[Behavioral-electrophysiological observation of the involvement of dopamine D1 receptor of the rat anterior cingulate cortex in the regulation of pain-related emotion].

The present study was aimed to explore the involvement of dopamine D1 receptor of the anterior cingulate cortex (ACC) in the regulation of chronic inflammatory pain-related emotion. On the first day, the rats were acclimated to the environment and the baseline indices were measured. On the second day, the rats were administered with the dopamine D1 receptor antagonist SCH-23390 or agonist SKF38393 in the ACC, and then they were subcutaneously injected with complete Freund's adjuvant (CFA, 0.08 mL) in the left hind paw to establish conditioned place avoidance (CPA) response after pairing with specific environment. On the third day, the CPA response and the firing frequency of ACC neurons were observed synchronously, and the open-field behavior, mechanical pain behavior and paw withdrawal latency (PWL) tests were also observed subsequently. In other experiments, rats were given subcutaneous injection of normal saline (NS) on the left hind paw after SCH-23390 or SKF-38393 was administered in the ACC, and then the same observations were performed. The results showed that: (1) Compared with the control group, the PWL and mechanical pain thresholds of rats injected with CFA on the left hind paw were significantly decreased (P < 0.05); (2) The residence time of rats injected with CFA in the "pain environment" and open field center was significantly shortened (P < 0.05); (3) Pre-injection of antagonist SCH-23390 in ACC (10 µg) alleviated the anxiety-like negative behavior response induced by CFA (P < 0.05) and reversed CFA-induced increases of discharge frequency of ACC neurons (P < 0.05); (4) Pre-injection of agonist SKF-38393 in the ACC (10 µg) induced CPA-like behavioral response in rats injected with NS in the left hind paw, and increased the firing frequency of ACC neurons (P < 0.05); (5) Immunofluorescence detection showed that dopamine D1 receptor and NMDA receptor were co-expressed in the same neuron. These results suggest that inhibition of dopamine D1 receptor in ACC can alleviate the negative emotional response induced by persistent pain.

Behavioral-electrophysiological observation of the involvement of dopamine D1 receptor of the rat anterior cingulate cortex in the regulation of pain-related emotion / 生理学报

The present study was aimed to explore the involvement of dopamine D1 receptor of the anterior cingulate cortex (ACC) in the regulation of chronic inflammatory pain-related emotion. On the first day, the rats were acclimated to the environment and the baseline indices were measured. On the second day, the rats were administered with the dopamine D1 receptor antagonist SCH-23390 or agonist SKF38393 in the ACC, and then they were subcutaneously injected with complete Freund's adjuvant (CFA, 0.08 mL) in the left hind paw to establish conditioned place avoidance (CPA) response after pairing with specific environment. On the third day, the CPA response and the firing frequency of ACC neurons were observed synchronously, and the open-field behavior, mechanical pain behavior and paw withdrawal latency (PWL) tests were also observed subsequently. In other experiments, rats were given subcutaneous injection of normal saline (NS) on the left hind paw after SCH-23390 or SKF-38393 was administered in the ACC, and then the same observations were performed. The results showed that: (1) Compared with the control group, the PWL and mechanical pain thresholds of rats injected with CFA on the left hind paw were significantly decreased (P < 0.05); (2) The residence time of rats injected with CFA in the "pain environment" and open field center was significantly shortened (P < 0.05); (3) Pre-injection of antagonist SCH-23390 in ACC (10 μg) alleviated the anxiety-like negative behavior response induced by CFA (P < 0.05) and reversed CFA-induced increases of discharge frequency of ACC neurons (P < 0.05); (4) Pre-injection of agonist SKF-38393 in the ACC (10 μg) induced CPA-like behavioral response in rats injected with NS in the left hind paw, and increased the firing frequency of ACC neurons (P < 0.05); (5) Immunofluorescence detection showed that dopamine D1 receptor and NMDA receptor were co-expressed in the same neuron. These results suggest that inhibition of dopamine D1 receptor in ACC can alleviate the negative emotional response induced by persistent pain.

Dyskinetic potential of dopamine agonists is associated with different striatonigral/striatopallidal zif-268 expression.

In the dopamine-depleted striatum, an altered post-synaptic signalling of efferent neurons might underline the onset of variable dyskinetic responses to dopaminergic agonists. We have previously shown that a subchronic treatment with the D1 agonist SKF-38393 and the D2 agonist ropinirole induces a dyskinetic response of high and low intensities respectively, in 6-hydroxydopamine-lesioned rats. Here, zif-268 mRNA expression was evaluated in striatonigral and striatopallidal neurons to assess a neurochemical marker of these different dyskinetic responses upon drug administration. Acute and subchronic SKF-38393 (3mg/kg) increased zif-268 expression per neuron in the striatonigral pathway, albeit the number of neurons displaying high early-gene levels was reduced by the subchronic treatment. Zif-268 mRNA in striatopallidal neurons was not affected by SKF-38393 treatments. In contrast, ropinirole (5mg/kg) did not alter zif-268 mRNA in striatonigral neurons acutely, whereas ropinirole decreased zif-268 mRNA subchronically. Both acute and subchronic ropinirole decreased zif-268 levels in the striatopallidal pathway. The differential expression of zif-268 in striatonigral and striatopallidal neurons might provide a biochemical correlate of the dyskinetic outcome displayed by SKF-38393 and ropinirole treatments, suggesting that evaluation of neuronal responses upon drug administration provides a tool for the preclinical characterization of dyskinetic potential beyond behavioural tests.

Chronic SKF83959 induced less severe dyskinesia and attenuated L-DOPA-induced dyskinesia in 6-OHDA-lesioned rat model of Parkinson's disease.

SKF83959, a recently identified selective agonist of putative phosphoinositide-linked (PI-linked) D(1) dopamine (DA) receptor, is found to elicit excellent anti-parkinsonism effects in monkeys and rodents. In the present study, the effects of SKF83959 on L-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID) were assessed in a unilateral 6-hydroxydopamine (6-OHDA) lesioned rat model of Parkinson's disease (PD). The results indicated that chronic L-DOPA (6 mg/kg) induced a progressive dyskinesia-like behavior in PD rats, whereas SKF83959 (0.5 mg/kg) elicited significantly less severe dyskinesia while exerts its anti-parkinsonian action effectively. Application of D(1) receptor, but not D(2), alpha or 5-HT receptor antagonist attenuated SKF83959-induced dyskinesia, indicating that a D(1) receptor-mediated events, assumed via PI-linked D(1) receptor. Interestingly, chronic co-administration of SKF83959 significantly reduced LID at no expanse of reduction in the anti-parkinsonian potency in PD rats. However, this anti-dyskinesia effect was not observed while SKF83959 was acutely administered in rats with established LID. This implies that chronic SKF83959 attenuated the development of dyskinesia. Immediate early gene FosB is previously reported to positively associate with dyskinesia. However, we found that the anti-dyskinesia effect of chronic SKF83959 was independent of FosB since SKF83959 produced stronger FosB expression in the lesioned striatum than that of L-DOPA while exerting its anti-dyskinesia action. The present data demonstrated that SKF83959 reduces LID by attenuating the development of dyskinesia; the underlying signaling pathway for the anti-dyskinesia action of SKF83959 appears not to depend on FosB.

Drug discrimination in methamphetamine-trained monkeys: agonist and antagonist effects of dopaminergic drugs.

The involvement of D1 and D2 subtypes of dopamine receptors in behavioral effects of methamphetamine was studied in squirrel monkeys using a two-lever drug discrimination procedure. In monkeys that discriminated i.m. injections of 0.3 mg/kg methamphetamine from saline, methamphetamine (0.03-0.3 mg/kg), cocaine (0.1-1.0 mg/kg) and the selective dopamine uptake inhibitor, GBR 12909 (3.0-17.8 mg/kg) produced dose-related increases in responding on the methamphetamine-associated lever and, at the highest doses, full substitution. In contrast, the norepinephrine and serotonin uptake inhibitors, tomoxetine (1.0-17.8 mg/kg) and fluoxetine (0.3-10.0 mg/kg), respectively, did not substitute appreciably for methamphetamine. Substitution for methamphetamine also was observed with the D1 receptor agonists, SKF 81297, SKF 82958 and dihydrexidine, and the D2 receptor agonist, (+)-PHNO in the majority of monkeys. Lower-efficacy D1 or D2 agonists substituted for methamphetamine either partially (SDZ 208-911) or not at all (SKF 77434, SDZ 208-912). Pretreatment with dopamine receptor blockers [D1 (SCH 39166, 0.1 mg/kg) or D2 (remoxipride, 3.0 mg/kg and nemonapride, 0.003 mg/kg)] and low-efficacy agonists [D1 (SKF 77434; 3.0 mg/kg) or D2 (SDZ 208-911 and SDZ 208-912; 0.01-0.03 mg/kg)] antagonized the discriminative-stimulus effects of methamphetamine. In separate studies, comparable doses of each of these drugs, except SKF 77434, induced significant levels of catalepsy-associated behavior. These results support the view that both dopaminergic D1 and D2 mechanisms mediate the discriminative-stimulus effects of methamphetamine; further, they indicate that selected dopamine D1 partial agonists may have antagonist actions at doses that do not produce undesirable effects associated with dopamine receptor blockade.

D2 dopamine antisense RNA expression vector, unlike haloperidol, produces long-term inhibition of D2 dopamine-mediated behaviors without causing Up-regulation of D2 dopamine receptors.

Long-term inhibition of D2 dopamine receptors using classic D2 dopamine receptor antagonists such as haloperidol often causes a compensatory up-regulation of the D2 dopamine receptors. We investigated whether the long-term inhibition of D2 dopamine receptors using an eukaryotic expression vector housing a cDNA sequence encoding an antisense RNA directed to the D2 dopamine receptor transcript (D2 antisense vector) would also produce up-regulation of the D2 receptors. Single, bilateral injections of the D2 antisense vector into the corpora striata of mice inhibited the stereotypy induced by acute challenge injections with the D2/D3 dopamine receptor agonist quinpirole but did not inhibit the grooming induced by acute challenge injections with the D1 agonist SKF 38393. Similar treatment with the D2 antisense vector produced a long-term (>1 month) cataleptic response without producing tolerance to challenge injections with haloperidol. By contrast, catalepsy induced by a single injection of haloperidol lasted only approximately 2 days, and tolerance developed to its effects after long-term treatment. Repeated treatment of mice with haloperidol resulted in an inhibition of apomorphine-induced climbing behavior throughout the time of treatment with haloperidol, but the climbing behavior markedly increased to levels significantly higher than that of the control mice immediately after withdrawal from haloperidol treatment. This increased climbing was accompanied by increased levels of D2 dopamine receptors in the striatum. By contrast, single, bilateral intrastriatal injections of the D2 antisense vector significantly inhibited apomorphine-induced climbing for approximately 30 days but failed to increase the climbing behavior or the levels of D2 dopamine receptors in striatum over those of the control values. These results suggest that a single injection of a D2 antisense RNA expression vector into mouse striatum produces specific, long-term inhibition of D2 dopamine receptor behaviors without causing a compensatory increase in the levels or function of D2 dopamine receptors.

Intravenous fenoldopam infusion in severe heart failure.

Fenoldopam, a selective DA1-receptor agonist, infused intravenously for 24 hours (0.6 +/- 0.3 microgram/kg/min, range 0.1-1.5) in 25 patients with NYHA functional class III or IV heart failure, produced a prompt and sustained hemodynamic response. Cardiac index rose from an average preinfusion baseline value of 1.8 to 2.6/l min. Stroke volume index increased from 19 to 26 ml/m2 and stroke work index increased from 18 to 25 g M/m2. These changes were accompanied by a reduction in systemic vascular resistance from an average of 2400 to 1500 dynes sec/cm5. There was no change in the heart rate or right atrial pressure. There was a transient reduction in the left ventricular filling pressure from 25 to 20 mmHg. Urinary sodium excretion did not change significantly. Transient asymptomatic thrombocytopenia developed in four patients. The drug was well tolerated by all patients. These results suggest that continuous intravenous infusion of fenoldopam is safe and produces favorable hemodynamic responses in severe heart failure. However, unlike its effects in patients with hypertension, it failed to produce sustained natriuresis in these patients.

The effect of fenoldopam on renal haemodynamics and natriuresis in chronic renal failure.

The effect of oral administration of fenoldopam, a dopamine-1 receptor agonist, on blood pressure, renal haemodynamics and natriuresis was studied in 12 patients with chronic renal insufficiency. In addition, the effect of administering a low intravenous dose of fenoldopam on top of the oral dose was compared with the effect of the same intravenous dose given immediately before oral fenoldopam. Oral administration of fenoldopam (50 mg t.i.d. for 3 +/- 1 days followed by 100 mg t.i.d. for 8 +/- 1 days) induced a significant fall in blood pressure (median MAP from 107 to 101 mm Hg). Compared to baseline values, body weight, effective renal plasma flow (ERPF), glomerular filtration rate (GFR) and fractional sodium excretion remained unchanged. Infusion of fenoldopam (0.05-0.1 micrograms/kg/min) on day 1 led to a significant fall in blood pressure (median mean arterial pressure from 107.0 to 98.5 mm Hg), and a significant rise in effective renal plasma flow (median ERPF from 132 to 146 ml/min/1.73 m2). Median fractional sodium excretion increased significantly from 2.1 to 3.3%. GFR, filtration fraction and plasma aldosterone concentration did not change. No relationship was found between the fenoldopam-induced changes in ERPF and natriuresis, nor between baseline GFR or ERPF and fenoldopam-induced urinary sodium loss. Infusion of fenoldopam while patients were on oral fenoldopam had no effect on blood pressure, ERPF or GFR. However, again natriuresis was induced, which did not differ significantly from the fenoldopam-induced natriuresis on day 1. We conclude that oral fenoldopam has a moderate blood pressure lowering effect in patients with chronic renal insufficiency, but exerts no effect on ERPF or GFR. Secondly, a fenoldopam-induced natriuresis does not appear to be related to changes in ERPF or aldosterone secretion.

Intravenous fenoldopam versus sodium nitroprusside in patients with severe hypertension.

In an open-label study, we compared the efficacy and safety of intravenous infusion of fenoldopam mesylate with that of sodium nitroprusside in patients with severe hypertension or in hypertensive crisis. Both antihypertensive medications were infused at a maximal dose increment of 0.2 microgram/kg/min (fenoldopam) and 1 microgram/kg/min (nitroprusside), with a maximal infusion rate of 1.5 micrograms/kg/min fenoldopam mesylate or 8 micrograms/kg/min sodium nitroprusside. Once the desired reduction in diastolic blood pressure was achieved (less than 110 mm Hg if initial diastolic blood pressure was 120-149 mm Hg, or by at least 40 mm Hg if initial diastolic blood pressure was 150-190 mm Hg), the maximal infusion rate used was maintained for at least 1 hour, and then, the infusion was slowed gradually over 2 hours. After the infusion treatment, patients remained in the hospital for 2 days of follow-up. Both antihypertensive agents successfully controlled the blood pressure in all the patients by the end of the maintenance periods. Between the baseline and the end of the maintenance period, analysis of variance showed that the changes in the variables induced by fenoldopam mesylate did not differ significantly from those induced by sodium nitroprusside. The incidence of side effects listed were similar in both groups of patients. The detection of toxic levels of thiocyanate in two patients treated with nitroprusside, however, shows that fenoldopam might be preferable for the control of a hypertensive crisis or severe hypertension in patients with decreased renal function.

Assessment of hemodynamic tolerance from a 24-hour intravenous infusion of fenoldopam mesylate in congestive heart failure.

To determine the maintenance of pharmacodynamic effects of fenoldopam mesylate, a dopamine-1 agonist, the invasive hemodynamic profiles of 33 patients with New York Heart Association functional class III to IV congestive heart failure were examined. Fenoldopam mesylate was initiated at 0.1 micrograms/kg/min and titrated to a cardiac index greater than or equal to 25% above baseline. Upon achievement of optimal hemodynamics, maintenance infusion was begun (mean dose 0.6 micrograms/kg/min). Fenoldopam mesylate (baseline vs maximal effect) decreased systemic vascular resistance by 37% (p less than 0.001), left ventricular filling pressure by 16% (p less than 0.05) and mean arterial pressure by 11% (p less than 0.05), with an associated augmentation in cardiac index and stroke volume index by 27% (p less than 0.001). Attenuation of hemodynamic effect (maximal effect vs time) was noted in cardiac index (14% p less than 0.001), systemic vascular resistance (13% p less than 0.05) and stroke volume index (13% p less than 0.05). None of the parameters exhibited complete attenuation to baseline values. Fenoldopam mesylate improves cardiac output and lowers systemic vascular resistance with relative attenuation of pharmacodynamic effect during a 24-hour intravenous infusion.

A preliminary study of the dopamine DA1 agonist fenoldopam in the treatment of chronic left ventricular failure due to ischaemic heart disease.

The effects of chronic oral fenoldopam in the treatment of NYHA grade II-III heart failure secondary to ischaemic heart disease, were studied in a placebo controlled, double blind, randomised, parallel group fashion in 20 patients. Nine patients taking placebo and six taking fenoldopam completed the study. Adverse events were similar in each group. There were no significant changes in exercise capacity, ejection fraction, body weight or symptom questionnaires with either treatment. This preliminary study has not revealed any benefit of fenoldopam in heart failure due to ischaemic heart disease.