Pharmacological interaction of the calcium channel blockers verapamil and flunarizine with the opioid system

Ronit Weizman, Valery Getslev, Irena A. Pankova, Shaul Schrieber, Chaim G. Pick*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)187-195
Number of pages9
JournalBrain Research
Volume818
Issue number2
DOIs
StatePublished - 13 Feb 1999

Funding

FundersFunder number
Tel Aviv University

    Keywords

    • Analgesia
    • Flunarizine
    • Hotplate test
    • Opioid receptor subtype
    • Verapamil

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