Fig. 2: Antagonism of spinal D2DR, but not D1DR, attenuates morphine tolerance and a D2DR agonist reverses the inhibitory effects of l-CDL on morphine tolerance in mice.

a, b Intrathecal administration of the D2DR antagonist sulpiride (4 μg/10 μl) attenuated morphine tolerance, while the D1DR antagonist SCH-23390 (4 μg/10 μl) did not attenuate morphine tolerance. Neither sulpiride nor SCH-23390 affected the pain threshold of naïve mice. The analgesia was further reported in area under the curve (AUC) units. Data are presented as means ± SE. n = 12, ^*P < 0.05, ^**P < 0.01, compared with the morphine group. c, d Intrathecal administration of the D2DR agonist quinpirole (1 μg/10 μl) abolished l-CDL (3.3 μg/10 μl)-induced inhibition of morphine tolerance in mice. The analgesia was further reported as area under the curve (AUC) units. Data are presented as means ± SE. n = 12, ^*P < 0.05, **P <0.01, compared with the group treated with the combination of morphine, l-CDL and quinpirole. e, f Multiple daily intrathecal injections of the D2DR siRNA for 7 days effectively attenuated the development of morphine tolerance, while the nonspecific oligonucleotide had no effect. Neither the D2DR siRNA nor the nonspecific oligonucleotide altered the pain threshold of naïve mice. Data are presented as means ± SE. n = 12, ^*P < 0.05, ^**P < 0.01, compared with the morphine group. g, h Intrathecal administration of the D2DR siRNA for 7 days obviously reduced the expression of D2DR in the spinal cord. Representative western blot bands and a summary of the data are shown. Data are presented as means ± SE. ⁿ = 4, ^#P < 0.05, ^##P < 0.01, compared with the vehicle; ^*P < 0.05, ^**P < 0.01, compared with the siRNA group