Antisenses to opioid receptors attenuate ATP-gated K(+) channel opener-induced antinociception.
The ATP-gated K(+) channel openers diazoxide, levcromakalim and morphine induce cell hyperpolarization by opening the K(+) channels and enhancing K(+) efflux. This hyperpolarization decreases intracellular Ca(2+) levels, lessening neurotransmitter release thus leading to antinociception. Previous findings implicate the release of endogenous opioids as the mediator of the antinociceptive effects of ATP-gated K(+) channel openers. Antisense oligodeoxynucleotides to the opioid receptor clones, which decrease the number of available receptors, were used to demonstrate the involvement of endogenous opioids in diazoxide- and levcromakalim-induced antinociception. Antisense to all three opioid receptors attenuated the effect of diazoxide, suggesting that diazoxide is inducing the release of endogenous opioids activating the mu(MOR-1)-, delta(DOR-1)-, and kappa(KOR-1)-opioid receptors. Antisense to the mu-opioid receptor clone and delta-opioid receptor clone attenuated levcromakalim-induced antinociception, indicating that endogenous opioids acting at the mu- and delta-opioid receptors are potential candidates for the mediation of the antinociceptive effects of levcromakalim.
Lohmann
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AB
Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Box 980613, Richmond, VA 23298-0613, USA.
Welch
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SP
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000255:Adenosine Triphosphate / Q000502:physiology*; D000698:Analgesia; D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D019806:Cromakalim / Q000494:pharmacology; D003981:Diazoxide / Q000494:pharmacology; D020881:Enkephalin, D-Penicillamine (2,5)- / Q000494:pharmacology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009020:Morphine / Q000494:pharmacology; D009619:Nociceptors / Q000187:drug effects; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology*; D010146:Pain / Q000503:physiopathology / Q000517:prevention & control; D015221:Potassium Channels / Q000187:drug effects*; D011957:Receptors, Opioid / Q000235:genetics / Q000502:physiology*; D017465:Receptors, Opioid, delta / Q000235:genetics / Q000502:physiology; D017473:Receptors, Opioid, kappa / Q000235:genetics / Q000502:physiology; D017450:Receptors, Opioid, mu / Q000235:genetics / Q000502:physiology
D000700:Analgesics; D020319:Oligodeoxyribonucleotides, Antisense; D015221:Potassium Channels; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D019806:Cromakalim; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D009020:Morphine; D020881:Enkephalin, D-Penicillamine (2,5)-; D000255:Adenosine Triphosphate; D003981:Diazoxide