ANALGESIC EFFECT OF THE DIRECT D-2 DOPAMINE-RECEPTOR AGONIST RU-24926AND CROSS-TOLERANCE WITH MORPHINE

The direct D-2 dopamine receptor agonist RU 24926, administered subcut aneously to mice, elicited, starting at the dose of 0.125 mg/kg, a dos e dependent analgesic effect, assessed as the jump latency from a hot plate (55 degrees C). The analgesic effect induced by 0.25 mg/kg RU 24 926 was dose dependently antagonized by the preferential D-2 dopamine receptor antagonist haloperidol (ID50=15.1+/-3.3 mu g/kg sc) as well a s by the opioid receptor antagonist naloxone (ID50=0.59+/-0.17 mg/kg s c). The reversion of RU 24926-induced analgesia by naloxone was not ac companied by a reversion of hypothermia. Semi-chronic administration o f RU 24926 (2.5 mg/kg, sc, 3 times a day for 3 days) completely desens itized to the analgesic effect induced by a 0.25 mg/kg test dose of RU 24926 and partially reduced the analgesic effect of low doses of morp hine (0.5, 1, 1.5 mg/kg). Conversely, semi-chronic administration of m orphine (32 mg/kg sc, twice daily for 4 days) completely desensitized the analgesic effect induced by a 2 mg/kg test dose of morphine and pa rtially reduced the analgesic effect of RU 24926 (0.25, 0.5 and 1 mg/k g). The RU 24926-induced analgesia did not seem to be the nonspecific consequence of its hypothermic effect since: i) the time course of hyp othermia was shorter than that of analgesia, ii) the analgesic effect was observed in inbred C3H mice which have a low sensitivity to the hy pothermic effect of direct agonists of D-2 dopamine receptors and iii) in mice semi-chronically treated with morphine and thereby made toler ant to the RU 24926-induced analgesia, the hypothermic effect of RU 24 926 was found unchanged. It is suggested that the stimulation of D-2 d opamine receptors, without obvious link with the resultant hypothermia , releases an opioid material which induces analgesia.