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.
Welch
S P
SP
Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond.
Cooper
C W
CW
Dewey
W L
WL
D000700:Analgesics; D000818:Animals; D016227:Benzoquinones; D015740:Calcitonin Gene-Related Peptide; D002118:Calcium / Q000493:pharmacokinetics*; D004347:Drug Interactions; D006358:Hot Temperature; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology*; D009270:Naloxone / Q000494:pharmacology; D009479:Neuropeptides / Q000008:administration & dosage / Q000494:pharmacology*; D011809:Quinones; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism*; D013997:Time Factors
D000700:Analgesics; D016227:Benzoquinones; D009479:Neuropeptides; D011809:Quinones; C029322:phenylbenzoquinone; D009270:Naloxone; D009020:Morphine; D015740:Calcitonin Gene-Related Peptide; D002118:Calcium