The antinociception produced by intrathecal morphine, calcium, A23187, U50,488H, [D-Ala2, N-Me-Phe4, Gly-ol]enkephalin and [D-Pen2, D-Pen5]enkephalin after intrathecal administration of calcitonin gene-related peptide in mice.
Calcitonin gene-related peptide (CGRP), which has been shown to modulate calcium in both the brain and in peripheral tissues, has not previously been shown to modulate calcium in the spinal cord. This study shows that the effects of CGRP given intrathecally (i.t.) appear to result from calcium modulation. Evidence for this hypothesis is the parallel shift to the right in the dose-effect curves of both i.t. calcium and i.t. A23187 (a calcium ionophore) by i.t. CGRP, and the enhancement by ethylene glycol bis(beta-aminoethyl ether)-N,N'-tetraacetic acid of the ability of CGRP to antagonize morphine-induced antinociception. The CGRP-induced modulation of spinal calcium appears to occur in opiate-sensitive pathways as well as nonopioid pathways, as evidenced by parallel shifts to the right in the dose-response curves of i.c.v. and i.t. morphine in either the tail-flick or the hot-plate test and nonparallel shifts in the dose-response curve of s.c. morphine in the tail-flick test. CGRP attenuates the antinociceptive effect of the delta receptor-specific ligand [D-Pen2, D-Pen5]enkephalin (i.t.), but enhances the antinociceptive effect of the kappa ligand, U50, 488H. CGRP does not appear to interact directly with the opiate receptor because it does not mimic the activity of naloxone i.t. However, CGRP-induced alterations of calcium in opiate-sensitive spinal pathways appear to produce subtle modulation of opiate antinociception without direct opiate receptor interaction.
Welch
S P
SP
Department of Pharmacology and Toxicology, Virginia Commonwealth University/Medical College of Virginia, Richmond.
Singha
A K
AK
Dewey
W L
WL
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000698:Analgesia; D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D000001:Calcimycin / Q000037:antagonists & inhibitors; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism / Q000502:physiology*; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D020881:Enkephalin, D-Penicillamine (2,5)-; D004745:Enkephalins / Q000494:pharmacology; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D009020:Morphine / Q000037:antagonists & inhibitors; D011759:Pyrrolidines / Q000494:pharmacology; D011957:Receptors, Opioid / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects*
D000700:Analgesics; D004745:Enkephalins; D011759:Pyrrolidines; D011957:Receptors, Opioid; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D000001:Calcimycin; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D009020:Morphine; D020881:Enkephalin, D-Penicillamine (2,5)-; D015740:Calcitonin Gene-Related Peptide; D002118:Calcium