title: ATP-gated K(+) channel openers enhance opioid antinociception: indirect evidence for the release of endogenous opioid peptides.
abstract: The ATP-gated K(+) channel openers - diazoxide, levcromakalim and morphine - enhance K(+) efflux by opening ATP-gated K(+) channels, thereby inducing cell hyperpolarization. Hyperpolarization decreases intracellular Ca(2+) levels, which leads to a decrease in neurotransmitter release contributing to the antinociceptive effects of the drugs. Previous findings implicate the release of endogenous opioids as the mediator of the antinociceptive effects of ATP-gated K(+) channel openers. Diazoxide and levcromakalim, administered intracerebroventricularly (i.c.v.), produced dose-dependent antinociception as determined by the tail-flick method ¿ED(50) 44 microg/mouse [95% confidence limits (CLs) from 28 to 68 microg/mouse] for diazoxide¿. Glyburide (10 microg/mouse), an ATP-gated K(+) channel antagonist, attenuated the effects of diazoxide, levcromakalim and morphine. Diazoxide- and levcromakalim-induced antinociception were both antagonized by CTOP (D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr amide), a mu-opioid receptor selective antagonist, and ICI 174,864 (N, N-diallyl-Tyr-Aib-Aib-Phe-Leu), a delta-opioid receptor antagonist, but were differentially attenuated by the kappa-opioid receptor antagonist, nor-Binaltorphimine. Combinations of inactive doses of the K(+) channel openers and opioid receptor agonists produced significant antinociceptive enhancement. Diazoxide (2 microg/mouse) shifted morphine's dose-response curve 47-fold, while levcromakalim (0.1 microg/mouse) shifted the curve 27-fold. The dose-response curve of kappa-opioid receptor agonist U50,488H (trans-(+/-)-3, 4 Dichloro-N-[2-(1-pyrrolidinyl)-cyclohexyl] benzeneacetamide methane sulfonate) was shifted 106-fold by diazoxide in a parallel manner, while levcromakalim administration increased the potency of U50,488H by 15-fold. Diazoxide shifted the dose-response curve of the delta-opioid receptor agonist, DPDPE [(D-Pen(2,5))-enkephalin], leftward in a non-parallel manner, while DPDPE was 6-fold more potent when combined with levcromakalim. We hypothesize that endogenous opioids mediate ATP-gated K(+) channel opener-induced antinociception and enhancement of opioids.
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, P.O. Box 980613, Richmond, VA 23298-0613, USA.
authors.forename: A B
authors.initials: AB
authors.lastname: Lohmann
authors.forename: S P
authors.initials: SP
authors.lastname: Welch
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000502:physiology*; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D019806:Cromakalim / Q000494:pharmacology; D003981:Diazoxide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D020881:Enkephalin, D-Penicillamine (2,5)- / Q000494:pharmacology; D004743:Enkephalin, Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D005905:Glyburide / Q000494:pharmacology; D007276:Injections, Intraventricular; D015640:Ion Channel Gating / Q000502:physiology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009020:Morphine / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists; D009619:Nociceptors / Q000187:drug effects; D018847:Opioid Peptides / Q000187:drug effects / Q000378:metabolism; D010146:Pain / Q000517:prevention & control; D015221:Potassium Channels / Q000187:drug effects* / Q000502:physiology; D011957:Receptors, Opioid / Q000819:agonists / Q000502:physiology*; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000037:antagonists & inhibitors; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors; D013004:Somatostatin / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D000700:Analgesics; D009292:Narcotic Antagonists; D018847:Opioid Peptides; D015221:Potassium Channels; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D019806:Cromakalim; C049352:phenylalanyl-cyclo(cysteinyltyrosyl-tryptophyl-ornithyl-threonyl-penicillamine)threoninamide; C051844:norbinaltorphimine; D013004:Somatostatin; D004743:Enkephalin, Leucine; D009271:Naltrexone; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D009020:Morphine; D020881:Enkephalin, D-Penicillamine (2,5)-; C040643:N,N-diallyl-tyrosyl-alpha-aminoisobutyric acid-phenylalanyl-leucine; D000255:Adenosine Triphosphate; D003981:Diazoxide; D005905:Glyburide