Evidence for a dopamine receptor subtype sensitive to combination of D1 with D2 antagonist in measurement of G-protein activity using rat striatal membranes

In rat striatal membranes, various kinds of dopamine receptor agonists stimulated low-Km GTPase activity in a concentration-dependent manner. This stimulation by bromocriptine, pergolide and apomorphine was partially inhibited by sulpiride (SUL), a D2-selective antagonist, markedly inhibited by combination of SUL with SCH 23390 (SCH), a D1-selective antagonist, and not modified by SCH alone. The stimulation by BAM-1110 was resistant to SUL or SCH alone but abolished by combination of SUL with SCH. These findings suggest the presence of another subtype of a dopamine receptor in a functional in vitro bioassay system in rat striata.     

The action of dopamine receptor antagonists on the secretory response of the cockroach salivary gland in vitro

1. A study has been made of the potency of a number of dopamine antagonists to inhibit dopamine-induced secretion from the cockroach salivary gland in vitro. 2. Chlorpromazine (0.5-5 microM), SCH23390 (10-100 microM), haloperidol (10-100 microM) and metoclopramide (2 mM) competitively inhibited the secretory response to dopamine. In contrast (+/-)sulpiride (1-100 microM) and domperidone (1-100 microM) had no effect on either basal or dopamine-induced secretion. 3. Apparent dissociation constants (KDapp) were obtained using a 'three point assay'. The rank order of potency (KDapp in parentheses) was as follows: chlorpromazine (0.2 microM) greater than SCH23390 (2.2 microM) greater than haloperidol (17.5 microM) much greater than metoclopramide (1.2 mM). 4. It is concluded that the receptor mediating dopamine-induced secretion in the cockroach salivary gland is similar to the D1/DA1 dopamine receptor and distinct from the D2/DA2 receptor found in mammalian systems.     

多巴胺D1和D2受体拮抗剂对针刺镇痛的增强

在兔K~+透入测痛模型上,应用高选择性的D_1或D_2受体拮抗剂、观察其对针刺镇痛的影响。结果表明,iv.D_2受体拮抗剂氟哌啶醇和氯氮平加强针刺镇痛,且与剂量有关。icv.D_2受体拮抗剂domperidone和舒必利及D_1受体拮抗剂SCH23390,亦能加强针刺镇痛。本文对D_1和D_2受体拮抗剂在针刺镇痛中的作用进行了讨论。     

Exposure to Far Infrared Ray Protects Methamphetamine-Induced Behavioral Sensitization in Glutathione Peroxidase-1 Knockout Mice via Attenuating Mitochondrial Burdens and Dopamine D1 Receptor Activation

Evidence indicates that stress conditions might lead to drug dependence. Recently, we have demonstrated that exposure to far infrared ray (FIR) attenuates acute restraint stress via induction of glutathione peroxidase-1 (GPx-1) gene. We investigated whether FIR affects methamphetamine (MA)-induced behavioral sensitization and whether FIR-mediated pharmacological activity requires interaction between dopamine receptor and GPx-1 gene. We observed that MA treatment significantly increased GPx-1 expression in the striatum of wild-type (WT) mice. Interestingly, exposure to FIR potentiated MA-induced increase in GPx-1 expression. This phenomenon was also observed in animals receiving MA with dopamine D1 receptor antagonist SCH23390. However, dopamine D2 receptor antagonist sulpiride did not affect MA-induced GPx-1 expression. FIR exposure or SCH23390, but not sulpiride, significantly attenuated MA-induced behavioral sensitization. Exposure to FIR significantly attenuated MA-induced dopamine D1 receptor expression, c-Fos induction and oxidative burdens. FIR-mediated antioxidant effects were also more pronounced in mitochondrial- than cytosolic-fraction. In addition, FIR significantly attenuated against MA-induced changes in mitochondrial superoxide dismutase and mitochondrial GPx activities, mitochondrial transmembrane potential, intramitochondrial Ca²⁺ level, mitochondrial complex-I activity, and mitochondrial oxidative burdens. The attenuation by FIR was paralleled that by SCH23390. Effects of FIR or SCH23390 were more sensitive to GPx-1 KO than WT mice, while SCH23390 treatment did not exhibit any additive effects on the protective activity mediated by FIR, indicating that dopamine D1 receptor constitutes a molecular target of FIR. Our result suggests that exposure to FIR ameliorates MA-induced behavioral sensitization via possible interaction between dopamine D1 receptor and GPx-1 gene.     

大鼠鞘内注射多巴胺受体激动剂与拮抗剂对痛及针刺镇痛的影响

在大鼠电刺激甩测痛模型上,应用鞘内注射（ｉｔ）多巴胺（ＤＡ）受体选择性激动剂与拮抗剂,分析大鼠脊髓ＤＡ受体亚型Ｄ１和Ｄ２在痛及针刺镇痛（ＡＡ）中的作用。结果显示,在正常清醒大鼠,ｉｔ Ｄ２受体选择性激动剂,Ｙ１７１５５５（ＬＹ）或Ｄ１／Ｄ２受体激动剂阿朴吗啡（ＡＰＯ）有镇痛作用（呈剂量依赖式增加）,并加强ＡＡ,而ｉｔ Ｄ１受体选择性激动剂ＳＫＦ３８３９３（ＳＫＦ）对痛及ＡＡ均无影响;ｉｔ Ｄ１受体     

Influence of D-1 receptor system on the D-2 receptor-mediated hypothermic response in mice

The hypothermia induced by apomorphine, a mixed dopamine (DA) agonist in male Swiss-Webster mice, was not blocked by the selective D-1 antagonist SCH 23390 but was completely blocked by the selective D-2 antagonists haloperidol, sulpiride and YM-09151-2. The selective D-1 agonist SKF 38393 did not elicit hypothermic response but the selective D-2 agonist quinpirole caused a marked lowering of rectal temperature. D-2 antagonists blocked this response to quinpirole. SCH 23390 enhanced and SKF 38393 attenuated the hypothermia induced by quinpirole. Ineffective doses of haloperidol and SKF 38393, when given together, completely blocked the effect of quinpirole. It was concluded that hypothermia is a D-2 receptor mediated response but modulated by the D-1 receptor system. In another series of experiments the influence of neuroleptics and antidepressants on the hypothermic effect of apomorphine and quinpirole was investigated. The hypothermic effect of a low dose (1 mg/kg) of apomorphine was blocked by the D-2 receptor antagonists, but not by classical antidepressants. However, the response to a high dose (10 mg/kg) of apomorphine was blocked by both classical antidepressants and D-2 antagonists (except haloperidol). These drugs did not show similar effect on quinpirole-induced hypothermia. It is clear that the hypothermic response, especially that of quinpirole, is not a suitable model for testing either neuroleptics or antidepressants.     

Hyperactivity induced by stimulation of separate dopamine D-1 and D-2 receptors in rats with bilateral 6-OHDA lesions

The effects of DA agonists and antagonists with different dopamine (DA) D-1 and D-2 receptor selectivity have been studied in rats with bilateral 6-OHDA lesions. The D-1 agonist SK & F 38393, the D-2 agonist pergolide and the mixed agonist apomorphine all induced marked hyperactivity in lesioned rats in doses which were without stimulant effect in sham-operated animals. The hyperactivity induced by SK & F 38393 was blocked by the DA D-1 antagonist SCH 23390, but unaffected by the D-2 antagonists spiroperidol or clebopride. Pergolide-induced hyperactivity showed the reverse selectivity. The mixed D-1/D-2 antagonists, cis(Z)-flupentixol and cis(Z)-clopenthixol, however blocked the effect of both agonists. Apomorphine-induced hyperactivity was neither blocked by selective D-1 nor D-2 antagonists, but was dose-dependently inhibited by cis(Z)-flupentixol and cis(Z)-clopenthixol. Potent blockade was also obtained by combined treatment with SCH 23390 and spiroperidol, indicating the need of blocking both D-1 and D-2 receptors simultaneously. The results indicate that D-1 and D-2 receptor function can be independently manipulated in denervated rats and they confirm similar results obtained in rats with unilateral 6-OHDA lesions using circling behaviour.     

Selective D2 dopamine receptor agonists prevent catalepsy induced by SCH 23390, a selective D1 antagonist

SCH 23390, an apparently selective antagonist of central D1 dopamine receptors, produced profound catalepsy at low doses (0.1 mg/kg, s.c.). Pretreatment with the selective D2 receptor agonists LY 141865, RU 24213 or LY 171555, the active (-) enantiomer of LY 141865, elicited a dose-dependent inhibition of the cataleptic response. Pergolide and apomorphine were also effective. This effect was not due to altered disposition or penetration of SCH 23390 into the brain since pretreatment with a dose of LY 171555 which completely blocked catalepsy had no effect on the ID50 of SCH 23390 to inhibit 3H-cis-piflutixol binding to D1 receptors measured ex vivo. Alternative mechanisms are considered to explain the results, which offer new insights into striatal dopaminergic regulation of motor activity.     

NMDA receptor antagonism produces antinociception which is partially mediated by brain opioids and dopamine.

Inhibition of nitric oxide synthase (NOS) activity results in opioid-mediated supraspinal analgesia in the rat, as indicated by increased reaction time in the hot plate test. It is documented that a relationship exists between NMDA receptor activation and the activity of NOS. The present investigation sought to determine if inactivation of the NMDA receptor produced antinociception of supraspinal origin, as was observed in response to inhibition of NOS, and if this response was mediated by brain opioids, by activation of receptors for the neurotransmitter, dopamine, or both. Administration of MK-801, a non-competitive antagonist of the NMDA receptor, produced significant antinociception as measured by reaction time in the hot plate test of analgesia. Antinociception resulting from treatment with MK-801 appeared to be mediated by brain opioids, as indicated by the ability of the opioid antagonist, naloxone, to partially reverse the effect of MK-801 administration. This analgesic response was also partially diminished by administration of the dopamine D1 receptor antagonist, SCH 23390 and the dopamine D2 receptor antagonist, sulpiride. The analgesia resulting from NMDA receptor antagonism was found to be only partially attributable to dopamine and brain opioids, since co-administration of naloxone and SCH 23390 or naloxone and sulpiride, were unable to completely reverse the antinociceptive response to MK-801. The present findings suggest that inhibition of NMDA receptor activity produces supraspinal analgesia. Furthermore, it appears that antinociception induced by blockade of the NMDA receptor results, at least in part, from activation of endogenous brain opioids and stimulation of D1 and D2 subtypes of the dopamine receptor.     

Intermittent hypoxia augments carotid body and ventilatory response to hypoxia in neonatal rat pups.

Carotid bodies are functionally immature at birth and exhibit poor sensitivity to hypoxia. Previous studies have shown that continuous hypoxia at birth impairs hypoxic sensing at the carotid body. Intermittent hypoxia (IH) is more frequently experienced in neonatal life. Previous studies on adult animals have shown that IH facilitates hypoxic sensing at the carotid bodies. On the basis of these studies, in the present study we tested the hypothesis that neonatal IH facilitates hypoxic sensing of the carotid body and augments ventilatory response to hypoxia. Experiments were performed on 2-day-old rat pups that were exposed to 16 h of IH soon after the birth. The IH paradigm consisted of 15 s of 5% O2 (nadir) followed by 5 min of 21% O2 (9 episodes/h). In one group of experiments (IH and control, n = 6 pups each), sensory activity was recorded from ex vivo carotid bodies, and in the other (IH and control, n = 7 pups each) ventilation was monitored in unanesthetized pups by plethysmography. In control pups, sensory response of the carotid body was weak and was slow in onset (approximately 100 s). In contrast, carotid body sensory response to hypoxia was greater and the time course of the response was faster (approximately 30 s) in IH compared with control pups. The magnitude of the hypoxic ventilatory response was greater in IH compared with control pups, whereas changes in O2 consumption and CO2 production during hypoxia were comparable between both groups. The magnitude of ventilatory stimulation by hyperoxic hypercapnia (7% CO2-balance O2), however, was the same between both groups of pups. These results demonstrate that neonatal IH facilitates carotid body sensory response to hypoxia and augments hypoxic ventilatory chemoreflex.     

Characterization of Dopamine and β-Adrenergic Receptors Linked to Cyclic AMP Formation in Intact Cells of the Clone D384 Derived from a Human Astrocytoma

3,4-Dihydroxyphenylethylamine (dopamine) and beta-adrenergic receptor agonists and antagonists were assessed for their effects on cyclic AMP accumulation in human astrocytoma derived clone D384 cells. Dopamine, SKF 38393, and 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene increased cyclic AMP content with Ka values of 2.0, 0.2, and 1.6 microM. The D1-selective antagonists SCH 23390 (Ki, 1.2 nM) and SKF 83566 (Ki, 0.8 nM) were over 5,000-fold more potent than the D2-selective antagonist domperidone (Ki, 6.7 microM) at inhibiting dopamine stimulation of cyclic AMP formation. SCH 23388 (Ki, 560 nM; the S-enantiomer of SCH 23390) was 400-fold less potent than SCH 23390. Isoprenaline, adrenaline, salbutamol, and noradrenaline increased cyclic AMP content with Ka values of 0.13, 0.12, 0.22, and 7.60 microM. The beta 2-selective antagonist ICI 118,551 (Ki,0.8 nM) was almost 8,000-fold more potent than the beta 1-selective antagonist practolol (Ki, 5.9 microM) at inhibiting isoprenaline stimulated cyclic AMP accumulation. These results demonstrate that D384 cells express D1-dopamine and beta 2-adrenergic receptors linked to adenylate cyclase. Furthermore, the dopamine receptor expressed by D384 cells exhibits a pharmacological profile typical of a mammalian striatal D1-receptor and therefore the use of this clone represents another approach to studying central D1-receptors.     

Positive interaction between alpha-1 adrenergic and dopamine-2 receptors in locomotor activity of normo and supersensitive mice

In normosensitive mice either the D1 antagonist SCH 23390 or the D2 antagonist sulpiride inhibited the reversion of reserpine-induced akinesia elicited by the mixed D1/D2 agonist pergolide. In mice rendered supersensitive by a five days' reserpine treatment, sulpiride did not prevent the pergolide-induced reversal of akinesia while SCH 23390 disclosed two subpopulations of mice. One population responded to pergolide with marked locomotor activity whereas in the other subpopulation this response was absent. However, all mice challenged with pergolide failed to reverse reserpine-akinesia after alpha-methyl-p-tyrosine (AMPT) pretreatment. The alpha 1/alpha 2 agonist clonidine restored the ability of pergolide to overcome reserpine akinesia in supersensitive mice pretreated with SCH 23390. Clonidine reversed the akinesia in supersensitive mice but in normal animals it did not. However, in these last conditions, the combined use of clonidine plus the D2 agonist LY 171555 was effective to induce locomotion. Neither AMPT nor SCH 23390 inhibited this response whereas the alpha-adrenergic antagonists prazosin and yohimbine did prevent it. The alpha 2 agonist B-HT 920 failed to induce locomotor responses when given together with LY 171555. The same occurred with the D1 agonist SKF 38393 when given together with clonidine. The combined use of SCH 23390 plus prazosin in chronic reserpinized mice prevented pergolide-induced locomotion. Adrenergic stimulation, acting on alpha 1 receptors, could be an alternative to D1 stimulation as a necessary factor to obtain D2-induced motor responses under normo and supersensitive conditions.     

Dopamine induces hyperpolarization of locust salivary gland acinar cells via D(1)-like receptors

The effect of dopamine on the salivary gland acinar cells of the locust was examined using conventional intracellular recording techniques. Application of dopamine induced a reversible, dose-dependent hyperpolarization of the acinar cells, with an EC(50) of 0.1 &mgr;M dopamine. We investigated the pharmacology of the dopamine receptor mediating hyperpolarization of the acinar cells using a range of dopaminergic agonists and antagonists. The effect of dopamine could be mimicked by the selective D(1) receptor agonist SKF82958, whilst the D(2) receptor agonists PPHT-HCl and TNPA-HBr were far less potent at inducing hyperpolarization. The receptor also showed selectivity to certain synthetic D(1)-like agonists. SKF82958 was much more effective at inducing a hyperpolarization than SKF81297. The dopamine-induced hyperpolarization of locust acinar cells could be blocked using the selective D(1) receptor antagonist SCH23390 whilst the D(2) receptor antagonists sulpiride and spiperone were inactive. The rank order of potency of several dopaminergic agonists and antagonists was obtained and suggests that the dopamine receptor mediating the hyperpolarization in locust salivary gland acinar cells is similar to a mammalian D(1) receptor. Stimulation of the salivary nerve mimicked the effect of dopamine on the acinar cells, inducing a rapid reversible hyperpolarization. This neurally-evoked hyperpolarization of the locust acinar cells was suppressed using 1.0 &mgr;M SCH23390, whilst 10 &mgr;M sulpiride was inactive. This demonstrated that both exogenously applied dopamine and endogenously released dopamine are probably acting on the same receptor.     

Affinity chromatography of the D1 dopamine receptor from rat corpus striatum

The D1 dopamine receptor from rat corpus striatum has been purified 200-250-fold by using a newly developed biospecific affinity chromatography matrix based on a derivative of the D1 selective antagonist SCH 23390. This compound, (RS)-5-(4-aminophenyl)-8-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benz azepin-7-o l (SCH 39111), possesses high affinity for the D1 receptor and, when immobilized on Sepharose 6B through an extended spacer arm, was able to adsorb digitonin-solubilized D1 receptors. The interaction between the solubilized receptor and the affinity matrix was biospecific. Adsorption of receptor activity could be blocked in a stereoselective fashion [SCH 23390 greater than SCH 23388; (+)-butaclamol greater than (-)-butaclamol]. The elution of [3H]SCH 23390 activity from the gel demonstrated similar stereoselectivity for antagonist ligands. Agonists eluted receptor activity with a rank order of potency consistent with that of a D1 receptor [apomorphine greater than dopamine greater than (-)-epinephrine much greater than LY 171555 greater than serotonin]. SCH 39111-Sepharose absorbed 75-85% of the soluble receptor activity, and after the gel was washed extensively, 35-55% of the absorbed receptor activity could be eluted with 100 microM (+)-butaclamol with specific activities ranging from 250 to 450 pmol/mg of protein. The affinity-purified receptor retains the ligand binding characteristics of a D1 dopamine receptor. This affinity chromatography procedure should prove valuable in the isolation and molecular characterization of the D1 dopamine receptor.     

Further characterisation of the dopamine-inhibitory receptor in Helix and evidence for a noradrenaline-preferring receptor

1. The cells in this study responded with a hyperpolarization to the following agents in this order of potency; dopamine greater than noradrenaline phenylephrine = octopamine. 2. 6,7 ADTN had a relative potency of 0.1 compared to dopamine. 5,6 ADTN did not inhibit the cells in this study. 3. The D1 receptor agonists SKF38393 and dihydroxynomifensine mimicked the effect of dopamine on these cells but were over 100 times less active, whereas the D2 selective agonists quinpirole and RU24213 were without effect. 4. Both the D1 antagonist SCH23390 and the D2 antagonist sulpiride antagonised the dopamine response with pA2 values of 6.1 and 6.7, respectively. 5. Five cells that responded to dopamine with a hyperpolarization were depolarized by noradrenaline. The order of potency of compounds at eliciting this depolarization, noradrenaline greater than phenylephrine greater than octopamine indicated that this response may be mediated by a noradrenaline-preferring receptor.     

Role of adenosine in hypoxic ventilatory depression

The role of adenosine in the ventilatory depression induced by hypoxia was studied in 82 spontaneously breathing urethan-anesthetized 4-day-old rabbit pups. Respiration was monitored with a pneumotachograph. The animals were exposed to hypoxia (6% O2 in N2) for 30 min or until the occurrence of terminal apnea. In all animals hypoxia produced an initial increase in ventilation followed by a decrease. In the control group 52% of the animals became apneic after 7 min of hypoxic exposure. By contrast, pretreatment with dipyridamole (10 or 20 mg/kg), an adenosine uptake blocker, significantly shortened the time needed to reach apnea. Thus at 7 min of hypoxia 93% of the animals that received dipyridamole became apneic. On the other hand, administration of adenosine antagonists 8-p-sulfophenyltheophylline (5 or 8 mg/kg) and aminophylline (10 or 25 mg/kg) significantly prolonged the time required to produce apnea. Only 20% of the animals that received these antagonists became apneic at 7 min of hypoxia. These results suggest that adenosine is potentially involved in the ventilatory depression produced by hypoxia in neonatal rabbit pups.     

Ventilatory responses to acute and chronic hypoxia in mice: effects of dopamine D(2) receptors.

We used genetically engineered D(2) receptor-deficient [D(2)-(-/-)] and wild-type [D(2)-(+/+)] mice to test the hypothesis that dopamine D(2) receptors modulate the ventilatory response to acute hypoxia [hypoxic ventilatory response (HVR)] and hypercapnia [hypercapnic ventilatory response (HCVR)] and time-dependent changes in ventilation during chronic hypoxia. HVR was independent of gender in D(2)-(+/+) mice and significantly greater in D(2)-(-/-) than in D(2)-(+/+) female mice. HCVR was significantly greater in female D(2)-(+/+) mice than in male D(2)-(+/+) and was greater in D(2)-(-/-) male mice than in D(2)-(+/+) male mice. Exposure to hypoxia for 2-8 days was studied in male mice only. D(2)-(+/+) mice showed time-dependent increases in "baseline" ventilation (inspired PO(2) = 214 Torr) and hypoxic stimulated ventilation (inspired PO(2) = 70 Torr) after 8 days of acclimatization to hypoxia, but D(2)-(-/-) mice did not. Hence, dopamine D(2) receptors modulate the acute HVR and HCVR in mice in a gender-specific manner and contribute to time-dependent changes in ventilation and the acute HVR during acclimatization to hypoxia.     

Evidence that the stimulus properties of apomorphine are mediated by both D1 and D2 receptor activation

Male and female rats were trained to discriminate between the stimulus properties of apomorphine (0.16 mg/kg i.p.) and saline in a two-lever, food-motivated operant procedure. Apomorphine, at doses different than the training dose, produced a similar dose-dependent relationship in both sexes. Consistent with the hypothesis that the behavioral effects of apomorphine are mediated by D2 activation, the apomorphine interoceptive cue generalized to bromocriptine, a drug considered to be a preferential D2 agonist. In addition, the dose-response curve after 5-15 mg/kg bromocriptine administration was parallel to that of apomorphine. Consistent with the biochemical evidence that apomorphine's effects are mediated, to a lesser extent, by D1 activation, the apomorphine cue partially generalized to the selective D1 agonist SKF 38393. Furthermore, the apomorphine cue was not blocked by the selective D1 antagonist SCH 23390. Somewhat surprising was the partial generalization of the apomorphine cue to SCH 23390. However, this is not the first time that the administration of SCH 23390 has resulted in unexpected behavioral responses. Other novel findings include the lack of sex differences in acquisition training to the apomorphine cue and in the generalization tests to the selective agonists. The behavioral results are consistent with previous biochemical evidence that the effects of apomorphine are mediated by both D1 and D2 activation and is further behavioral support that apomorphine's effects are not the result of D2 activation alone, as previously hypothesized.     

Selective depletion of dopamine in the goldfish pituitary caused by domperidone.

The effects of the dopamine type-2 receptor (D-2) antagonist domperidone on pituitary and brain amine concentrations and serum gonadotropin levels in the goldfish were investigated. Domperidone caused a long-lasting, dose-dependent depletion of dopamine in the goldfish pituitary. Pituitary concentrations of 5-hydroxytryptamine (5HT) were unaffected by domperidone treatment. Concentrations of noradenaline, dopamine, and 5HT in the hypothalamus and telencephalon were also unaffected by domperidone treatment. In contrast to the goldfish, dopamine levels in both mouse pituitary and hypothalamus were unaffected by domperidone treatment. The depletion of dopamine was observed in both sexually regressed and recrudescent, male and female fish, but elevation of serum gonadotropin levels in response to domperidone treatment occurred only in sexually recrudescent fish. Treatment of sexually recrudescent fish with the D-2 antagonists pimozide, (-)-sulpiride and eticlopride and the dopamine type-1 (D-1) antagonists SKF 83566 and SCH 23390 failed to elicit a depletion of pituitary dopamine or elevation of serum gonadotropin. Treatment of sexually recrudescent fish with domperidone, alpha-methyl-p-tyrosine or carbidopa elicited comparable depletions of pituitary dopamine and elevations of serum gonadotropin. The results suggest that in addition to D-2 receptor antagonist activity, domperidone has some other neuropharmacological action on dopaminergic neurones in the goldfish pituitary.     

D2-dopamine receptor and alpha2-adrenoreceptor-mediated analgesic response of quercetin

Quercetin, a bioflavonoid (100-300 mg/kg) produced dose dependent increase in tail-flick latency, the analgesic effect being sensitive to reversal by naloxone (1 mg/kg). Prior treatment with haloperidol (1 mg/kg), D1/D2 receptor antagonist haloperidol, sulpiride (50 mg/kg), a selective D2 receptor antagonist, yohimbine (5 mg/kg), a alpha2-adrenoreceptor antagonist but not by SCH 23390 a, selective D1 receptor antagonist blocked this response. Apomorphine (1 mg/kg) a mixed D1/D2 dopamine receptor agonist, and quinpirole (0.5 mg/kg), a selective D2 receptor agonist also produced antinociception, that was reversed by haloperidol (1 mg/kg), sulpiride (50 mg/kg), but not by yohimbine (5 mg/kg). The antinociceptive action of quercetin (200 mg/kg) was potentiated by D2 agonist quinpirole (0.2 mg/kg). Dopamine D1 receptor agonist SKF38393 (10 and 15 mg/kg) failed to alter the antinociceptive effect of quercetin (200 mg/kg). Quercetin (200 mg/kg) reversed reserpine (2 mg/kg-4 hr) induced hyperalgesia, which was reversed by sulpiride but not by yohimbine. Thus, a role of dopamine D2 and alpha2-adrenoreceptors is postulated in the antinociceptive action of quercetin.