Interactions of metoclopramide and ergotamine with human 5-HT(3A) receptors and human 5-HT reuptake carriers

1. The actions of metoclopramide and ergotamine, drugs which are used as a combined migraine medication, on human (h)5-HT(3A) receptors and 5-HT reuptake carriers, stably expressed in HEK-293 cells, were studied with patch-clamp- and ([(3)H]5-HT)-uptake techniques. 2. At clinical concentrations, metoclopramide inhibited peak and integrated currents through h5-HT(3A) receptors concentration-dependently (IC(50)=0.064 and 0.076 μM, respectively) when it was applied in equilibrium (60 s before and during 5-HT (30 μM) exposure). The onset and offset time constants of metoclopramide action were 1.3 and 2.1 s, respectively. The potency of metoclopramide when exclusively applied during the agonist pulse decreased more than 200-fold (IC(50)=19.0 μM, peak current suppression). 3. Metoclopramide (0.10 μM) did not alter the EC(50) of 5-HT-induced peak currents. In contrast to the lack of competitive interaction between metoclopramide and 5-HT in this functional assay, metoclopramide inhibited specific [(3)H]GR65630 binding to human h5-HT(3A) receptors in a surmountable manner. This seeming discrepancy between functional studies and radioligand binding experiments may be accounted for by (1) the slow kinetics of inhibition of peak currents by metoclopramide compared with the fast onset and offset kinetics of 5-HT-induced currents and (2) the low efficacy of metoclopramide in inhibiting radioligand binding (e.g. only 20% binding inhibition compared to 79% peak current suppression by 200 nM metoclopramide). 4. At low concentrations (1–10 nM), ergotamine had no effect on 5-HT (30 μM)-induced peak currents. Above clinical concentrations, ergotamine (>3 μM) inhibited them. 5. When both drugs were applied together (0.10 μM metoclopramide+0.001 to 0.01 μM ergotamine), an inhibition of both, peak and integrated current responses was observed. 6. Neither metoclopramide (⩽30 μM) nor ergotamine (⩽30 μM) had an effect on the 5-HT reuptake carrier as they did not alter the citalopram-sensitive [(3)H]5-HT uptake

The 5-HT3B subunit affects high-potency inhibition of 5-HT3 receptors by morphine

BACKGROUND AND PURPOSE: Morphine is an antagonist at 5-HT(3)A receptors. 5-HT(3) and opioid receptors are expressed in many of the same neuronal pathways where they modulate gut motility, pain and reinforcement. There is increasing interest in the 5-HT3B subunit, which confers altered pharmacology to 5-HT(3) receptors. We investigated the mechanisms of inhibition by morphine of 5-HT(3) receptors and the influence of the 5-HT3B subunit. EXPERIMENTAL APPROACH: 5-HT-evoked currents were recorded from voltage-clamped HEK293 cells expressing human 5-HT3A subunits alone or in combination with 5-HT3B subunits. The affinity of morphine for the orthosteric site of 5-HT(3)A or 5-HT(3)AB receptors was assessed using radioligand binding with the antagonist [(3)H]GR65630. KEY RESULTS: When pre-applied, morphine potently inhibited 5-HT-evoked currents mediated by 5-HT(3)A receptors. The 5-HT3B subunit reduced the potency of morphine fourfold and increased the rates of inhibition and recovery. Inhibition by pre-applied morphine was insurmountable by 5-HT, was voltage-independent and occurred through a site outside the second membrane-spanning domain. When applied simultaneously with 5-HT, morphine caused a lower potency, surmountable inhibition of 5-HT(3)A and 5-HT(3)AB receptors. Morphine also fully displaced [(3)H]GR65630 from 5-HT(3)A and 5-HT(3)AB receptors with similar potency. CONCLUSIONS AND IMPLICATIONS: These findings suggest that morphine has two sites of action, a low-affinity, competitive site and a high-affinity, non-competitive site that is not available when the channel is activated. The affinity of morphine for the latter is reduced by the 5-HT3B subunit. Our results reveal that morphine causes a high-affinity, insurmountable and subunit-dependent inhibition of human 5-HT(3) receptors

Treatment of nausea and vomiting in terminally ill cancer patients

Nausea and vomiting is a common and distressing symptom complex in patients with far-advanced cancer, affecting up to 60% of individuals at some stage of their illness. The current approach to the palliative care of patients with nausea and vomiting is based on identifying the cause, understanding its pathophysiology and knowing the pharmacology of the drugs available for its amelioration. The following six main syndromes are identified: gastric stasis, biochemical, raised intracranial pressure, vestibular, mechanical bowel obstruction and ileus. A careful history, focused physical examination and appropriate investigations are needed to elucidate the syndrome and its cause, so that therapy is rational. Drugs are the mainstay of treatment in terminal cancer, and the main classes of antiemetic agents are prokinetics, dopamine antagonists, antihistamines, anticholinergics and serotonin antagonists. Dexamethasone and octreotide are also used, especially in bowel obstruction. Non-drug measures are important in relieving the associated distress. Patients should be able to die comfortably, without tubes. Despite decades of practice affirming this approach, the evidence base is weak and well designed studies are urgently needed