TY - JOUR
T1 - Pharmacological interaction of the calcium channel blockers verapamil and flunarizine with the opioid system
AU - Weizman, Ronit
AU - Getslev, Valery
AU - Pankova, Irena A.
AU - Schrieber, Shaul
AU - Pick, Chaim G.
N1 - Funding Information:
This work was supported in part by the Tel Aviv University Foundation for Basic Research and by The Adams Super-Center for Brain Studies at Tel Aviv University. We thank Mrs. Gloria Ginzach for editing this manuscript.
PY - 1999/2/13
Y1 - 1999/2/13
N2 - We evaluated the opioid antinociceptive mechanism of the calcium channel blockers verapamil and flunarizine in groups of mice with the hotplate test. Both produced a naloxone-sensitive dose-dependent analgesia. The antinociceptive effect of both was reversed by β-FNA, (μ1 and μ2 antagonists), and both enhanced the antinociceptive activity of morphine, implying a role for μ receptors. Furthermore, since the analgesic effect of flunarizine, but not verapamil, was reversed by naloxonazine (μ1 antagonist), we suggest that the μ1 subtype is involved in flunarizine analgesia, but not in verapamil analgesia. Studies with the selective δ opioid agonist DPDPE and the selective antagonists naltrindole indicated that the antinociceptive activity of verapamil is also mediated by δ receptor agonistic activity (primarily following i.c.v, administration); flunarizine, by contrast, exhibited antagonistic activity at this receptor. Verapamil amplified the antinociceptive activity of κ1 (U50,488H) and κ3 (nalorphine) agonists, but its known analgesic activity was inhibited only partially by the κ1 antagonist Nor-BNI, indicating partial involvement of κ1 receptor. Flunarizine, however, demonstrated antagonistic activity at both κ1 and κ3 receptors, with more prominent inhibitory activity at the latter one. These findings suggest that verapamil and flunarizine elicit analgesia at both the spinal and supraspinal levels. Verapamil's analgesia was explained by agonistic activity at the μ, δ and may also be κ3 receptor subtypes. Flunarizine exhibited a mixed agonistic-antagonistic opioid activity as shown by its agonistic activity at the μ1 receptor and antagonistic activity at δ, κ1 and κ3 receptor subtypes.
AB - We evaluated the opioid antinociceptive mechanism of the calcium channel blockers verapamil and flunarizine in groups of mice with the hotplate test. Both produced a naloxone-sensitive dose-dependent analgesia. The antinociceptive effect of both was reversed by β-FNA, (μ1 and μ2 antagonists), and both enhanced the antinociceptive activity of morphine, implying a role for μ receptors. Furthermore, since the analgesic effect of flunarizine, but not verapamil, was reversed by naloxonazine (μ1 antagonist), we suggest that the μ1 subtype is involved in flunarizine analgesia, but not in verapamil analgesia. Studies with the selective δ opioid agonist DPDPE and the selective antagonists naltrindole indicated that the antinociceptive activity of verapamil is also mediated by δ receptor agonistic activity (primarily following i.c.v, administration); flunarizine, by contrast, exhibited antagonistic activity at this receptor. Verapamil amplified the antinociceptive activity of κ1 (U50,488H) and κ3 (nalorphine) agonists, but its known analgesic activity was inhibited only partially by the κ1 antagonist Nor-BNI, indicating partial involvement of κ1 receptor. Flunarizine, however, demonstrated antagonistic activity at both κ1 and κ3 receptors, with more prominent inhibitory activity at the latter one. These findings suggest that verapamil and flunarizine elicit analgesia at both the spinal and supraspinal levels. Verapamil's analgesia was explained by agonistic activity at the μ, δ and may also be κ3 receptor subtypes. Flunarizine exhibited a mixed agonistic-antagonistic opioid activity as shown by its agonistic activity at the μ1 receptor and antagonistic activity at δ, κ1 and κ3 receptor subtypes.
KW - Analgesia
KW - Flunarizine
KW - Hotplate test
KW - Opioid receptor subtype
KW - Verapamil
UR - http://www.scopus.com/inward/record.url?scp=0033550670&partnerID=8YFLogxK
U2 - 10.1016/S0006-8993(98)01175-5
DO - 10.1016/S0006-8993(98)01175-5
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AN - SCOPUS:0033550670
SN - 0006-8993
VL - 818
SP - 187
EP - 195
JO - Brain Research
JF - Brain Research
IS - 2
ER -