Pharmacological and genetic evidence for pre- and postsynaptic D2 receptor involvement in motor responses to nociceptin/orphanin FQ receptor ligands.

A combined pharmacological and genetic approach was undertaken to investigate the contribution of endogenous dopamine to the motor actions of nociceptin/orphanin FQ (N/OFQ) receptor (NOP receptor) ligands. Motor activity was evaluated by a battery of behavioural tests in mice. The involvement of the various DA receptor subtypes in the motor effects of N/OFQ and NOP receptor antagonists was evaluated pharmacologically, using D1/D5 (SCH23390), D2/D3 (raclopride, amisulpride) and D3 (S33084) receptor antagonists, and by using D2 receptor knockout mice. Low doses of N/OFQ and NOP receptor antagonists promoted movement whereas higher doses inhibited it. Motor facilitation was selectively prevented by raclopride while motor inhibition was prevented by amisulpride. Amisulpride also attenuated the hypolocomotion induced by the D2/D3 receptor agonist pramipexole and dopamine precursor l-3,4-dihydroxyphenylalanine, whereas raclopride (and S33084) worsened it. To dissect out the contribution of pre- and postsynaptic D2 receptors, mice lacking the D2 receptor (D2R(-/-)) or its long isoform (D2L(-/-)) were used. Motor facilitation induced by N/OFQ and NOP receptor antagonists was lost in D2R(-/-) and D2L(-/-) mice whereas motor inhibition induced by NOP receptor antagonists (and pramipexole) was lost in D2R(-/-) but preserved in D2L(-/-) mice. N/OFQ-induced hypolocomotion was observed in both genotypes. We demonstrate that motor actions of NOP receptor ligands rely on the modulation of endogenous dopamine. Motor facilitation induced by NOP receptor antagonists as well as low dose N/OFQ is mediated through D2L postsynaptic receptors whereas motor inhibition observed with higher doses of N/OFQ occurs by direct inhibition of mesencephalic DA neurons. Motor inhibition seen with high doses of NOP receptor antagonists appears to be mediated through the D2 presynaptic autoreceptors. These data confirm that endogenous N/OFQ is a powerful modulator of dopamine transmission in vivo and that the effects of NOP receptor antagonists on motor function reflect the blockade of this endogenous N/OFQ tone.