Calcium agonists and antagonists of the dihydropyridine type: Antinociceptive effects, interference with opiate-?-receptor agonists and neuropharmacological actions in rodents

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Abstract
The calcium antagonist dihydropyridine derivative nimodipine and its enantiomers BAY N 5247, BAY N 5248, as well as BAY R 4407 (calcium antagonist (+)-enantiomer of the calcium agonist dihydropyridine BAY K 8644) do not exert antinociceptive effects in the rat as measured by the vocalization test in doses up to 100 μg/kg IV, and in the mouse as measured by the hot plate test in oral doses up to 100 mg/kg. The calcium agonists BAY K 8644 and BAY R 5417 ((−)-enantiomer of BAY K 8644) are also ineffective in the rat vocalization test but BAY K 8644 increases reaction time in the hot plate test (mouse) dose-dependently (1–10 mg/kg PO). μ-Receptor agonist (fentanyl) antinociceptive effects are potentiated by simultaneous IV administration of the calcium antagonists, the (−)-enantiomer of nimodipine BAY N 5248 being the most potent. This applies for the rat (vocalization test) and the mouse (hot plate test). The influence on fentanyl antinociception in the rat of the calcium agonist BAY K 8644 and its (−)-enantiomer BAY R 5417 is biphasic: low doses attenuate, high doses potentiate fentanyl antinociception. In the mouse (hot plate test) antinociceptive effects of BAY K 8644 plus fentanyl are less than additive, indicating that the calcium agonist decreases fentanyl effects. The relative potency of calcium antagonists in potentiation of fentanyl antinociception correlates with their relative potency as calcium antagonists as measured by receptor binding studies, effects on vascular and cardiac muscle, and with their neuropharmacological actions (anticonvulsive effects, inhibition of balance and spontaneous motility as well as tranquilizing effects in the mouse). It is concluded that calcium antagonism potentiates μ-receptor agonist antinociceptive effects, whereas calcium agonism antagonizes μ-receptor agonist antinociception.