Cellular Mechanism for Specific Mechanical Antinociception by D2-like Receptor at the Spinal Cord Level

Intrathecal (i.t.) administration of quinpirole, a dopamine (DA) D2-like receptor agonist, produces antinociception to mechanonociceptive stimuli but not to thermonociceptive stimuli. To determine a cellular mechanism for the specific antinociceptive effect of D2-like receptor activation on mechanonociception, we evaluated the effect of quinpirole on voltage-gated Ca²⁺ influx in cultured dorsal root ganglion (DRG) neurons and the D2 DA receptor distribution in subpopulations of rat nociceptive DRG neurons. Small-diameter DRG neurons were classified into IB₄+ (nonpeptidergic) and IB₄- (peptidergic). Intracellular [Ca²⁺] microfluorometry and voltage-clamp experiments showed that quinpirole reduced Ca²⁺ influx and inhibited the high voltage-activated Ca²⁺ current (HVA-I_Ca) in half of IB₄+ neurons, leaving Ca²⁺ entry and HVA-I_Ca in IB₄- neurons nearly unaffected. Pretreatment with ω-conotoxin MVIIA prevented the effect of quinpirole on HVA-I_Ca from IB₄+ neurons, indicating that quinpirole mainly inhibits Ca_V2.2 channels. Immunofluorescence experiments showed that D2 DA receptor was present mainly in IB₄+ small DRG neurons. Finally, in behavioral experiments in rats, the clinically approved D2-like receptor agonist pramipexole produced spinal antinociception in a similar fashion to quinpirole, with a significant effect only in the mechanonociceptive test. Our results explain, at least in part, why D2-like receptor agonists produce antinociception on mechanonociceptors.