Central effects of opioid agonists and naloxone on blood pressure and heart rate in normotensive and hypertensive rats

• 1.1. The central cardiovascular effects of several opioid receptor selective agonists and the nonselective opioid antagonist, naloxone, were studied in anesthetized normotensive control rats, in spontaneously hypertensive rats (SHR), and in foot-shock-stressed rats.
• 2.2. Receptor-selective agonists injected into the rostral ventrolateral medulla (RVLM), paraventricular nucleus (PVN), and dorsal hippocampus (dHip) were DAGO (μ), DADLE (δ), and U50, 488H (κ).
• 3.3. DAGO and DADLE (3 nM) decreased arterial pressure and heart rate in RVLM and PVN of all rat strains, while U-50,488H (9 nM) had only minimal effects in these areas.
• 4.4. In dHip, only DADLE (3 nM) had depressor and bradycardic effects, and then, only in SHR, with DAGO and U50,488H being ineffective in any strain, even at 9 nM.
• 5.5. Prior injection of naloxone (10 nM) into the RVLM, PVN and dHip blocked and postinjection reversed the cardiovascular effects of the agonists. Naloxone alone increased blood pressure and heart rate in all three areas, in all rat strains except SHR, suggesting a tonic depressor effect of endogenous opioids.
• 6.6. Lack of significant quantitative differences in opioid agonist and antagonist effects between normotensive and hypertensive or stressed rats argues against a role for endogenous brain opioids in experimental hypertension.

     

Different influences of adenosine receptor agonists and antagonists on morphine antinociception in mice

• 1.1. Subcutaneous (s.c.) administration of morphine to mice induced a dose-dependent antinociception.
• 2.2. Pretreatment of animals with adenosine receptor antagonists NECA (5′-N-ethylcarboxamidermadenosine) and l-PIA (N⁶-phenylisopropyladenosine) potentiated, while adenosine agonist CHA (N⁶-cyclohexyladenosine) decreased the morphine response.
• 3.3. Adenosine antagonist theophylline decreased, but adenosine receptor antagonist 8-PT (8-phenyltheophylline) increased the antinociception effect of morphine. Inhibitory effect of CHA on morphine antinociception was also reversed by 8-PT pretreatment.
• 4.4. NECA or l-PIA induced a high degree of antinociceptive effect in animals pretreated with 8-PT.
• 5.5. Dipyridamole pretreatment did not alter the effect of morphine.
• 6.6. It is concluded that A-1 and/or A-2 adenosine receptors are involved in morphine antinociception and the adenosine mechanism(s) may exert a modulatory role in this respect.

     

Possible opioid receptor function changes in isolated atria of the spontaneously hypertensive rat

• 1.1. A comparison of the effects of various opioid peptides on the heart rates of self-paced right atria was made, as taken from spontaneously hypertensive (SHR), Wistar Kyoto (WKY) and Sprague-Dawley (SD) rats at 4, 8, 12 and 16 weeks of age.
• 2.2. Beta-endorphin, dynorphin, met-enkephalin, DAGO and DADLE slightly decreased the spontaneously beating rate of all rat strains and ages, at 0.1 μM. Leu-enkephalin at 0.2 μM increased the spontaneous beating rate of SHR atria, but not that of atria from normotensive strains.
• 3.3. SHR atria were somewhat more sensitive than WKY atria to norepinephrine (NE)-induced positive chronotropy, but the differences were not statistically significant.
• 4.4. In the presence of mu, delta or kappa opioid receptor agonists, SHR atrial sensitivity to NE-induced chronotropy was enhanced at all ages studied. By contrast, NE chronotropy was not significantly altered by the opioids in normotensive rat atria.
• 5.5. Based on the above results, all the three major opioid receptor subtypes (mu, delta and kappa) appear to be present in rat atria but the function of these receptors appears to be greater in SHR than in WKY and SD atria.
• 6.6. The results suggest a possible involvement of altered opioid responsiveness in atria during hypertension development in SHR but the nature of this involvement appears to be complex and is not readily understandable on the basis of the present study.

     

The CCKA receptor antagonist devazepide inhibits the effect of apomorphine on vasopressin release in pigs

• 1.1. A transient increase in plasma vasopressin concentrations represents a physiological correlate of nausea in animals that vomit.
• 2.2. The CCK_A receptor antagonist devazepide has previously been shown to inhibit vasopressin release induced in pigs by intravenous (i.v.) CCK.
• 3.3. This study investigated whether devazepide (70 μg/kg i.v.) would affect vasopressin secretion induced in pigs (n = 6) by the emetic drug apomorphine (25 μg/kg i.v.).
• 4.4. Apomorphine stimulated vasopressin release in the 30 min period following injection; this effect was prevented by prior administration of devazepide.
• 5.5. The results suggest that CCK_A receptor antagonists may have the ability to prevent nausea and/or emesis.

     

Pre- and postjunctional muscarinic receptor subtypes in the vas deferens of rat

• 1.1. A pharmacological study of the pre- and postjunctional muscarinic receptors of the isolated rat vas deferens was carried out using more selective agonists and antagonists.
• 2.2. The prejunctional receptor was characterized on electrically stimulated preparations, while the postjunctional receptor was studied on vasa deferentia without stimulation.
• 3.3. The results indicate that atropine exhibited a similar affinity for the two populations of muscarinic receptor subtypes of this tissue.
• 4.4. 4-DAMP was able to differentiate with high affinity a subtype located at postjunctional level which had pharmacological similarities with the M₃-ACh subtype and with low affinity a subtype located at prejunctional level.
• 5.5. The selective M₁-ACh agonist McN-A-343 was not able to activate the postjunctional receptor, but showed a similar affinity to ACh for the prejunctional one.
• 6.6. At present, the prejunctional receptor can be considered as an atypical M₁-ACh subtype based on the results obtained with the selective drugs available.

     

Lowering temperature increases cardiac muscarinic receptor site affinity towards agonists and antagonists

• 1.1. The effect of temperature on the binding of agonists and antagonists to cardiac muscarinic receptor sites was investigated.
• 2.2. Compared to 37°C, carbachol-[³H]QNB and atropine-[³H]QNB competition curves were shifted to the left at lower temperatures. This was also observed with other agonists and antagonists.
• 3.3. Such an effect of temperature persisted in the N-ethylmaleimide (NEM)- and dithiothreitol (DTT)-treated membranes.
• 4.4. Dissociation of the membrane-bound [³H]QNB was higher at 37°C (∼40% at 60 min) compared to 18°C (∼20%). Both carbachol and atropine increased the dissociation at 37°C to a similar maximum (to about 60%).
• 5.5. The results show marked temperature-dependent alterations in the cardiac muscarinic receptor sites and suggest that these occur either by direct action of the temperature on receptor conformation or its indirect action via membrane fluidity. The likely significance of these results is discussed.

     

Kainate produces concentration-dependent elevation of glutamate release but not cGMP levels in cultured neuron

• 1.1. Treatment of cultured cerebellar granule cells for 3 min with N-methyl-D-aspartate (NMDA) resulted in a concentration-dependent elevation of cyclic GMP. However, neither kainate (KA) nor NMDA produced a concentration-dependent elevation of this nucleotide after exposing cells to the agonist for 60 min.
• 2.2. Unlike the case for cGMP, both KA and NMDA produced concentration-dependent elevations of glutamate for 60 min incubation.
• 3.3. The NMDA-induced elevations of cGMP and glutamate were blocked by selective NMDA receptor antagonists.
• 4.4. The selective KA/α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor antagonist, 6,7-nitroquinoxaline-2,3-dione (DNQX), blocked the KA-induced elevations of cGMP with 3-min exposures, but it augmented the response with 60-min exposures. However, the KA-induced release of glutamate was prevented by DNQX.
• 5.5. The KA/AMPA receptor antagonist, GYKI 52466, blocked all KA-induced responses regardless of the incubation times.

     

Are imidazoline receptors involved in sympathetic neurotransmission in rat vas deferens

• 1.1. An involvement of imidazoline receptors in the modulation of neurotransmitter release was investigated in the prostatic portion of the rat vas deferens stimulated transmurally at 0.2 Hz or by single pulses.
• 2.2. Idaxozan and yohimbine induced a concentration-dependent potentiation of the contractile response to 0.2-Hz transmural stimulation in the epididymal and prostatic portion of the vas.
• 3.3. After reserpine treatment, idazoxan, but not yohimbine, still potentiated the contractile response, suggesting a possible involvement of imidazoline receptors.
• 4.4. Clonidine and rilmenidine, agonists with different affinities to α₂-adrenoceptors and imidazoline receptors, inhibited with the same potency the contractile responses to a single pulse transmural stimulation.
• 5.5. Yohimbine (a selective α₂-adrenoceptor antagonist) antagonized the inhibitory concentration effect curve to rilmenidine in a competitive manner. pA₂ values for idaxozan (an antagonist to α₂-adrenoceptors and imidazoline receptors) were not different when noradrenaline or rilmenidine were used as agonists. Phenoxybenzamine blocked the effect of both agonists.
• 6.6. Thus, the potency relationship of agonists, as well as the effect of the antagonists, did not favor the hypothesis that imidazoline receptors are involved in the idazoxan-potentiating effect in the rat vas deferens.

     

The dermorphin peptide family

• 1.1. In 1980, the skin of certain frogs belonging to the genus Phyllomedusinae was found to contain two new peptides that proved to be selective μ-opioid agonists. Given the name dermorphins, these were the first members of a peptide family that in the past 15 years has grown to reach a total of seven naturally occurring peptides and nearly 30 synthetic analogs.
• 2.2. Dermorphin peptides are potent analgesics in rodents and primates, including man. Some dermorphins can enter the blood-brain barrier and produce central antinociception after peripheral administration.
• 3.3. The dermorphin family also includes μ₁-opioid receptor selective agonists that produce intense opioid analgesia, but stimulate pulmonary ventilation.
• 4.4. Experiments in rats and mice chronically exposed to dermorphins have shown that not only do they have higher antinociceptive efficacy and potency than morphine, but they are also less likely than morphine to produce tolerance, dependence and opiate side effects.

     

Stimulation of angiotensin subtype 2 receptor reduces basal cGMP levels in the neointima of rat aorta after balloon injury

• 1.1. The association between the stimulation of the angiotensin subtype 2 receptor (AT2-R) and the change in tissue levels of cyclic nucleotide was assessed on neointima formation in rat aorta following aortic balloon injury.
• 2.2. Tissue levels of guanosine 3′,5′-cyclic monophosphate (cGMP) and adenosine 3′,5′-cyclic monophosphate levels (cAMP) in the injured and uninjured aorta was determined by enzyme immunoassay at baseline and again 30 s after administration of 10⁻⁷ M angiotension II.
• 3.3. Injured and uninjured aorta showed no difference in basal levels of cGMP. Angiotension II reduced the basal level of cGMP in the injured aorta only.
• 4.4. This decrease was blocked by a selective AT2-R antagonist (PD123319) and by a nonselective angiotensin II antagonist (angiotensin II antipeptide), but not by a selective angiotensin subtype 1 antagonist (CV-11974).
• 5.5. Stimulation with a selective AT2-R caused no change in the level of cAMP in the injured or uninjured aorta.
• 6.6. Results suggest that stimulation of AT2-R in proliferative neointima leads to a decreased tissue level of cGMP.

     

Effects of selective dopamine receptor compounds on single,spontaneously-active neostriatal neurons

• 1.1. The effects of selective dopamine receptor compounds on the spontaneous activity of single neostriatal neurons were examined extracellularly.
• 2.2. Intravenous administration of quinpirole, the D₂ agonist, elicited a dose-dependent depression in discharge rate.
• 3.3. Quinpirole-evoked depression was reversed by the D₂ antagonist eticlopride, but not the D₁ antagonist SCH 23390.
• 4.4. The partial D₁ agonist, SKF 38393 induced depression and excitation in equal proportion.
• 5.5. A dose of 0.25 mg/kg SCH 23390 blocked SKF 38393-induced depression but not excitation.
• 6.6. SKF 38393-induced excitation was antagonized by eticlopride and in some cases by a higher dose of SCH 23390.

     

Central and peripheral dopamine D1/DA1 receptor modulation of gastric secretion and experimental gastric mucosal injury

• 1.1. Dopamine D₁ (central)/DA₁ (peripheral) receptors are believed to influence gastrointestinal function and pathology.
• 2.2. When given i.c.v. or i.p., an agonist (SKF38393) and an antagonist (SCH23390) of this DA receptor subtype inhibit and enhance, respectively, gastric secretion and gastric mucosal injury.
• 3.3. When given both i.c.v. and i.p., their respective effects in the gut were amplified.
• 4.4. Antagonist or agonist given i.p., blocked the corresponding protective and worsening effect of the agonist or antagonist given i.c.v.
• 5.5. Both central and peripheral D₁/DA₁ receptors modulate gastric function and response to injury.

     

Aspects of the thromboxane receptor system

• 1.1. The aim of this review is to establish what is known about the thromboxane (TP) receptor, and to identify where future research is headed. In addition, the impact of the recent advances at the molecular level on resolving pharmacological controversies, such as possible subtypes of the TP receptor, is discussed and what molecular information is known about the TP receptor presented.
• 2.2. The clinical status of TP receptor anatagonists is considered particularly in relation to the potential role of epi prostaglandins.
• 3.3. Basic information about TP agonists, antagonists and signal transduction pathways is also given.

     

Spinal adenosine modulates capsaicin-induced depressor reflex: Involvement of adenosine A2 receptor

• 1.1. The depressor responses to i.a. and i.v. injection of capsaicin (CAP) were blocked following intrathecal (i.t.) perfusion of [d-Pro², d-Trp^7,9] substance P, a specific substance P antagonist. This confirmed that the CAP-elicited depressor reflex is mediated by substance P-containing afferent fibres.
• 2.2. The regulatory roles of spinal adenosine in the CAP-evoked substance P release and the possible involvement of adenosine A₂ receptors were analyzed by analyzing the changes in cardiovascular responses to i.a. and i.v. injection of CAP after various pretreatments with adenosine agonists and antagonists, administered subcutaneously or intrathecally.

     

5-HT receptors on identified Lymnaea neurones in culture: Pharmacological characterization of 5-HT3 receptors

• 1.1. The selective agonist, 1-(m-chlorophenyl)-biguanide (m-CPBG) and antagonist, 3-tropanyl-3,5-dichlorobenzoate (MDL 72222) were used to characterize the 5-HT₃ receptors in cultured identified neurones; the serotonin-containing cerebral giant cells (CGCs) and some follower neurones in the buccal ganglia of Lymnaea stagnalis.
• 2.2. 5-HT and its agonists were pressure ejected, while the 5-HT antagonists were bath applied.
• 3.3. Although m-CPBG evoked mostly depolarizing responses, hyperpolarizing responses were sometimes evoked.
• 4.4. At 10⁻⁴ M, m-CPBG failed to mimic the responses of 5-HT, but at a concentration higher. 10⁻³ M, pressure-ejected m-CPBG mimicked most 5-HT responses.
• 5.5. The 5-HT₂ antagonist ketanserin failed to block the m-CPBG-evoked responses, whilst partially blocking the 5-HT responses.
• 6.6. These results suggest the presence of 5-HT₃ receptors similar to those found in mammalian neurones, and that multiple subtypes of these receptors may be present in Lymnaea neurones.

     

Investigation into the effect of 5-hydroxytryptamine on fluid transport in the rat small intestine

• 1.1. 5-Hydroxytryptamine (5-HT) has been shown to cause a consistent secretory effect in the rat small intestine only when administered luminally or by close intraarterial infusion. Intraluminal 5-HT-induced secretion is possibly mediated by 5-HT₄ receptors. Therefore, it was decided to investigate the effect of 5-HT and selective 5-HT₄ receptor agonists (SC 53116 and DAU 6236) on intestinal fluid transport in rat jejunum and ileum. The study also investigated the effect of a selective 5-HT₄ receptor antagonist (GR 113808) against the intraluminally administered 5-HT.
• 2.2. 5-HT receptor agonists and antagonists were administered intraluminally in pentobarbitoneanesthetized rats. Changes in intestinal fluid transport across the intestinal wall were measured by a single pass technique.
• 3.3. Intraluminal 5-HT produced significant antiabsorptive effects is both the jejunum and ileum. The 5-HT-induced responses were blocked by intraluminal administration of the 5-HT₄ receptor antagonist GR 113808. The 5-HT₄ agonist SC 53116 induced antiabsorptive effects in both regions of the small intestine, but DAU 6236 did not affect the rates of fluid transport.
• 4.4. The results indicate that a 5-HT₄ receptor has a role in the luminal 5-HT-induced antiabsorptive effect on intestinal fluid transport in the rat.

     

The mechanism of the histamine-induced desensitization of guinea-pig ileum

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1. 1.1. Histamine and the selective H₁ receptor agonist 2-pyridlethylamine show cross-desensitization when tested in guinea-pig ileum.
2. 2.2. The H₁ receptor blocking agent produces a smaller parallel shift in desensitized tissues when compared with non-desensitized controls.
3. 3.3. We conclude that desensitization in this system occurs at the receptor level and is reflected by a decreased sensitivity to both agonists and antagonists.

     

Forced swim stress: Supersensitivity of the isolated rat pacemaker to the chronotropic effect of isoprenaline and the role of corticosterone

• 1.1. Forced swim (three daily sessions) resulted in an increased plasma corticosterone level and supersensitivity of the isolated rat pacemaker to the chronotropic effect of isoprenaline.
• 2.2. Bilateral adrenalectomy, performed 2 days before forced swim, abolished the development of pacemaker supersensitivity to isoprenaline.
• 3.3. Administration to rats of the antiglucorticoid compound RU-38486 prevented the development of pacemaker supersensitivity to isoprenaline. Pretreatment of rats not submitted to forced swim with the synthetic glucocorticoid RU-28362 causes pacemaker supersensitivity to isoprenaline.
• 4.4. Pretreatment of rats with diazepam or imipramine which block the forced swim-induced increase in the plasma level of corticosterone prevented the development of pacemaker supersensitivity to isoprenaline.
• 5.5. It is concluded that corticosterone plays a critical role in the modulation of the sensitivity to catecholamines of the pacemaker β-adrenoceptors during adaptation to repeated stress.

     

Adenosine modulates the antinociceptive action of benzodiazepines

• 1.1. In the present study, adenosine modulation on the antinociceptive action of benzodiazepines (BZD) using the writhing test in mice was evaluated.
• 2.2. The i.c.v. BZDs tested (diazepam, midazolam and lorazepam) induced a dose-dependent antinociceptive action, that was not antagonized either by naloxone or by aminophylline.
• 3.3. The i.p. administration of adenosine-related compounds also produced a dose-dependent reduction in the number of writhings in mice. These effects were not antagonized by i.p. injection of naloxone but were antagonized by i.p. aminophylline.
• 4.4. The antinociceptive effect of BZDs was significantly enhanced by the administration of adenosine compounds, but this increased response was not modified by naloxone or by aminophylline.
• 5.5. The present findings could be explained by the fact that BZDs and adenosine-related compounds may interact in an additive manner, since the effects of these drugs may be due to a common mechanism of action or a common pathway.

     

Abnormal modulation of cholinergic neurotransmission by opioid in hyperresponsive bronchus of rats

• 1.1. The electrical field stimulation (EFS)-induced bronchoconstriction in vitro in rats challenged by DNP-Ascaris antigen was significantly greater than that in normal rats.
• 2.2. Morphine inhibited the EFS-induced bronchoconstriction in normal rats. Whereas the inhibition of EFS-induced bronchoconstriction by the opioid was little, if any, in the DNP-Ascaris-challenged rats.
• 3.3. These findings suggest that dysfunction of presynaptic inhibitory modulation through the opioid receptor may take place in the airways of DNP-Ascaris-challenged rats.