European Journal of Pharmacology, 137 (1987) 155-160 155 Elsevier EJP 00754 Analgesic effects of several calcium channel blockers in mice Esperanza Del Pozo, Gerardo Caro and Jos6 M. Baeyens * Department of Pharmacology, University of Granada Medical School, A vda. de Madrid s / n, 180] 2 Granada, Spain Received 10 November 1986, revised MS received 9 February 1987, accepted 3 March 1987 The possibility that calcium channel blockers might produce antinociception and increase morphine analgesia was examined using the acetic acid writhing test in mice. Subcutaneous injections of diltiazem, verapamil, nicardipine, flunarizine and cinnarizine produced a dose-dependent antinociception. This activity of diltiazem was.stereospecific; d-cis-diltiazem was more potent than 1-cis-diltiazem. All the calcium channel blockers studied increased morphine analgesia and displaced to the left the morphine dose-response curve. This effect of diltiazem was also stereospecific. These results suggest that calcium channel blockers can induce analgesia and increase morphine analgesia, possibly through a decrease in cellular calcium availability. Calcium channel blockers; Morphine; Analgesia; Writhing test 1. Introduction Several investigations have suggested that calcium has a physiological role in the control of pain either through a direct action or through modulation of the analgesic activities of other endogenous substances. In particular, it has been shown that intracerebroventricular (i.c.v.) injec- tions of calcium produce hyperalgesia in rodents (Chapman and Way, 1982; Ben-Sreti et al., 1983) whereas the calcium chelators EDTA and EGTA, and the inorganic inhibitor of calcium cellular influx, lanthanum, produce antinociceptive effects which are antagonized by calcium (Hano et al., 1964; Harris et al., 1975; Iwamoto et al., 1978; Schmidt and Way, 1980). Furthermore, it has been reported that i.c.v. calcium injections antagonize the analgesic effects * To whom all correspondence should be addressed: Depart- ment of Pharmacology, University of Granada Medical School, Avda. de Madrid s/n, 18012 Granada, Spain. of morphine (Hano et al., 1964; Harris et al., 1975; Iwamoto et al., 1978; Vocci et al., 1980), fl-endorphin and [MetS]enkephalin (Guerrero Muhoz et al., 1981; Chapman and Way, 1982), and acetylcholine (Widman et al., 1978). These effects of calcium can be potentiated by the calcium ionophores A23187 and X537A (Harris et al., 1975; Widman et al., 1978; Vocci et al., 1980; Chapman and Way, 1982). By contrast EDTA, EGTA and lanthanum increase the analgesic ef- fects of morphine, fl-endorphin, [MetS]enkephalin and acetylcholine (Hano et al., 1964; Harris et al., 1975; Harris et al., 1976; Widman et al., 1978; Vocci et al., 1980; Chapman and Way, 1982). These various facts make it conceivable that other inhibitors of cellular calcium influx, such as the organic calcium channel blockers, could exert analgesic effects per se and increase morphine analgesia. We now report on the analgesic activity of several calcium channel blockers and their ability to increase morphine analgesia in mice. 0014-2999/87/$03.50 © 1987 Elsevier Science Publishers B.V. (Biomedical Division)