Quinpirole

The transfer of nociceptive information at the level of dorsal horn is subject to extensive processing by both local segmental and supraspinal mechanisms, including descending dopaminergic controls, originating from the hypothalamic A11 nucleus. The inhibitory role of dopamine on evoked pain via activation of D2-like receptors at the level of the dorsal horn is well established. Here, by use of behavioral, electrophysiological, and anatomical techniques, we examined within the trigeminal sensory complex, first, whether descending dopaminergic controls also modulate pain behavior after an inflammatory insult, and second, under which physiological conditions these descending dopaminergic controls are actually recruited. We show that D2 receptors are mostly located within superficial medullary dorsal horn where trigeminal nociceptive fibers abut. Activating these D2-like receptors inhibits, whereas blocking them enhances, both formalin- and capsaicin-evoked pain behavior and C-fiber-ev...

Earlier studies indicate that striatal dopamine D(2) receptors are involved in pain regulation in non-neuropathic conditions. We assessed whether striatal dopamine D(2) receptors contribute to pain regulation also in neuropathic conditions. The spared nerve injury model of neuropathy was induced by unilateral ligation of the tibial and common peroneal nerves in the rat. In awake nerve-injured animals, pain-related withdrawal responses to calibrated monofilaments or noxious heating were attenuated following striatal administration of a dopamine D(2) receptor agonist quinpirole. Pain-related responses were attenuated only in the nerve-injured limb ipsilateral to the injection and in the midline (tail). In unoperated controls, striatal administration of quinpirole at an antihypersensitive dose did not influence withdrawal responses to mechanical stimulation. Attenuation of pain-related responses induced by striatal administration of quinpirole was reversed by intrathecal administration of a dopamine D(2) receptor antagonist (eticlopride) or a non-selective 5-HT receptor antagonist (methysergide), but not by an alpha(2)-adrenoceptor antagonist (atipamezole). In the rostroventromedial medulla of lightly anesthetized neuropathic animals, striatal administration of quinpirole significantly decreased the activity of presumably pronociceptive cells that are activated by noxious stimulation. The innocuous H-reflex in lightly anesthetized control animals was not suppressed by striatal administration of quinpirole at an antihypersensitive dose. The results indicate that striatal dopamine D(2) receptors attenuate neuropathic hypersensitivity. The antihypersensitive effect induced by striatal dopamine D(2) receptors in peripheral neuropathy involves suppression of impulse discharge of presumably pronociceptive neurons in the rostroventromedial medulla, and a descending influence acting on spinal 5-HT and dopamine D(2) receptors.

Dose-effect curves were obtained for five specific components of stereotyped behavior (locomotor hyperactivity, rearing, sniffing, grooming and oral activity) elicited by the nonselective dopamine agonists N-propylnorapomorphine (NPA; 0.001-4.5 mg/kg) and apomorphine (APO; 0.3-10.0 mg/kg), the selective D2 agonists LY 171555 (0.1-18.0 mg/kg) and RU 24213 (0.7-20.0 mg/kg) and the selective D1 agonist SKF 38393 (0.6-40.0 mg/kg) in male Sprague-Dawley rats. All the agonists except SKF 38393 elicited dose-dependent sniffing. Both NPA and APO produced robust oral activity at high doses, with concomitant reductions in other behaviors. Neither RU 24213 nor SKF 38393 elicited dose-dependent oral behavior, whereas LY 171555 induced a maximal level of oral activity which was much less intense than that produced by NPA or APO. SKF 38393 alone induced only dose-dependent grooming. Co-treatment of Sprague-Dawley rats with SKF 38393 (5-40 mg/kg) and either LY 171555 (0.1-1.6 mg/kg) or RU 24213 (6.7 mg/kg) produced significant enhancement of sniffing but not of oral activity. Significant enhancement of both behavioral components was observed in male Wistar rats. Differences in specific components of behavioral response on treatment with combinations of D1 and D2 agonists may reflect use of animal strains with different ratios of D1/D2 innervation and/or different behavioral criteria.

1.The D2-type dopamine receptors are thought to inhibit adenylyl cyclase (AC), via coupling to pertussis toxin (PTX)-sensitive G proteins of the Gi family. We examined whether and to what extent the various D2 receptors (D2S, D2L, D3S, D3L, and D4) couple to the PTX-insensitive G protein Gz, to produce inhibition of AC activity. 2.COS-7 cells were transiently transfected with the individual murine dopamine receptors alone, as well as together with the α subunit of Gz. PTX treatment was employed to inactivate endogenous αi, and coupling to Gi and Gz was estimated by measuring the inhibition of cAMP accumulation induced by quinpirole, in forskolin-stimulated cells. 3.D2S or D2L receptors can couple to the same extent to Gi and to Gz. The D4 dopamine receptor couples preferably to Gz, resulting in about 60% quinpirole-induced inhibition of cAMP accumulation. The D3S and D3L receptor isoforms couple slightly to Gz and result in 15 and 30% inhibition of cAMP accumulation, respectively. 4.We have demonstrated for the first time that the two D3 receptor isoforms, and not any of the other D2 receptor subtypes, also couple to Gs in both COS-7 and CHO transfected cells, in the presence of PTX. 5.Thus, the differential coupling of the D2 dopamine receptor subtypes to various G proteins may add another aspect to the diversity of dopamine receptor function.

Intracellular recordings in in vitro slice preparations of rat brain were used to compare the actions of dopamine and dopamine receptor agonists on the subthreshold membrane properties of neostriatal neurons. A reproducible response for dopaminergic agonists was evoked after firing produced by current ramp injections that induced a subthreshold voltage displacement. Dopamine (10–100 μM) decreased both firing rate and membrane slope input resistance in virtually all cells tested. Input resistance change appeared as an increase in inward rectification. Approximate reversal potential was around -87 mV. The D1 receptor agonists SKF 38393 and C1-APB (1–10 μM) mimicked both dopamine effects with a reversal potential around -89 mV. The effects were blocked by the presence of 5–10 μM caesium (Cs+) but not by 1 μM tetrodotoxin, suggesting that main D1 effects on input resistance are due to subthreshold Cs+ sensitive conductances. cAMP analogues mimicked the actions of D1 receptor agonists. The D2 agonist, quinpirole (1–10 μM), did not produce any input resistance change, nonetheless, it still produced a decrease in firing rate. This suggests that the main D2 effect on firing is due to actions on suprathreshold ion conductances. All effects were blocked by D1 and D2 antagonists, respectively. D1 or D2 effects were found in the majority of cells tested.

1q21.1 hemizygous microdeletion is a copy number variant leading to eightfold increased risk of schizophrenia. In order to investigate biological alterations induced by this microdeletion, we generated a novel mouse model (Df(h1q21)/+) and characterized it in a broad test battery focusing on schizophrenia-related assays. Df(h1q21)/+ mice displayed increased hyperactivity in response to amphetamine challenge and increased sensitivity to the disruptive effects of amphetamine and phencyclidine hydrochloride (PCP) on prepulse inhibition. Probing of the direct dopamine (DA) pathway using the DA D1 receptor agonist SKF-81297 revealed no differences in induced locomotor activity compared to wild-type mice, but Df(h1q21)/+ mice showed increased sensitivity to the DA D2 receptor agonist quinpirole and the D1/D2 agonist apomorphine. Electrophysiological characterization of DA neuron firing in the ventral tegmental area revealed more spontaneously active DA neurons and increased firing variabi...