Dynorphins other than dynorphin A(1-17) lack spinal antianalgesic activity but do act on dynorphin A(1-17) receptors.
In recent publications we have proposed that dynorphin (Dyn) A(1-17) functions as an antianalgesic modulator to oppose opioid-induced antinociception in mice. In the present experiments using the tail-flick response in mice, other Dyns [Dyn A(1-8), Dyn A(1-13), Dyn A(2-17), Dyn B and alpha- and beta-neoendorphin] when administered intrathecally (i.t.) were shown not to have antianalgesic activity even at high doses (0.5-1 pmol). These Dyns, i.t., did not antagonize the antinociception produced by physostigmine administered i.c.v. or morphine given i.t. These Dyns lacked the intrinsic antianalgesic activity of Dyn A(1-17). However, they had affinity for Dyn A(1-17) receptors as shown in several ways. 1) The antagonism of physostigmine antinociception produced by Dyn A(1-17) given i.t. was reversed by these Dyns given together with Dyn A(1-17). 2) The effect of endogenously released Dyn A(1-17) was reversed. Administered i.c.v., clonidine simultaneously activates antinociceptive and antianalgesic systems [latter mediated spinally by Dyn A(1-17) release]. Thus, these Dyns given i.t. inhibited the action of endogenously released Dyn A(1-17) and allowed the full manifestation of the antinociceptive action of clonidine.(ABSTRACT TRUNCATED AT 250 WORDS)
Research Service, Veterans Administration Medical Center, Milwaukee, Wisconsin.
J J
JJ
Rady
J M
JM
Fujimoto
L F
LF
Tseng
D000818:Animals; D004347:Drug Interactions; D004399:Dynorphins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009020:Morphine / Q000494:pharmacology; D009619:Nociceptors / Q000187:drug effects; D010446:Peptide Fragments / Q000494:pharmacology; D010830:Physostigmine / Q000494:pharmacology; D011957:Receptors, Opioid / Q000187:drug effects*; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism
D010446:Peptide Fragments; D011957:Receptors, Opioid; C030738:dynorphin receptor; C026843:dynorphin (1-13); D004399:Dynorphins; D009020:Morphine; D010830:Physostigmine