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

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 micrograms/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). mu-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).(ABSTRACT TRUNCATED AT 250 WORDS)

Role of L‐Type Calcium Channel Modulation in Nonconvulsive Epilepsy in Rats

“…Because the mild effects on behavior were evident only after the highest dose and the effects on the number of spike-wave discharges was already apparent at the lowest dose, the antiepileptic action of BAY K 8644 probably is not due to its behavioral-activating effects. The protective effects of BAY K 8644 and the facilitatory effects of nimodipine were contrary to effects previously described indicating that calcium antagonists act like AEDs (Ashton and Wauquier, 1979;Hoffmeister et al, 1982;Drago et al, 1986;Heinemann and Hamon, 1986;Hoffmeister and Tetterhorn, 1986;Meyer et al, 1986Meyer et al, ,1987De Sarro et al, 1988;Yuasa et al, 1989;Kamal et al, 1990). Moreover, agonists or channel activators such as BAY K 8644 act like convulsant drugs (De Sarro et al, 1990).…”

Reduction of morphine dependence and potentiation of analgesia by chronic co-administration of nifedipine

“…Nifedipine and Other dihydropyridine calcium channel blocking agents were known to potentiate the analgesic action of opioids (Hoffmeister and Tettenborn 1986;Kavaliers 1987;Contreras et al 1988, and other compounds (Ramaswamy et al 1986;Thirugnanasambantham et al 1988;AntkiewiczMichaluk et al 1991) in naive animals and to counteract the acute symptoms of opiate withdrawal in vivo (Bongianni et al 1986;Baeyens et al 1987;Caro et al 1988;Pellegrini-Giampietro et al 1988;Ramkumar and E1-Fakahany 1988;Antkiewicz-Michaluk et al 1990)and in vitro (Valeri et al t990), but our present results show that nifedipine also potentiates the analgesic effect of morphine in rats in which, due to chronic morphine administration, the analgesic effect of the drug disappeared, and that chronic co-administration of nifedipine with morphine prevents the development of physical abstinence. In addition, our findings indicate that the potentiation of analgesic action of morphine by nifedipine is mainly caused by the drug action on supraspinal pain centers, as hired±pine in the dose used does not influence the morphine effect in the tail-flick test, reflecting spinal pain mechanisms, but potentiates the analgesia measured in the hot-plate test, reflecting supraspinal pain mechanisms (Yaksh 1978a, b).…”

“…Thus, after the finding that an c~2-adrenoceptor agonist clonidine inhibits nalorphine-precipitated abstinence syndrome (Vetulani and Bednarczyk 1977) the drug was successfully introduced into therapy of opiate addicts (Gold et al 1978;Charney et al 1982). Another class of drugs which seem to have a considerable potential as nonopioid agents depressing the signs of abstinence are calcium channel blockers, which not only relieve the signs of morphine abstinence in animals in vivo and in vitro (Bongianni et al 1986;Baeyens et al t987;Caro et al 1988;Pellegrini-Giampietro et al 1988;Ramkumar and E1-Fakahany 1988;Antkiewicz-Michaluk et al 1990), but also potentiate the analgesic action of opioids (Hoffmeister and Tettenborn 1986;Kavaliers 1987;Contreras et al 1988) and some non-opioid drugs (Antkiewicz-Michaluk et al 1991).…”

Involvement of calcium in pain and antinociception

“…Low doses of BAY K 8644 reduced, whereas high doses enhanced, the antinociception induced by sc opioids in rodents (14,16). The dualistic effect of BAY K 8644 may derive from its Ca 2+ agonistic property, which is prominent at low concentrations but declines at higher concentrations (15). Intracerebroventricular EGTA, but not EDTA increases morphineand k-agonist-induced antinociception in the mouse tail-flick test.…”