Increase in dopamine D 2 receptor binding following long-term treatment with neuroleptics in humans

Abstract

The present study examined the role of dopamine and D1-and D2-like dopamine receptors in ventrolateral orbital cortex (VLO)-evoked anti-hypersensitivity in a rat model of neuropathic pain, as well as the possible underlying mechanisms. Results showed that microinjection of apomorphine [(R(−)-apomorphine hydrochloride)], a non-selective dopamine receptor agonist, into the VLO attenuated spared nerve injury (SNI)-induced mechanical allodynia in a dose-dependent manner. This effect was completely blocked by the D2-like dopamine receptor antagonist S(−)-raclopride(+)-tartrate salt (1.5 μg), but was enhanced by the D1-like dopamine receptor antagonist SCH23390 (R(+)-SCH-23390 hydrochloride, 5.0 μg). The attenuating effect of apomorphine on mechanical allodynia was mimicked by application of the D2-like dopamine receptor agonist quinpirole [((−)-quinpirole hydrochloride, 0.5, 1.0, and 2.0 μg)]. In addition, microinjection of larger doses (10 and 20 μg) of SCH23390 into the VLO significantly attenuated allodynia. Furthermore, microinjections of GABAA receptor antagonists, bicuculline [(+)-bicuculline,(S), 9(R)] and picrotoxin (200 and 300 ng for both drugs), into the VLO attenuated mechanical allodynia. A small dose of bicuculline or picrotoxin (100 ng) resulted in increased quinpirole (0.5 μg)-induced anti-allodynia. In contrast, GABAA receptor agonists, muscimol hydrochloride (250 ng) or THIP [(2,5,6,7-retrahydroisoxazolo(5,4-c)pyridine-3-ol hydrochloride, 1.0 μg)], blocked quinpirole (2.0 μg)-induced attenuation. These results suggest that the dopaminergic system is involved in mediating VLO-induced anti-hypersensitivity, activation of D2-like dopamine receptors, and inhibition of D1-like receptors resulting in anti-hypersensitivity. In addition, the mechanisms of GABAergic disinhibition might be involved in D2-like receptor mediating effects in neuropathic pain.