An investigation of the antinociceptive activity of calcitonin gene-related peptide alone and in combination with morphine: correlation to 45Ca++ uptake by synaptosomes.

A 5- or 30-min incubation of synaptosomes with calcitonin gene-related peptide (CGRP) (10(-6), 10(-7), 10(-8) M) produced increases in 45Ca++ uptake upon depolarization of the synaptosomes, whereas a naloxone-reversible decrease in 45Ca++ uptake was seen after a 1-hr incubation with CGRP. Morphine-induced (10(-6) M) decreases in 45Ca++ uptake were reversed by simultaneous 5-min incubation of synaptosomes with CGRP (10(-6) M) and were enhanced by a 1-hr preincubation of the synaptosomes with CGRP (10(-6) M). CGRP produced naloxone-reversible antinociception in both the p-phenylquinone and hot-plate tests at 1 hr after i.c.v. administration, a time which corresponds to the peak CGRP-induced decrease in 45Ca++ uptake. CGRP (0.02 microgram through 40 micrograms i.c.v.) failed to produce antinociception in the tail-flick test. However, 30-min pretreatment of mice with CGRP (2 micrograms i.c.v.), a time point corresponding to a CGRP-induced increase in 45Ca++ uptake in vitro, significantly antagonized morphine-induced antinociception in the tail-flick test. A 1-hr pretreatment of mice with CGRP (2 micrograms i.c.v.), a time point in which a CGRP-induced decrease in 45Ca++ uptake was observed, slightly potentiated morphine in the tail-flick and hot-plate tests, but not in the p-phenylquinone test. The effects of CGRP on Ca++ uptake are suggestive of, but do not entirely predict, its activity in vivo and in vitro.