcholine, suggesting sequential channel-blocking activity. As selective agonists, anabaseine derivatives such as DMAC may be useful for elucidating the function of alpha 7 nicotinic receptors, including their potential role(s) in the cytoprotective and memory-enhancing effects of nicotinic agents.

Alkaloids↗
PubMed1993

Opioid thermal antinociception in rhesus monkeys: receptor mechanisms and temperature dependency.

The antinociceptive effects of the opioid agonists etonitazene and alfentanil, as well as the agonist/antagonists nalbuphine, [(1)-beta-2'-hydroxy-2,9-dimethyl-5-phenyl-6,7-benzomorphan (GPA 1657)] and profadol were studied in the warm water (48 degrees and 55 degrees C) tail-withdrawal assay in rhesus monkeys. Etonitazene and alfentanil produced dose-dependent increases in tail-withdrawal latency up to the maximum possible latency of 20 sec in 48 degrees and 55 degrees C water. Nalbuphine, GPA 1657 and profadol produced the maximum possible effect only at 48 degrees C, and were ineffective at 55 degrees C. The opioid antagonist quadazocine produced a dose-dependent antagonism of all agonists except profadol. In a Schild plot analysis, apparent pA2 values for quadazocine with alfentanil, etonitazene and nalbuphine were homogeneous (7.3-7.7 mol/kg), suggesting their effects were probably mediated by mu opioid receptors. The apparent pA2 value for GPA 1657 was significantly lower (6.2 mol/kg), suggesting GPA 1657 may have produced antinociception by a non mu receptor-mediated mechanism. The selective delta antagonist naltrindole (0.32-1.0 mg/kg) antagonized the antinociceptive effect of GPA 1657. The kappa-selective antagonist nor-binaltorphimine (nor-BNI, 3.2 mg/kg) caused a small rightward shift in the GPA 1657 dose-effect curve. Nalbuphine, GPA 1657 or profadol produced a rightward shift in the alfentanil dose-effect curve in 55 degrees C water, consistent with possible low-efficacy mu agonist effects of these compounds. These studies suggest agonists may be differentiated based on antinociceptive effectiveness, receptor selectivity and intrinsic efficacy in the rhesus monkey tail-withdrawal procedure.

Alfentanil↗
PubMedDate not supplied

[Results of clinical investigation of anti-nicotine drug patches].

The paper gives the results of clinical trials of antinicotinic therapeutical films containing anabasinum, cytisinum or their combination in equal ratios. They were used in 74 patients with chronic nicotinism. The level of the drug in a film was 1.5 gm. The mode of its application was to apply it to the gingiva beneath the upper lip. The biosoluble polymer carrier-based antinicotinic films are easy-to-use and rather effective in the control of smoking. The films produced effects in 75.8% of patients, including a full effect, i.e. a full refusal of smoking in 46.8%. The films in combination with cytisinum and anabasinum, or those with cytisinum alone was the most effective. There were no adverse reaction when the films were applied. The drug is well tolerated by patients with coronary heart disease, arterial hypertension, and diabetes mellitus.

Administration, Topical↗
PubMed1994

(+/-)-Epibatidine elicits a diversity of in vitro and in vivo effects mediated by nicotinic acetylcholine receptors.

(+/-)-Epibatidine, exo-2-(6-chloro-3-pyridyl)-7-azabicyclo-[2.2.1] heptane, is a novel, potent analgesic agent that acts through nicotinic acetylcholine receptor (nAChR) mechanisms. This study sought to establish whether (+/-)-epibatidine, like (-)-nicotine, also displays a wide diversity of behavioral responses that are known to be elicited by nAChR activation or whether it demonstrates subtype selectivity for its interactions with nAChRs.(+/-)-Epibatidine displaced [3H](-)-cytisine binding to the alpha 4 beta 2 nAChR subtype in rat brain membranes with high affinity (Ki, 43 pM). The compound was approximately 5000-fold less potent (Ki = 230nM) in the displacement of [125I] alpha-bungarotoxin binding from the alpha-bungarotoxin-sensitive nAChR subtype present in rat brain but was a potent inhibitor (Ki, 2.7 nM) of [125I] alpha-bungarotoxin binding to the nAChR subtype in Torpedo electroplax, which is similar to that present in the neuromuscular junction. Functionally, (+/-)-epibatidine enhanced 86Rb+ flux in IMR 32 cells with an EC50 value of 7 nM. It was some 3000-fold more potent than (-)-nicotine (EC50 value, 21,000 nM) and was approximately 150-fold more potent (EC50 value, 0.4 nM) than (-)-nicotine (EC50 value = 60 nM) in increasing [3H]dopamine release from rat striatal slices. Remarkably, (+/-)-epibatidine was 40% to 50% more efficacious than (-)-nicotine in both functional assays. Both functional effects were blocked by the nAChR channel blocker, mecamylamine (100 microM). (+/-)-Epibatidine was 300 to 1000 times more potent than (-)-nicotine in the reduction of body temperature and locomotor activity in mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Alkaloids↗
PubMed1994

Antinociceptive and response rate-altering effects of kappa opioid agonists, spiradoline, enadoline and U69,593, alone and in combination with opioid antagonists in squirrel monkeys.

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.

Analgesics↗
PubMed1994

Stimulatory pathways and sites of action of intrathecally administered nicotinic agents.

Intrathecal (i.t.) administration of nicotinic agonists to rats elicits a receptor-mediated pressor response, a heart rate increase and irritation-nociceptive behavior. We examined the stimulatory pathways and sites of action of spinally administered nicotinic agonists. The thoracic region appears more sensitive to nicotine-elicited pressor actions than the lumbar or cervical regions of the spinal cord. Nicotinic receptors evoking a nociceptive response appear to be located over an area extending from the lumbar rostrally to the thoracic region. Similar to the pressor response, the thoracic spinal cord is the most sensitive region to nicotine in producing the heart rate increase. The cervical region is the least responsive to nicotine, suggesting sites of actions caudal to the brain stem. Intravenous infusion of trimethaphan inhibited the nicotine-elicited pressor response and tachycardia without affecting the irritation response. This suggests that the cardiovascular responses to spinal nicotinic agonists result from enhanced sympathetic outflow. Intrathecal morphine and MK-801 block spinal nicotine-elicited irritation and tachycardia but not the pressor response, indicating that pressor and irritation responses involve independent receptor-mediated pathways. Tachycardia may be associated with the irritation response. In contrast to nicotine, both pressor and irritation responses to cytisine were blocked by morphine with no effect on heart rate. Spinal transection at the T1-2 level eliminated the nociceptive response to nicotine but not the pressor response. Cytisine responses were similar to nicotine; however, cytisine was significantly less potent as a pressor agent in the transected compared with intact animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Alkaloids↗
PubMed1994

Cardiovascular and behavioral responses to nicotinic agents administered intrathecally.

We have examined the role of the spinal nicotinic receptors in mediating cardiovascular and behavioral responses in conscious rats. Intrathecal administration of nicotinic agonists to the lumbosacral region of the spinal cord caused a dose-dependent increase in systolic blood pressure, heart rate and a nociceptive (behavioral) response. The order of potencies for the pressor response was l-nicotine > or = cytisine > N-methylcarbamylcholine > or = dimethylphenylpiperazinium > d-nicotine. However, cytisine was the most potent in producing the heart rate increase and nociceptive response. Unlike the other agonists, cytisine also exhibited marked desensitization of the three responses upon repeated administration. The effects of nicotine were antagonized in a dose-dependent fashion by mecamylamine, hexamethonium, alpha-lobeline, dihydro-beta-erythroidine and methyllycaconitine. By contrast, cytisine-induced responses were blocked effectively by mecamylamine and methyllycaconitine, but not by alpha-lobeline or dihydro-beta-erythroidine. However, when alpha-lobeline or dihydro-beta-erythroidine antagonism of the pressor response to cytisine was monitored during the initial minute following intrathecal administration, both antagonists significantly inhibited the response. The competitive ganglionic blocker, trimethaphan, or the elapid alpha-toxin, alpha-bungarotoxin, when administered intrathecally, had no effect on nicotine- or cytisine-elicited responses. The cardiovascular responses to intrathecal nicotine and cytisine have two components. The first is likely mediated through direct sympathetic output and desensitizes rapidly to cytisine, the second is coupled indirectly to the nociceptive response and shows a diminished capacity for rapid desensitization. Agonist and antagonist specificities indicate that the spinal nicotinic receptor differs from those in ganglia and those characterized in brain to date. Although antagonist specificity of the blockade of nicotine and cytisine elicited responses differ, this may be due to the unique desensitization capacity of cytisine rather than an action mediated by distinct receptor subtypes.

Aconitine↗
PubMed1994

Ligand specificity of nicotinic acetylcholine receptors in rat spinal cord: studies with nicotine and cytisine.

Administration of nicotinic agonists to the spinal cord leads to a variety of cardiovascular and behavioral responses. The discrete localization of afferent and efferent fibers presents a system in which occupation of nicotinic receptor subtypes might be correlated with specific pharmacologic responses. To this end, we examined [3H]cytisine and [3H]nicotine binding to membranes isolated from regions of the rat spinal cord. [3H]Cytisine showed saturable, noncooperative (nH congruent to 1) binding to a single-class of sites with a Kd of 0.44 +/- 0.01 nM and total saturable sites of 19.9 +/- 0.9 fmol/mg of protein. [3H]Cytisine binding to membranes from intermediolateral cell column and dorsal and ventral sections of the lumbosacral regions each revealed a single class of binding sites with virtually identical Kd values. However, the dorsal sections of the lumbar spinal cord contained a higher number of total binding sites than ventral lumbar or intermediolateral sections. The rank order potencies of the nicotinic agonists competing for [3H]cytisine binding was cytisine > I-nicotine > N-methylcarbamylcholine > dimethylphenylpiperazinium > acetylcholine > d-nicotine > carbamylcholine. Competitive antagonists also competed with high affinities (Ki as low as nanomolar) with the order of potencies being alpha-lobeline > or = dihydro-beta-erythroidine >> methyllycaconitine, whereas the channel blockers, mecamylamine and hexamethonium, only competed at concentrations > or = 100 microM. Competitive ganglionic blockers such as d-tubocurarine or trimethaphan and neurotoxins such as alpha-bungarotoxin, alpha-cobratoxin or neuronal bungarotoxin had weak affinities for cytisine sites. Similar to [3H]cytisine, [3H]nicotine also revealed a saturable single class of binding sites, but of lower affinity. The rank order of Ki values of the agonists, antagonists and neurotoxins for competing with [3H]nicotine binding was similar to the order for [3H]cytisine. Nicotinic receptors in the spinal cord membrane show a specificity for both agonists and antagonists that differ from neuronal receptors in the ganglia or the regions of the brain characterized to date. These findings, when correlated with the pharmacological responses documented in the comparison article suggests that the spinal nicotinic receptors may define a new member of the neuronal nicotinic receptor family.

Alkaloids↗
PubMed1993

Apparent pA2 analysis on the respiratory depressant effects of alfentanil, etonitazene, ethylketocyclazocine (EKC) and Mr2033 in rhesus monkeys.

Respiratory depression is a limiting factor in the therapeutic use of opioid analgesics. It has been suggested that respiratory depression is mediated by mu rather than kappa receptors and may involve a decrease in central nervous system sensitivity to hypercapnia. This study investigated opioid receptor mechanisms underlying respiratory depression in unanesthetized rhesus monkeys (n = 3) breathing air or 5% CO2 in air into a pressure displacement head plethysmograph. Apparent pA2 analyses of s.c. quadazocine (a mu-selective antagonist) were carried out on the effects of cumulative doses of s.c. bremazocine, ethylketocyclazocine (EKC) and (+/-)-(1-R/S,5-R/S,2 = R/S)-5,9-dimethyl-2'-hydroxy-2- tetrahydrofurfuryl-6,7-benzomorphan (Mr2033) (compounds with kappa agonist effects in other in vivo assays), alfentanil and etonitazene (compounds with mu agonist effects in other in vivo assays). Alfentanil, bremazocine, EKC and Mr2033 were approximately equipotent in causing dose-dependent depression of respiratory minute volume of CO2-stimulated and air respiration, whereas etonitazene was approximately 10-fold more potent than the above compounds. Dose-effect curves for respiratory frequency, tidal volume and respiratory minute volume for all of the agonists except bremazocine were shifted to the right by increasing quadazocine doses. Together with data previously obtained in drug discrimination and analgesia assays, results of the present study demonstrating homogeneous pA2 values for quadazocine with alfentanil, etonitazene, EKC and Mr2033 strongly suggest that the latter two compounds decrease respiratory function in rhesus monkeys by acting on mu receptors.

Alfentanil↗
PubMed1993

Effects of clonidine, dexmedetomidine and xylazine on thermal antinociception in rhesus monkeys.

The antinociceptive effects of the s.c. administration of the alpha-2 agonists clonidine (0.0032-1.0 mg/kg), dexmedetomidine (0.001-0.032 mg/kg) and xylazine (0.1-3.2 mg/kg) were examined in the warm-water tail withdrawal assay in rhesus monkeys. The three agonists were dose-dependently effective in this assay; their potency order being dexmedetomidine > clonidine > xylazine. The alpha-2 antagonist idazoxan (0.1-3.2 mg/kg) caused dose-dependent and roughly parallel rightward shifts in the dose-effect curves for the three agonists. Apparent pA2 analysis with idazoxan yielded homogeneous values for the three agonists, supporting the notion that similar receptors mediate their antinociceptive effects. The opioid antagonist quadazocine (1.0 mg/kg) did not antagonize the antinociceptive effects of clonidine and xylazine, indicating that opioid receptors do not participate in the effects of the compounds in this assay. At dose ranges found to be effective in the antinociceptive assay, clonidine, dexmedetomidine and xylazine also dose-dependently caused sedation, muscle relaxation, bradycardia and moderate respiratory depression. The sedative, muscle relaxant and respiratory depressant effects of xylazine could be antagonized by idazoxan, suggesting that these effects may be mediated through alpha-2 receptors. These data indicate that the three imidazoline alpha-2 agonists, clonidine, dexmedetomidine and xylazine are effective s.c. in the warm-water tail withdrawal assay in rhesus monkeys, but only at doses that produce other behavioral and physiological effects.

Adrenergic alpha-Agonists↗
PubMed1993

Area tempestas modulates the behavioural responses to nociceptive stimuli in rats.

The antinociception of opiates is mediated through the activation of opioid receptors in several mid brain and brain stem areas. This paper reports that the forebrain area termed area tempestas (AT), first identified as a convulsant trigger area, is also a component of the endogenous pain suppression system. Unilateral AT application of DAMGO, morphine and U-50,488H in rats at doses in the nanogram range produced marked and dose-dependent increases in the latency to respond to nociceptive stimuli. A lower effect is found after application of DPDPE and DADLE. Antinociception is more evident in the hot plate than in the tail flick test. In the former test, the effect was restricted to the paws contralateral to the hemisphere of injection. Unilateral AT application of naltrexone (4 ng) reduced in the contralateral paws the antinociceptive effect that the bilateral AT application of morphine (20 ng/hemisphere) had induced in both body sides. Unilateral application of naltrexone, (20 ng) ICI 154, 129 (20 ng) and Win 44,441-3 (8 ng) antagonized the antinociceptive effect elicited by the systemic injection of morphine (2.5 mg/kg s), DPDPE (20 mg/kg s) and U-50,488H (20 mg/kg s), respectively. In the hot plate test, the antagonism was found in the paws ipsilateral and contralateral to the hemisphere of injection of the antagonists.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1993

Nicotinic agonists modulate basal forebrain control of cortical cerebral blood flow in anesthetized rats.

Previous studies have indicated that electrical microstimulation of the cholinergic (basal forebrain, BF) elicits profound increases in cortical cerebral blood flow (CBF) that are selectively attenuated by nicotinic receptor antagonists. This study sought to determine whether nicotinic receptor agonists such as (-)-nicotine, and related agents, can enhance the increases in CBF elicited by electrical stimulation of the BF of urethane-anesthetized rats. The magnitude of cortical CBF responses, measured by laser-Doppler flowmetry, increased progressively with higher frequencies (range = 6.25-50 Hz) to a maximum of 248% of control. (-)-Nicotine and (-)-lobeline each further enhanced the responses to BF stimulation, with (-)-nicotine having the most potent effect (up to 350%). (+)-Nicotine and (-)-cotinine were without effect, suggesting stereoselectivity and that the effects were not mediated by the major metabolite of (-)-nicotine. In contrast, (-)-cystisine, another nicotinic receptor agonist, modestly inhibited the BF-elicited increase in CBF suggesting nicotinic receptor subtype selectivity in mediating the response. Arecoline, a potent muscarinic agonist, was without effect suggesting that muscarinic mechanisms are not involved in the mediation of this response. None of the nicotinic agents had overt effects on heart rate or blood pressure in the dose ranges examined. In experiments targeting the site of action of the nicotinically mediated enhancement, (-)-nicotine microinjections into the BF elicited profound increases in cortical CBF, whereas similar injections into the cerebral cortex were without effect suggesting that nicotine receptors mediating CBF increases are localized to the BF.(ABSTRACT TRUNCATED AT 250 WORDS)

Alkaloids↗
PubMed1993

Effects of opioid agonists selective for mu, kappa and delta opioid receptors on schedule-controlled responding in rhesus monkeys: antagonism by quadazocine.

Rhesus monkeys were trained to respond under a fixed-ratio 30 schedule of food reinforcement. The mu opioid agonists alfentanil and fentanyl, the kappa opioid agonists ethylketocyclazocine (EKC) and U69,593, the delta opioid agonist BW373U86 [(+-)-4-((R*)-a-((2S*5R*)-4-allyl-2,5-dimethyl-1-piperazinal)-3-h ydroxy- benzyl)-N,N-diethylbenzamide dihydrochloride] and the nonopioid, noncompetitive N-methyl-D-aspartate antagonist ketamine all produced a dose-dependent decrease in rates of responding. Quadazocine (0.1-10 mg/kg) antagonized the rate-decreasing effects of all the opioid agonists, but not of ketamine. The in vivo apparent pA2 values (95% CL) for quadazocine in combination with each agonist were: alfentanil, 7.7 (7.6-7.8); fentanyl, 7.7 (7.6-7.8); EKC, 6.3 (5.9-6.7); U69,593, 6.5 (5.9-7.0); and BW373U86, 5.5 (5.3-5.8). Additionally, antagonist effects of individual doses of quadazocine in combination with each agonist were evaluated by using in vivo apparent pKB analysis, and pKB values were found to be similar to the more rigorously determined pA2 values. The relative pA2 and pKB values of quadazocine in antagonizing the rate-decreasing effects of mu, kappa and delta opioid agonists corresponded to the relative potency of quadazocine in displacing the specific binding of the mu agonist [3H]Tyr-D-Ala-Gly-(Me)-Phe-Gly-ol (IC50 = 0.080 nM), the kappa agonist [3H]U69,593 (IC50 = 0.52 nM) and the delta agonist [D-Pen2,D-Pen5]-[3H]enkephalin (IC50 = 4.6 nM) from binding sites in membranes from monkey brain cortex.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1994

Partial agonist properties of cytisine on neuronal nicotinic receptors containing the beta 2 subunit.

As previously reported by Luetje and Patrick [J. Neurosci. 11:837-845 (1991)], the nicotine-like alkaloid cytisine is relatively ineffective in evoking current responses from nicotinic receptors containing the beta 2 subunit. In our experiments, the responses of alpha 4 beta 2- and alpha 3 beta 2-injected oocytes to the application of 1 mM cytisine were only 14.7 +/- 4% and 2.5 +/- 0.8% of the responses to 1 mM acetylcholine (ACh), respectively. Concentration-response relationships for ACh were examined in the presence and absence of cytisine. Although cytisine was relatively ineffective in stimulating current, the coapplication of cytisine and ACh reduced the responses to ACh. For alpha 4 beta 2 receptors, 3 microM cytisine shifted the dose-response curve for ACh to the right, resulting in a 60-fold increase in the apparent EC50 for ACh. For alpha 3 beta 2 receptors, 30 microM cytisine shifted the apparent EC50 for ACh from approximately 150 microM to 1 mM. Although the efficacy of cytisine for alpha 3 beta 2 receptors was very low, cytisine could effectively inhibit the responses of these receptors, with an IC50 of approximately 10 microM. The efficacy of cytisine for alpha 4 beta 2 receptors was greater than that for alpha 3 beta 2 receptors, and it was possible to evaluate the partial agonist properties of cytisine for these receptors. Although the EC50 of cytisine for stimulating current through alpha 4 beta 2 receptors was about 1 microM, concentrations of cytisine as low as 20 nM were able to inhibit 50% of the response to 1 microM ACh. The inhibitory effects of cytisine were reversible over a period of 5 min. Our analysis suggests that cytisine is a true partial agonist for beta 2-containing ACh receptors and as such can inhibit the response of these receptors to ACh through a competitive mechanism. In the case of alpha 4 beta 2 receptors cytisine binds with high apparent affinity and low efficacy to a site shared with ACh, and for alpha 3 beta 2 receptors both the apparent affinity and efficacy of cytisine are relatively low.

Acetylcholine↗
PubMed1993

Prostaglandin E2-induced thermal hyperalgesia and its reversal by morphine in the warm-water tail-withdrawal procedure in rhesus monkeys.

Four monkeys were seated in primate restraint chairs and the terminal 10 cm of their shaved tails were dipped into water maintained at a series of temperatures ranging from 38-54 degrees C. The latency to tail withdrawal from several temperatures was measured and temperature-effect curves for each monkey were generated. When administered s.c. into the tail, prostaglandin E2 (PGE2; 0, 1.58, 5.0 and 15.8 micrograms) produced a dose-dependent hyperalgesia manifested as dose-dependent leftward shifts in the temperature-effect curves. This hyperalgesia peaked 15 to 45 min after administration and lasted for approximately 2 hr. PGE2-induced hyperalgesia was mediated locally, because administration of 15.8 micrograms of PGE2 into the back had no effect on the temperature-effect curve. The hyperalgesic effects of PGE2 were reversed potently by morphine (0.32-3.2 mg/kg), and the effects of morphine were antagonized in a surmountable manner by both the opioid antagonist quadazocine (0.1 mg/kg) and by systemic administration of the charged opioid antagonist quaternary naltrexone (3.2 mg/kg). These results indicate that PGE2 produces thermal hyperalgesia in rhesus monkeys and also suggests that this hyperalgesia may be reversed by activation of peripheral opioid receptors. PGE2-induced hyperalgesia in the warm-water tail-withdrawal procedure may provide a useful assay for evaluating the effects of pharmacological and nonpharmacological treatments on hyperalgesia associated with inflammation in primates.

Animals↗