The effect of naloxone on restraint-induced antinociception in mice.

Restraint for a period from 15-60 min induced significant antinociceptive effect in both male and female mice. The restraint animals all showed an increase in response time to the hot plate test at 55 degrees C. The antinociceptive activity was still apparent one hour after restraint. In the male animals, prior administration of naloxone s.c. 15 min before restraint for 60 min did not affect the degree of antinociceptive activity induced by restraint. In addition, naloxone administered s.c. immediately after restraint for 60 min also did not affect the degree of antinociceptive activity in male mice. These findings indicate that in male animals the endogenous opioid mechanism is most likely not involved in the restraint-induced antinociception. However, for the female mice naloxone administered s.c. either before or immediately after restraint for 60 min dose-dependently suppressed the antinociceptive activity induced by restraint. It is concluded that restraint can induce antinociceptive activity in mice; however, different mechanisms may be involved in the antinociception observed. In male mice the endogenous opioid systems do not seem to play a significant role in restraint-induced antinociception, while for female animals blockade of opioid receptors would greatly diminish the antinociception observed after restraint.     

Enhanced morphine-induced antinociception in histamine H3 receptor gene knockout mice

Previous studies have implicated a potential role for histamine H3 receptor in pain processing. There have been conflicting data, however, on the roles of H3 receptors in pain perception, and little information is available about the role of spinal histamine H3 receptors in morphine-induced antinociception. In the present study we examined the role of histamine H3 receptor in morphine-induced antinociception using histamine H3 receptor knockout mice and a histamine H3 receptor antagonist. Anitinociception was evaluated by assays for four nociceptive stimuli: hot-plate, tail-flick, paw-withdrawal, and formalin tests. Antinociception induced by morphine (0.125 nmol/5 μl, i.t.) was significantly augmented in histamine H3 receptor knockout (−/−) mice compared to the wild-type (+/+) mice in all four assays of pain. Furthermore, the effect of intrathecally administered morphine with thioperamide, a histamine H3 antagonist, was examined in C57BL/6J mice. A low dose of i.t. administered thioperamide (0.125 nmol/5 μl) alone had no significant effect on the nociceptive response. In contrast, the combination of morphine (0.125 nmol/5 μl, i.t.) with the same dose of thioperamide resulted in a significant reduction in the pain-related behaviors in all four nociceptive tests. These results suggest that histamine exerts inhibitory effects on morphine-induced antinociception through H3 receptors at the spinal level.     

Nephrotoxicity and hepatotoxicity of histamine H2 receptor antagonists.

The extensive use of selective histamine H2 receptor antagonists provides a unique opportunity to describe very rare adverse drug reactions. Although mild elevation of serum creatinine level following the administration of cimetidine is relatively common, acute interstitial nephritis (AIN) is a rare hypersensitivity reaction. There have been 25 published reports of AIN associated with H2 antagonist therapy and we also identified 16 cases from the Australian Adverse Drug Reaction Advisory Committee (ADRAC) database. AIN was reported most commonly following cimetidine administration. AIN was supported by renal biopsy in 28 patients and by rechallenge in 6. H2 antagonist-induced AIN was more commonly reported in men older than 50 years. In the majority of cases the onset was within 2 weeks of initiation of therapy (1 day to 11 months). The clinical manifestations were nonspecific including sterile pyuria, elevated erythrocyte sedimentation rate, fatigue, proteinuria and leucocytosis whereas rash, arthralgia and flank pain were rarely reported. There were 170 cases of hepatotoxicity following H2 antagonist administration reported to ADRAC. These were more common following ranitidine and included cholestatic, hepatocellular and mixed reactions. Hepatotoxicity was proven following liver biopsy in several cases published in the literature and in 15 cases reported to ADRAC. Hepatotoxicity recurred upon rechallenge in 6 cases. Generally, renal and hepatic adverse effects resolved quickly after cessation of H2 antagonist therapy and did not require specific treatment. Nephrotoxicity and hepatotoxicity following administration of an H2 antagonist is rare and a high index of suspicion is necessary for early detection. Now that many H2 antagonists are available over the counter, awareness of these conditions and early detection with cessation of H2 antagonist therapy would appear paramount.     

Enhanced antinociception by intrathecally-administered morphine in histamine H1 receptor gene knockout mice

We previously reported that histamine H₁ receptor gene knockout mice (H1KO) showed lower spontaneous nociceptive threshold to pain stimuli when compared to wild-type mice. The objective of the present study was to examine the antinociceptive effect of intrathecally-administered morphine in H1KO mice. The antinociceptive effects of morphine were examined using assays for thermal (tail-flick, hot-plate, paw-withdrawal), mechanical (tail-pressure) and chemical nociception (formalin and capsaicin tests) using H1KO and wild-type mice. In these nociceptive assays, intrathecally-administered morphine produced significant antinociceptive effects in wild-type mice. The antinociceptive effect produced by intrathecally administered morphine was enhanced in the knockout mice. We also examined the effect of an histamine H₁ receptor antagonist, an active (d-) isomer of chlorpheniramine, on morphine-induced antinociception in ICR mice. The intrathecal co-administration of d-chlorpheniramine enhanced the effect of morphine in all nociceptive assays examined. The pharmacological experiments using d-chlorpheniramine further substantiate the evidence for the histamine H₁ receptor-mediated suppression of morphine-induced antinociception. These results suggest that existing H₁ receptors play an inhibitory role in morphine-induced antinociception at the spinal cord level.     

2-Deoxy-D-glucose antinociception and serotonin receptor subtype antagonists: test-specific effects in rats.

The antinociceptive actions of 2-deoxy-D-glucose (2-DG) are mediated in part by endogenous opioid, dopaminergic, cholinergic, histaminergic, and neurohormonal influences. Although 2-DG antinociception was not affected by tryptophan hydroxylase inhibition, a possible serotonergic role in 2-DG antinociception was investigated because of the existence of serotonin [5-hydroxytryptamine (5-HT)] receptor subtypes. The present study examined the effects of general (methysergide: 5 and 10 mg/kg), 5-HT2 (ritanserin: 2.5 mg/kg), and 5-HT3 (ICS-205,930: 0.25-5 mg/kg) receptor subtype antagonists upon 2-DG antinociception on the tail-flick and jump tests in rats. On the tail-flick test, 2-DG (450 mg/kg) antinociception was significantly reduced by all ICS-205,930 doses (48-58%) but unaffected by either methysergide (22-29% reduction) or ritanserin (6% reduction). In contrast, 2-DG antinociception on the jump test was significantly potentiated across the 120-min time course and across the 2-DG dose-response curve (100-650 mg/kg) by methysergide, ritanserin, and ICS-205,930 pretreatment. Each of the three antagonists produced significant leftward shifts in the peak and total 2-DG dose-response curve for the jump test. These data suggest different sites of action for 2-DG antinociception as a function of the pain test employed and a differential modulation by serotonin receptor subtypes at those sites.     

Inhibitory effects of histamine H4 receptor antagonists on experimental colitis in the rat

The histamine H(4) receptor is a G-protein coupled receptor with little homology to the pro-inflammatory histamine H(1) receptor, expressed on cells of the immune system with hematopoietic lineage such as eosinophils and mast cells. The effects of the recently described highly selective histamine H(4) receptor antagonists JNJ 10191584 and JNJ 7777120 have now been investigated on the acute colitis provoked by trinitrobenzene sulphonic acid over 3 days in the rat. Treatment with JNJ 10191584 (10-100 mg/kg p.o., b.i.d.) caused a dose-dependent reduction in macroscopic damage, inhibition of the TNBS-provoked elevation of both colonic myeloperoxidase and tumour necrosis factor-alpha (TNF-alpha), and a reduction in the histologically assessed increase in mucosal and submucosal thickness and neutrophil infiltration. JNJ 7777120 (100 mg/kg p.o., b.i.d.) likewise reduced the macroscopic injury and the increases in colonic myeloperoxidase and TNF-alpha levels. These findings indicate a pro-inflammatory role for the histamine H(4) receptor in this model and suggest a novel pharmacological approach to the treatment of colitis.     

Rodent antinociception following acute treatment with different histamine receptor agonists and antagonists

The effects of different histamine receptor agonists and antagonists on the nociceptive threshold were investigated in mice by two different kinds of noxious stimuli: thermal (hot plate) and chemical (acetic acid-induced abdominal writhing). Intracerebroventricular (icv) injection of the histamine H(1) receptor agonist, HTMT (6-[2-(4-imidazolyl)ethylamino]-N-(4-trifluoromethylphenyl) heptanecarboxamide) (50 microg/mouse), produced a hypernociception in the hot plate and writhing tests. Conversely, intraperitoneal (ip) injection of dexchlorpheniramine (30 and 40 mg/kg) and diphenhydramine (20 and 40 mg/kg) increased the pain threshold in both tests. The histamine H(2) receptor agonist, dimaprit (50 and 100 microg/mouse icv), or antagonist, ranitidine (50 and 100 microg/mouse icv), raised the pain threshold in both hot plate and writhing tests. In the mouse hot plate test, the histamine H(3) receptor agonist, imetit (50 mg/kg ip), reduced the pain threshold, while the histamine H(3) receptor antagonist, thioperamide (10 and 20 mg/kg ip), produced an antinociception. The hypernociceptive effects of HTMT and imetit were antagonized by dexchlorpheniramine (20 mg/kg ip) and thioperamide (5 mg/kg ip), respectively. The results suggest that histaminergic mechanisms may be involved in the modulation of nociceptive stimuli.     

Enhanced antinociceptive effects of morphine in histamine H2 receptor gene knockout mice

We have previously shown that antinociceptive effects of morphine are enhanced in histamine H1 receptor gene knockout mice. In the present study, involvement of supraspinal histamine H2 receptor in antinociception by morphine was examined using histamine H2 receptor gene knockout (H2KO) mice and histamine H2 receptor antagonists. Antinociception was evaluated by assays for thermal (hot-plate, tail-flick and paw-withdrawal tests), mechanical (tail-pressure test) and chemical (formalin and capsaicin tests) stimuli. Thresholds for pain perception in H2KO mice were higher than wild-type mice. Antinociceptive effects of intracerebroventricularly administered morphine were enhanced in the H2KO mice compared to wild-type mice. Intracerebroventricular co-administration of morphine and cimetidine produced significant antinociceptive effects in the wild-type mice when compared to morphine or cimetidine alone. Furthermore, zolantidine, a selective and hydrophobic H2 receptor antagonist, enhanced the effects of morphine in all nociceptive assays examined. These results suggest that histamine exerts inhibitory effects on morphine-induced antinociception through H2 receptors at the supraspinal level. Our present and previous studies suggest that H1 and H2 receptors cooperatively function to modulate pain perception in the central nervous system.     

H2 receptor antagonists.

The uses of the histamine H2 receptor antagonists (H2 antagonists) in the management of peptic ulcer disease and the Zollinger-Ellison syndrome are reviewed. Drugs included in the discussion are burimamide, metiamide and cimetidine. The secretion and the pharmacology of the H2 antagonists are described. A discussion of the clinical use of the H2 receptor antagonists in the treatment of gastric hyperacidity and hypersecretory states, and the side effects encountered is presented. Cimetidine is effective in the treatment of duodenal ulcer, and its use appears promising in Zollinger-Ellison syndrome and gastric ulceration.     

Theoretical studies on the histamine H2 receptor: molecular mechanism of action of antagonists.

The previously defined sites in the histamine H2 receptor model [Mol. Pharmacol. 40:980-987 (1991)] were used to elucidate the pharmacological mechanism of action of compounds that act as antagonists at the receptor. In this model, a formate anion is used both as the negative site at which the histamine cation is anchored to the receptor and as a proton acceptor site. An ammonium cation is used as a proton donor site. The proposed model of recognition of cimetidine, tiotidine, and ranitidine suggests that the monocationic form of the antagonists is the most favorable species to bind the receptor. Moreover, the mode of recognition follows the same trends obtained for compounds that act as agonists; the protonated site of the molecule, i.e., imidazolium in cimetidine, guanidinium in tiotidine, or substituted ammonium in ranitidine, anchors at the negative site of the receptor, whereas the nonbasic part, i.e., cyanoguanidine in cimetidine and tiotidine and nitrodiaminoethene in ranitidine, is located between the proton donor and acceptor sites. An energetic analysis of the interaction between the antagonists and the receptor model, including the energies of ligand desolvation, shows that histamine cannot compete effectively with cimetidine, tiotidine, or ranitidine for binding to the H2 receptor. The predicted order of antagonist potencies, based on differences of formation enthalpies (delta delta H1), reproduces qualitatively the experimental rank order.     

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.

     

Effects of histamine H(1) receptor antagonists on depressive-like behavior in diabetic mice

We previously reported that streptozotocin-induced diabetic mice showed depressive-like behavior in the tail suspension test. It is well known that the central histaminergic system regulates many physiological functions including emotional behaviors. In this study, we examined the role of the central histaminergic system in the diabetes-induced depressive-like behavior in the mouse tail suspension test. The histamine contents in the hypothalamus were significantly higher in diabetic mice than in non-diabetic mice. The histamine H(1) receptor antagonist chlorpheniramine (1-10 mg/kg, s.c.) dose-dependently and significantly reduced the duration of immobility in both non-diabetic and diabetic mice. In contrast, the selective histamine H(1) receptor antagonists epinastine (0.03-0.3 microg/mouse, i.c.v.) and cetirizine (0.01-0.1 microg/mouse, i.c.v.) dose-dependently and significantly suppressed the duration of immobility in diabetic mice, but not in non-diabetic mice. Spontaneous locomotor activity was not affected by histamine H(1) receptor antagonists in either non-diabetic or diabetic mice. In addition, the number and affinity of histamine H(1) receptors in the frontal cortex were not affected by diabetes. In conclusion, we suggest that the altered neuronal system mediated by the activation of histamine H(1) receptors is involved, at least in part, in the depressive-like behavior seen in diabetic mice.     

Clinical pharmacology of new histamine H1 receptor antagonists.

The recently introduced H1 receptor antagonists ebastine, fexofenadine and mizolastine, and the relatively new H1 antagonists acrivastine, astemizole, azelastine, cetirizine, levocabastine and loratadine, are diverse in terms of chemical structure and clinical pharmacology, although they have similar efficacy in the treatment of patients with allergic disorders. Acrivastine is characterised by a short terminal elimination half-life (t1/2 beta) [1.7 hours] and an 8-hour duration of action. Astemizole and its metabolites, in contrast, have relatively long terminal t1/2 beta values; astemizole has a duration of action of at least 24 hours and is characterised by a long-lasting residual action after a short course of treatment. Azelastine, which has a half-life of approximately 22 hours, is primarily administered intranasally although an oral dosage formulation is used in some countries. Cetirizine is eliminated largely unchanged in the urine, has a terminal t1/2 beta of approximately 7 hours and a duration of action of at least 24 hours. Ebastine is extensively and rapidly metabolised to its active metabolite; carebastine, has a half-life of approximately 15 hours and duration of action of at least 24 hours. Fexofenadine, eliminated largely unchanged in the faeces and urine, has a terminal t1/2 beta of approximately 14 hours and duration of action of 24 hours, making it suitable for once or twice daily administration. Levocabastine has a terminal t1/2 beta of 35 to 40 hours regardless of the route of administration, but is only available as a topical application administered intranasally or ophthalmically in patients with allergic rhinoconjunctivitis. Loratadine is rapidly metabolised to an active metabolite descarboethoxyloratadine and has a 24-hour duration of action. Mizolastine has a terminal t1/2 beta of approximately 13 hours and duration of action of at least 24 hours. Most orally administered new H1 receptor antagonists are well absorbed and appear to be extensively distributed into body tissues; many are highly protein-bound. Most of the new H1 antagonists do not accumulate in tissues during repeated administration and have a residual action of less than 3 days after a short course has been completed. Tachyphylaxis, or loss of peripheral H1 receptor blocking activity during regular daily use, has not been found for any new H1 antagonist. Understanding the pharmacokinetics and pharmacodynamics of these new H1 antagonists provides the objective basis for selection of an appropriate dose and dosage interval and the rationale for modification in the dosage regimen that may be needed in special populations, including elderly patients, and those with hepatic dysfunction or renal dysfunction. The studies cited in this review provide the scientific foundation for using the new H1 antagonists with optimal effectiveness and safety.     

Cardiovascular effects of the novel histamine H2 receptor agonist amthamine: interaction with the adrenergic system

The cardiovascular effects of the new histamine H₂ receptor agonist amthamine were studied in the anaesthetized rat, with particular reference to a possible interaction with the adrenergic system. Amthamine (0.03–3 mol/kg i.v.) caused vasodepressor responses which were antagonized by famotidine (3 mol/kg i.v.). At higher doses (30–100 mol/kg i.v.), amthamine induced a modest increase in the mean arterial pressure, which was significantly enhanced by the blockade of H₂ receptors and significantly reduced by the ₂ adrenoceptor antagonist yohimbine (1 mol/kg i.v.). The vasopressor response to amthamine was not modified in rats pre-treated with reserpine or 6-hydroxydopamine, and was only minimally modified in adrenalectomized animals, thus suggesting a predominant interaction with postjunctional ₂ adrenoceptors in the vascular muscle. The H₂ receptor agonist dimaprit (0.3–100 mol/kg i.v.) caused a reduction in arterial pressure, which was antagonized by famotidine, no pressor response being unmasked.Dimaprit (0.1–30 mol/kg i.v.) did not modify heart rate but caused a modest bradycardia at 100 mol/kg i.v. Amthamine (1-100 mol/kg i.v.) induced a dose-dependent tachycardia, which was only partially (approximately 20%) reduced by famotidine and was totally blocked by propranolol (0.3 mg/kg i.v.). This effect was significantly reduced in rats pre-treated with reserpine or 6-hydroxydopamine and was further reduced by cocaine, thus suggesting a tyramine-like action of amthamine.In conclusion, these data demonstrate that the H₂ receptor agonist amthamine can also interact with the adrenergic system when used at doses higher than those necessary to activate H2 receptors. Whereas the increase in blood pressure induced by amthamine seems to be mainly mediated by a direct activation of postjunctional ₂ adrenoceptors, the increase in heart rate is predominantly due to neuronal release of catecholamines. These effects should be considered when using amthamine in cardiovascular or other studies when high doses are employed.     

Antisecretory effects of two new histamine H2-receptor antagonists

N-(3-[3-(1-Piperidinylmethyl)phenoxy]propyl)acetoxyaceta mide hydrochloride (Hoe 760) and N-(3-[3-(1-piperidinylmethyl)phenoxy]propyl)glycolamine hydrochloride (Hoe 062) are highly specific H2-receptor antagonists. The compounds are equipotent after intragastrical or intravenous administration. The antagonists inhibited gastric acid secretion in the rat induced by all stimuli tested, carbachol, desglugastrin and histamine. In the Heidenhain pouch dog whose gastric acid secretion was stimulated by food or histamine the two receptor blockers proved to be 4-6 times more potent inhibitors than cimetidine.     

Central effects of histamine H2-receptor agonists and antagonists on nociception in the rat

The effects of intracerebroventricular injection of histamine H2-receptor agonists (4-methylhistamine, 4-MeH; dimaprit, DIM), H2-antagonists (cimetidine, CIM; ranitidine, RAN; famotidine, FAM) and of the DIM chemical analogue SK&F 91487 on hot-plate latency in rats were examined. Both DIM (0.4-0.8 mumol/rat) and 4-MeH (0.4-0.8 mumol/rat) significantly enhanced the pain threshold, whereas SF&F 91487 (0.8 mumol/rat) had no effect, indicating that DIM antinociception is specifically due to its activity on histamine (HA) receptors. The H2-antagonists CIM (0.8 mumol/rat) and RAN (0.6 mumol/rat) also enhanced the pain threshold, while FAM (0.03 mumol/rat) did not modify pain latency. When injected before 4-MeH, FAM reduced the antinociceptive effect of 4-MeH. These findings suggest that the antinociceptive activity of CIM and RAN is not related to specific blockade of H2-receptors and that the activation of HA-H2-receptors is inhibitory to nociception.     

Homologous histamine H1 receptor desensitization results in reduction of H1 receptor agonist efficacy.

Prolonged exposure of the guinea-pig intestinal longitudinal smooth muscle to histamine caused homologous desensitization of the H1 receptor, which led to reduced H1 receptor-mediated production of [3H]inositol phosphates as well as to reduced H1 agonist-induced contractions. [3H]Mepyramine binding studies showed that desensitization affected neither the agonist affinity nor the number of H1 receptors. Combining the data from the binding studies and the contraction measurements it was found that desensitization results in a selective reduction of agonist efficacy.     

Cardiac and gastric effects of histamine H2 receptor antagonists: no evidence for a correlation between lipophilicity and receptor affinity.

1. A series of histamine H2 receptor antagonists with different lipophilicity were tested in cardiac and gastric assays in order to reveal possible differences in receptor affinity. Lipophilicity of the compounds was expressed as CLOG P (theoretically-determined logarithm of octanol:water partition coefficient) and log k' (logarithm of capacity factor, experimentally-determined by reverse-phase high performance liquid chromatography). 2. Aminopotentidine (APT) and iodoaminopotentidine (I-APT), which are both lipophilic compounds, behaved as insurmountable antagonists of histamine responses in rat isolated gastric fundus (pKB = 6.20 +/- 0.16 and 6.89 +/- 0.19, respectively) and guinea-pig isolated papillary muscle (pKB = 6.34 +/- 0.37 and 6.81 +/- 0.26, respectively). They were approximately as effective as ranitidine (RAN) in reducing histamine-induced acid secretion in the anaesthetized rat, ID50 values being 0.018 +/- 0.02, 0.020 +/- 0.03 and 0.036 +/- 0.01 mumol kg-1 i.v. for APT, I-APT and RAN, respectively. Both APT and I-APT had a significantly longer duration of action than RAN. 3. The hydrophilic compound, SK&F 92857, was inactive up to 10 microM in modifying histamine-induced acid secretion in the isolated rat stomach. In the papillary muscle, low concentrations (0.1-1 microM) of this compound produced a competitive antagonism of the histamine responses (pA2 value = 7.38 +/- 0.11), while a higher concentration (10 microM) significantly reduced the maximal response to histamine. 4. RAN competitively antagonized histamine effects with a comparable affinity in cardiac and gastric preparations (pA2 values were 6.42 +/- 0.09 and 6.78 +/- 0.38 in heart and stomach, respectively). 5. Results obtained in this study clearly showed that the discrepancies between gastric and cardiac effects observed for some H2 antagonists are not explained solely by differences in lipophilicity of compounds. Moreover, the significant correlation found between CLOG P and log k' parameter, which takes into account, besides their lipophilicity, the ionization of the molecules, suggests that ionization has a similar influence for all the molecules on the partition between the lipophilic and aqueous phase.